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The expression of liver low-density lipoprotein receptor (LDLR)regulates human plasma LDL cholesterol (LDL-c) homeostasis 1,2.Increased hepatic LDLR expression results in improved clearance of plasma LDL-c through receptor-mediated endocytosis,which has been strongly associated with a decreased risk of developing cardiovascular disease in humans 3,4.LDLR expression is predomi-nantly regulated at the transcriptional level through a negative feedback mechanism by the intracellular cholesterol pool.This reg-ulation is controlled through specific interactions of sterol-regulatory element (SRE-1) of the LDLR promoter 5,6and SRE binding proteins (SREBPs)7–9.In the inactive state,SREBP resides in the endoplasmic reticulum (ER) and associates with another transmembrane protein,SREBP-cleavage activating protein (SCAP) which provides conditional chaperone activity to the SREBP 10–12.SCAP contains a cholesterol-sensing domain,which responds to the depletion of sterol with activation of the SCAP-SREBP transporting activity 13–15.Under cholesterol-depleted conditions,SCAP transports SREBP to the Golgi appara-tus,where the N-terminal transcription activation domain of the SREBP is released from the precursor protein through specific cleavages 11.The active form of the SREBP translocates to the nucleus,binds to its cognate SRE-1 site and activates transcription of the LDLR gene.In contrast,under cholesterol-replete condi-tions,the SCAP-SREBP complex remains in an inactive form in the ER through active repression by sterols and LDLR gene transcrip-tion is maintained at a minimal constitutive level.Clinically,statins have been the most widely prescribed drugs for hypercholesterolemia 3,4.Statins inhibit HMG-CoA reductase,the rate-limiting enzyme in cholesterol biosynthesis.Inhibition of choles-terol biosynthesis leads to a depletion of intracellular cholesterol and an activation of the SCAP-SREBP transporting activity,thereby resulting in upregulation of the LDLR and subsequent lowering of the LDL-c in blood.Statins effectively lower the plasma concentration of LDL-c and reduce mortality and morbidity from coronary artery dis-ease 16,17.Recent studies showed additional benefits of statin beyond its cholesterol-lowering effects 18.But despite the success of treatment with statins,there is a need for new therapies to reduce LDL-c.Some patients do not tolerate statins well,and more importantly,many patients under statin treatment alone do not achieve the LDL-c goal suggested by the US National Institutes of Health guidelines 19.Therefore,for the treatment of hypercholesterolemia,it is desirable to develop other therapeutic interventions that increase hepatic LDLR expression by mechanisms distinct from the current statin therapy.BBR as a new upregulator of liver LDLR expressionWe have conducted a rationalized screening to search for new LDLR upregulators from natural resources.Two criteria were applied to select the screening candidates.F irst,the herb samples have had major applications in Chinese medicine and have safety records in the clinic.Second,the chemical structures of active ingredients of the herbs are already defined.Cells from a human hepatoma–derived cell line,HepG2,were treated for 24 h with different compounds isolated1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China. 2Division of Endocrinologyand Laboratory of Molecular Medicine, First Hospital of Nanjing City, Nanjing Medical University, Nanjing, 210006, China. 3Research Service, Department ofVeterans Affairs Palo Alto Health Care System, Palo Alto, CA, 94304, USA. 4Department of Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA.5These authors contributed equally to this work. Correspondence should be addressed to: J-D.J. (jiandong.jiang@) or J.ßL. (jingwen.liu@).Published online 7 November 2004; doi:10.1038/nm1135Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statinsWeijia Kong 1,5,Jing Wei 2,5,Parveen Abidi 3,5,Meihong Lin 3,Satoru Inaba 3,Cong Li 3,Y anling Wang 4,Zizheng Wang 2,Shuyi Si 1,Huaining Pan 2,Shukui Wang 2,Jingdan Wu 2,Yue Wang 4,Zhuorong Li 1,Jingwen Liu 3&Jian-Dong Jiang 1,4We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5′proximal section of the LDLR mRNA 3′untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n efrom 700 Chinese herbs.The LDLR mRNA levels were subsequently determined by semi-quantitative RT-PCR assays.Among different compounds tested,BBR,an alkaloid originally isolated from Huanglian (Coptis chinensis),showed the highest activity in increas-ing LDLR expression.The chemical structure of BBR is benzyltetrahy-droxyquinoline (molecular weight = 371.8;Fig.1a ).In China,BBR has been extensively used as a nonprescription drug to treat diarrhea caused by bacteria since the 1950s 20–23.Treating HepG2 cells cultured in medium containing 0.5% lipoprotein-depleted fetal bovine serum (LPDS) or in LPDS supplemented with sterols (10 µg/ml cholesterol + 1 µg/ml 25-hydroxycholesterol) with BBR caused time-dependent increases in the expression of LDLR mRNA as determined by north-ern blot and real-time quantitative RT-PCR (Fig.1b ).Levels of LDLR mRNA,which reached a maximal level of 2.5-fold of control at 8 h,were increased as early as 2 h after the addition to the cells of BBR at a concentration of 7.5 µg/ml and expression of LDLR mRNA remained high throughout the 24-h treatment,regardless of the cholesterol concentration in the culture medium.The effect of BBR was also dose dependent.Northern blot showed a 50% increase in LDLR mRNA in cells treated with 2.5 µg/ml of BBR and a maximal increase of four-fold of control was seen with a concentration of 15 µg/ml.Similar magnitudes of increases in LDLRmRNA levels were confirmed byace fdbFigure 1Upregulation of LDLR expression by BBR in human hepatoma cell lines. (a ) Chemical structure of BBR. (b ) Time-dependent induction of LDLR mRNA expression. HepG2 cells cultured in EMEM containing 0.5% LPDS without cholesterol (–Cho) or LPDS + sterols including cholesterol (+Cho) were incubated with BBR (7.5 µg/ml) for the indicated times. The figure shown is representative of 3 separate kinetic studies. The abundance of LDLR mRNA in untreated cells in LPDS –Cho was defined as 1, and the amounts of LDLR mRNA from BBR-treated cells with or without sterols were plotted relative to that value. (c ) Dose-dependent induction of LDLR mRNA expression in HepG2 cells. Cells were treated with BBR for 8 h at the indicated concentrations and total RNA was isolated for analysis of LDLR and GAPD mRNA expression by northern blot and real-time PCR assays. (d ) Dose-dependent induction of LDLR mRNA expression in Bel-7402 cells examined by real-time RT-PCR. (e ) BBR increased cell-surface LDLR expression. (f ) The uptake of DiI-LDL was measured by FACScan with 2 ×104cells per sample. The mean fluorescence value (MFV) of untreated cells is expressed as 100%. The data shown are representative of 3 separate assays.©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n eFigure 2BBR increases LDLR expression by stabilizing LDLR mRNA through the 5′proximal section of the LDLR mRNA 3′UTR. (a ) Analysis of the precursor (P) and mature (M) forms of SREBP2 using a monoclonal antibody to SREBP2 in HepG2 cells. (b ) HepG2 cells were treated either with lovastatin (Lov) alone at indicated concentrations or BBR alone, or with Lov plus 10 µg/ml of BBR, for 24 h and total RNAs were harvested and analyzed for LDLR and GAPD mRNA expression. (c ) pLDLR234Luc and pRL-SV40 were cotransfected into HepG2 cells cultured in LPDS (–Cho) or LPDS (+Cho) medium for 24 h. BBR (10 µg/ml),GW707 (2 µm) and oncostatin M (50 ng/ml) were added to cells for 8 h prior to cell lysis. The firefly luciferase and renilla luciferase actvities were measured.(d ) Cells were untreated or treated with BBR for 15 h. Actinomycin D (5 µg/ml) was added to cells for different intervals. Total RNA was isolated and analyzed for the amount of LDLR mRNA by northern blot. The normalized LDLR mRNA signals were plotted as the percentage of the LDLR mRNA remaining. Decay curves were plotted versus time. (e ) Schematic presentation of the LDLR mRNA 3′UTR and the chimeric Luc-LDLR 3′UTR fusion constructs and the northern blot analysis of Luc-LDLR fusion mRNA. Plasmids pLuc and pLuc/UTRs were transfected (left panel) or were treated with BBR or BBR dilution bufferdimethylsulfoxide as control (right panel). The expression levels of Luc mRNA were determined by northern blot. (f ) ARE and UCAU motifs are involved in BBR-induced LDLR mRNA stabilization. The responses of the wt pLuc/UTR-2 and deletion constructs to BBR treatment were examined by transient transfection followed by quantitative real-time RT-PCR analysis of Luc mRNA expression levels in transfected cells untreated or treated with BBR. The amount of Luc mRNA in untreated cells was defined as 1, and the amount of Luc mRNA in BBR-treated cells was plotted relative to that value.quantitative real-time RT-PCR (Fig.1c ).The effect of BBR on LDLR was further confirmed in another human hepatoma cell line,Bel-7402.BBR at 2.5 µg/ml increased the LDLR mRNA in these cells by 2.3-fold (Fig.1d ).Accordingly,BBR increased LDLR protein on the cell surface,as determined by staining for antibodies to LDLR (Fig.1e ).The increase in LDLR mRNA expression directly translated into enhanced LDLR function.Uptake of 3,3′-dioctadecylindocarbo-cyanin-iodide (DiI)-LDL in hepatoma cells was increased in a dose-dependent manner in cells cultured with and without sterols (Fig.1f ).BBR increases LDLR mRNA stabilityThe ability of BBR to increase LDLR mRNA expression independent of intracellular cholesterol levels suggests that SREBPs,the key transcrip-tion factors for the cholesterol-mediated feedback regulation,were not involved in the actions of BBR.T o confirm this,we examined the matu-ration of endogenous SREBP-2 in HepG2 cells cultured with BBR,usingthe compound GW707 as a positive control.Previous studies have shown that GW707 can stimulate SREBP processing from the inactive precursor form (125 kDa) to the activated mature form (68 kDa),result-ing in an increased LDLR transcription 24.We harvested total cell lysates from untreated cells or cells treated with either BBR or GW707 for 8 h.Western blot showed that GW707 substantially increased the mature form of SREBP-2,whereas BBR had no effect (Fig.2a ).The lack of a sterol-regulatory effect through the SREBP pathway suggests that BBR increases LDLR expression by a mechanism distinct from statins.We were interested in determining the functionality of BBR in the presence of statins that inhibit HMG-CoA reductase.HepG2 cells cultured in LPDS medium were untreated,treated with lovastatin at 0.5 and 1 µM concentrations with or without BBR for 24 h,or treated with BBR alone.The results clearly showed that BBR and lovastatin had additive stimulating effects on LDLR mRNA expres-sion;BBR activity was not diminished at all by lovastatin (Fig.2b ).a ce fd b©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n eT o elucidate the mechanism by which BBR increases LDLR expres-sion,we analyzed LDLR promoter activity by transfection of HepG2cells with the reporter construct pLDLR234Luc,which contains the SRE-1 motif and the sterol-independent regulatory element that medi-ates the cytokine oncostatin M–induced transcription of the LDLRgene 25,26.After transfection,cells were cultured in LPDS or LPDS +cholesterol medium followed by an 8-h treatment with BBR,GW707 or oncostatin M.LDLR promoter activity was strongly elevated by GW707and oncostatin M under both culturing conditions (Fig.2c ),consistent with previous studies 24,27.Notably,BBR had no effect.These results prompted us to examine the possibility that BBR treatment may stabilize LDLR mRNA,resulting in higher expression levels.Actinomycin D was added to control and BBR-treated HepG2cells for the indicated period,and the half-lives of LDLR mRNA were determined by northern ing the observed decay values,we showed that BBR prolonged the turnover rate of LDLR transcript by approximately threefold (198 versus 64 min;Fig.2d ).In contrast,the mRNA stability of HMG-CoA reductase was not altered by BBR.The LDLR mRNA contains a 2.5-kb long segment of 3′UTR 28.Three AU-rich elements (ARE) are located in the 5′proximal region (Fig.2e )and these AREs have been shown to be responsible for the rapid turnover of LDLR mRNA 29,30.In the distal region of the UTR,three repeats of Alu-like sequences were reported to participate in the phor-bol 12-myristate 13-acetate–induced mRNA stabilization 30.Additionally,we have noticed that the nucleotide (nt) sequences (nt 5,085–5,175) at the extreme 3′end of the UTR are highly AU-rich and we designated this region as the AU-rich segment.T o determine whether regulatory sequences in the 3′UTR of LDLR mRNA are involved in the action of BBR on LDLR mRNA stability,we usedluciferase (Luc ) cDNA as a reporter gene.Three consecutive fragments of the LDLR 3′UTR were individually inserted into a cytomegalovirus promoter–driven Luc plasmid (pLuc) at the 3′end of the Luc coding sequence before the SV40 polyadenylation signal.We transfected the wild-type (pLuc) and the chimeric plasmids (pLuc–UTR-2,UTR-3 and UTR-4) into HepG2 cells.After 48 h,we lysed the cells and isolated total RNAs.Expression of Luc mRNA and Luc -LDLR 3′UTR chimeric fusion RNAs were examined by northern blot analysis with a 32P-labeld Luc cDNA as the probe.Inclusion of UTR-2 and UTR-3 sequences reduced expression levels of Luc mRNA by approximately 3–4-fold,indicating the presence of destabilization determinants within these regions,whereas the Luc mRNA level was only moderately reduced by fusing with UTR-4,containing the AU-rich segment sequence (Fig.2e ).BBRspecifically increased the level of Luc–UTR-2 mRNA up to 2.5-foldwithout affecting expressions of Luc–UTR-3 and Luc–UTR-4 (Fig.2e ).BBR also did not affect the expression of the wild-type Luc mRNA (data not shown).Because all Luc constructs used the same cytomegalovirus promoter,these results clearly indicate that BBR affected the mRNAstability of the heterologous Luc-LDLR transcript and the stabilization is mediated through regulatory sequences present in the 5′proximal region of the LDLR 3′UTR (nt 2,677–3,582).Without this region,sta-bilities of the chimeric transcripts were unchanged by BBR.T o narrow down the BBR-responsive region,we performed a detailed sequence analysis to search for potential regulatory motifs,which sug-gested that the BBR-responsive UTR-2 region (nt 2,677–3,582) contains three potential ARE sites and four repeats of the tetranucleotide UCAU (Fig.2f ).These UCAU repeats are clustered within sequences betweenARE1 and ARE2.It was recently reported that the UCAU repeats in the 3′UTR of Pmp1mRNA (encoding MAPK phosphotase) are required for the regulation of Pmp1mRNA stability through the binding of a K-homology-type RNA binding protein in fission yeast 31.T o assess the potential roles of the ARE and UCAU motif in BBR-mediated LDLR mRNA stabilization,we made three more constructs that either delete the ARE3 (Del-ARE3),both ARE 3 and ARE2 (Del-ARE3 + 2),or elimi-nate the UCAU motif by an internal deletion.We transfected these con-structs and the BBR-responsive wild-type construct into HepG2 cells,and then processed and treated the transfected cells (Fig.2e ).The effectsof BBR on the chimeric Luc transcripts were determined by measuring Luc mRNA using a quantitative real-time RT-PCR assay.Deletion of ARE3 region resulted in a partial loss of BBR stimulation and deletion of both ARE3 and ARE2 rendered the construct unresponsive to BBR.Notably,the stabilizing effect of BBR on the Luc chimeric transcript was also abolished by deleting the UCAU motifs (Fig.2f ).Results of real-time RT-PCR were independently confirmed by northern blot analysis.These findings suggest that both ARE and UCAU motifs are involved in the stabilization of LDLR mRNA in BBR-treated HepG2 cells.Activation of ERK is required for BBR to increase LDLRUsing different kinase inhibitors,including the inhibitor of MEK1U0126,the p38 kinase inhibitor SB203580,the c-Jun N-terminalabc Figure 3 Blocking ERK activation abolished the regulatory effect of BBR on LDLR. (a ) Relative amount of LDLR mRNA from total RNA from HepG2cells treated with 5 µg/ml of BBR for 8 h with or without 0.5 µM U0126 was measured by a quantitative real-time RT-PCR. The amount of LDLR transcript in untreated cells was defined as 1, and amounts of LDLR mRNA from BBR- or U0126-treated cells were plotted relative to that value. (b ) Total cell lysates were harvested from Bel-7402 cells or HepG2 cells that were untreated or treated with BBR at a dose of 5 µg/ml for different intervals as indicated. Total cellular proteins of 50 µg/lane were subjected to SDS-PAGE and western blotting using antibodies specific for either the activated and phosphorylated forms of ERK1/2, or total ERK 1/2. (c ) HepG2 cells were treated with BBR for 1 h at the indicatedconcentrations and total cell lysates were used to detect phosphorylated and nonphosphorylated ERK by western blotting. Data represent mean ±s.d.©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n ekinase inhibitor curcumin,the PI-3 kinase inhibitor wortmannin and the PKC inhibitor calphostin C,we found that the activity of BBR on LDLR expression was most sensitive to U0126.At 0.5 µM,U0126 abolished the activity of BBR on LDLR mRNA expression (Fig.3a ).To determine whether BBR directlyactivates the MEK1-ERK pathway,we treated cells with BBR for dif-ferent intervals and assessed levels of activated ERK in control and BBR-treated cells by western blotting using antibodies that only rec-ognize the activated (phosphorylated) ERK.In both hepatoma cell lines,BBR rapidly activated ERK and the kinetics of ERK activation preceded the upregulation of LDLR expression by BBR (Fig.3b ).The activation of ERK by BBR is also dose dependent (Fig.3c ).These data indicate that activation of ERK pathway is a prerequisite event in BBR-mediated stabilization of the LDLR transcript.BBR lowered serum LDL-c in hypercholesterolemic peopleWe enrolled 91 hypercholesterolemic people (52 males and 39females) and determined whether they could be considered hyperlipi-demic (IIa and IIb) according to the ‘Hyperlipidemia Diagnostic Criteria’recommended for the Chinese population 32.We randomly divided the study participants into BBR (n =63) and placebo treat-ment groups (n =28).Subjects in the BBR treatment group were given 0.5 g of BBR orally twice per day for 3 months.The same procedure was appliedto the placebo group.Blood samples determined fasting serum con-centrations of cholesterol,triglycerides,HDL-cholesterol (HDL-c)and LDL-c,as well as liver and kidney functions at baseline and at the end of treatment.BBR significantly lowered serum levels of cholesterol by 18% (P <0.001),triglycerides by 28% (P <0.001)and LDL-c by 20% (P <0.001) in the 63 hypercholesterolemic subjects,although serum HDL-c values remained unchanged (Supplementary T able 1online).All subjects tolerated BBR well and we observed no side effects,with the exception of one subject having mild constipation during treatment,which was relieved after reduc-ing the dose to 0.25 g twice per day.BBR did not change kidney functions,but improved liver function by reducing levels of alanine aminotransferase,aspartate aminotransaminase and gamma glu-tamyl transpeptidase.The placebo group showed no changes in these parameters.Because some participants were taking other medications that could have influenced the results,we re-evaluated the results by ana-lyzing the data only from those participants (32 of the BBR group and 11 of the placebo group) who were neither on other drugs or herbs nor on special diets before or during BBR therapy (Supplementary Table 2online).BBR significantly lowered the serum levels of choles-terol by 29% (P <0.0001),triglycerides by 35% (P <0.0001) and LDL-c by 25% (P <0.0001),although again serum HDL-c level remained unchanged (Table 1).In this study cohort,BBR showed an equal cholesterol-lowering effect in Type IIa and IIb patients;how-ever,we observed the triglycerides-lowering effect of BBR in Type IIb patients only,and not in IIa patients whose baseline values of tri-glycerides were not elevated (Supplementary Table 3online).BBR treatment also significantly improved liver function in this subgroup (Table 2).Lipid-lowering effects of BBR in hamstersTo verify that the increased hepatic LDLR expression by BBR was the primary reason for the reduced LDL-c in patients,an animal study was conducted in hamsters,in which the effects of added cholesterol and fat on the kinetics of hepatic LDLR-mediated LDL clearance have been well characterized 33–35.Before BBR treatment,animals were fedabFigure 4 BBR reduces plasma LDL-c and increases liver LDLR expression in hamsters. (a ) Serum was taken before and after a 2-week high-fat feeding, and was taken at the indicated times during and after BBR treatment at indicated daily doses. Results represent mean ±s.d. of 8–10 animals. *P <0.01 and **P <0.001as compared to untreated control; #P <0.01 and ##P <0.001 as compared to before treatment. (b ) Four hours after the last drug treatment, three animals from each group were killed and liver total RNA and protein extracts were immediately prepared and analyzed for LDLR mRNA and protein by quantitative real-time RT-PCR (upper panel) and western blot (lower panel). The western blot membrane was stripped and reprobed sequentially with antibodies that recognize phosphorylated ERK, total ERK and β-actin.Table 1Effects of BBR on serum lipids in the subgroup of hypercholesterolemic patients who were not taking other medication before or during BBR treatment.Treatment BBR aPlacebo(3 months)Hypercholesterolemia Hypercholesterolemia Serum level of cholesterol (>5.2 mmol/L, n =32)(>5.2 mmol/L, n =11)Cholesterol Before 5.9 ±0.7 6.1 ±0.6After 4.2 ±0.9* 6.0 ±0.8Triglyceride Before 2.3 ±1.8 2.2 ±0.8After 1.5 ±0.9* 2.1 ±0.9HDL-c Before 1.1 ±0.3 1.2 ±0.5After 1.1 ±0.3 1.2 ±0.4LDL-cBefore 3.2 ±0.7 3.7 ±0.7After2.4 ±0.6***3.7 ±0.8a Statistical analysis of the baselines of cholesterol, triglyceride, HDL-c and LDL-c showed that there were no significant differences between the BBR and placebo groups before therapy (P >0.05). ***P <0.0001, as compared to the baselines of ‘before treatment’ group.©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n ea high-fat and high-cholesterol (HFHC) diet for 2 weeks,which sig-nificantly increased total serum cholesterol (P <0.001) and LDL-c (P <0.001).Treatment of these hyperlipidemic animals with BBR by oral administration for 10 d resulted in dose-dependent decreases in both serum total cholesterol and LDL-c (Fig.4a ).After the 10-d treat-ment,BBR at a dose of 50 mg/kg/d reduced LDL-c by 26%,and at a dose of 100 mg/kg/d,reduced LDL-c by 42% as compared to the con-trol animals on the same HFHC diet.The BBR effect was also time dependent (Fig.4a ).Reductions in serum LDL-c were observed by day 5 and became significant by day 7 at both doses (P <0.01).At the end of treatment,three animals from each group were killed and liver LDLR mRNA and protein expressions were examined by quantitative real-time RT-PCR and western blot.LDLR mRNA and protein levels were elevated in all BBR-treated hamsters in a dose-dependent man-ner.We detected a 3.5-fold increase in mRNA and a 2.6-fold increase in protein in hamster livers treated with 100 mg/kg/d of BBR (Fig.4b ).Notably,increased expressions of LDLR were concurrent with the activations of ERK from BBR-treated hamsters.These results provide a direct link of the cholesterol-lowering effect of BBR with its activity on upregulation of hepatic LDLR and confirm the participa-tion of the ERK pathway in these processes in vivo .DISCUSSIONIncreasing hepatic LDLR expression by inhibition of cellular choles-terol biosynthesis through the SRE-1–SREBP pathway is the primary mechanism of statin therapy for hypercholesterolemia.Here,we identify a new cholesterol-lowering drug,BBR,that effectively lowers serum cholesterol,triglycerides and LDL-c to levels comparable to those of statins,but works through a different mechanism.Using human hepatoma–derived cell lines,we show that BBR increases mRNA and protein as well as the function of hepatic LDLR.This activity is independent of intracellular cholesterol levels and has no effects on the activation process of SREBP or the activity of HMG-CoA reductase (data not shown).BBR does not stimulate the tran-scription of LDLR ,as the LDLR promoter activity is not increased by this compound.The post-transcriptional regulation appears to be the main working mechanism underlying the effect of this drug on liver LDLR expression.In BBR-treated cells,the mRNA half-life of LDLR was considerably extended.We sought to understand how BBR affects the stability of the LDLR transcript by examining the LDLR mRNA 3′ing Luc mRNA as the reporter,we show that the 5′proximal ARE-containing region,covering nt 2,677–3,582,responds to BBR with an increased stability of the fusion transcript.Within this region,deletion of ARE3 resulted in a partial loss of BBR-mediated stabiliza-tion and deletion of both ARE2 and ARE3 rendered the construct unresponsive to BBR stimulation.These data support the functional role of AREs in BBR-regulated LDLR mRNA stabilization.It is possi-ble that an mRNA-binding protein may interact with AREs after BBR stimulation to protect these labile sequences from endonuclease-induced degradation,resulting in mRNA stabilization.In addition to AREs,we found that deletion of UCAU repeats located within the sequences between ARE1 and ARE2 also abolished BBR stimulation of the reporter construct.Notably,the UCAU motif has been recently linked to the MAP kinase pathway 31.Because ERK activation is required for BBR to stabilize the LDLR mRNA,interactions of mRNA binding proteins with these motifs may be a direct downstream event of the ERK signaling cascade.Interestingly,a recent study on bile acid–mediated LDLR mRNA expression also reported that ERK acti-vation was required for the stabilizing effect of bile acid on LDLR mRNA 36.These results warrant further investigations to firmly define the precise roles of ARE and UCAU motifs in BBR-elicited LDLR mRNA stabilization.The upregulatory effects of BBR on LDLR expression seen in human hepatoma cells and in hamsters are likely to be accountable for its LDL-c–lowering effects in people with hypercholesterolemia.A 29%reduction of serum cholesterol,35% reduction of triglyceride and 25% reduction of LDL-c were achieved in hypercholesterolemic par-ticipants after a 3-month pared to statin therapies that have shown to maximally lower LDL-c to 60%16–18,the effects of BBR seem moderate.The regimen used in this study is a pioneer trial for hypercholesterolemia with a modest dose;larger cholesterol-lowering effects of BBR may be achieved by improvement of the treatment pro-tocol.This notion is supported by our studies in hamsters.The dose-dependent effects of BBR on liver LDLR expression and plasma LDL-c reduction were observed in hyperlipidemic hamsters.BBR was well tolerated by all participants,consistent with other reports 20,21.Based on the clinical outcomes,we assumed that reduced fat stor-age in liver might be responsible for the improved liver function observed in BBR-treated patients.This speculation is supported by our results showing that heavy hepatic fat staining in control animals fed a HFHC diet were greatly reduced by BBR treatment (data not shown).In addition,we believe that the systemic effect of BBR,but not an inhibition in the adsorption of lipid in gut,plays a major role in reducing serum lipids,because in the hamster experiments we found that intraperitoneal administration of BBR at 20 mg/kg had better lipid-lowering effect than oral administration at 100 mg/kg,and oral administration of BBR did not increase fecal lipids of the hamsters (data not shown).These findings strongly suggest that BBR is a promising new hypolipidemic drug that acts through pathways distinct from those ofTable 2 Effect of BBR on liver and kidney functions of the subgroup of hypercholesterolemic patients who were not taking other medication before or during BBR treatment.nALT(U/L)AST(U/L)GGT (U/L)Bil-T(µM/L)Cr (µM/L)BUN (mM/L)BBR group:Before treatment 3244.9 ±21.839.3 ±22.253.7 ±24.417.4 ±8.875.5 ±14.6 5.76 ±1.2After treatment 3223.6 ±11.1**26.6 ±8.2*31.7 ±15.2**13.8 ±6.3**72.6 ±18.75.79 ±1.2Placebo group:Before treatment1145.7 ±1739.6 ±19.252.2 ±21.417.0 ±6.072.6 ±17.1 5.60 ±1.4After treatment 1144.8 ±10.238.8 ±8.352.0 ±14.817.3 ±5.373.1 ±19 5.66 ±1.3Normal range a0–40.00–40.010.0–50.03.4–26.639.8–134.42.1–7.9a “National Clinical Laboratory Manual” issued by The Ministry of Health of the People’s Republic of China, with minor modifications. *P <0.01; **P <0.001, as compared to those ‘beforetreatment.’ ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; GGT, gamma glutamyl transpeptidase; Bil-T, total bilirubin; Cr, creatinine; BUN, blood urea nitrogen.©2004 N a t u r e P u b l i s h i n g G r o u p h t t p ://w w w .n a t u r e .c o m /n a t u r e m e d i c i n e。

西安交通大学2015理学与工学门类“最有学术影响力的国际期刊”目录发布

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Conjugation vs hyperconjugation in molecular structure of acroleinSvitlana V.Shishkina a ,⇑,Anzhelika I.Slabko b ,Oleg V.Shishkin a ,caDivision of Functional Materials Chemistry,SSI ‘Institute for Single Crystals’,National Academy of Science of Ukraine,60Lenina Ave.,Kharkiv 61001,Ukraine bDepartment of Technology of Plastic Masses,National Technical University ‘Kharkiv Polythechnic Institute’,21Frunze Str.,Kharkiv 61002,Ukraine cDepartment of Inorganic Chemistry,V.N.Karazin Kharkiv National University,4Svobody Sq.,Kharkiv 61077,Ukrainea r t i c l e i n f o Article history:Received 4August 2012In ﬁnal form 16November 2012Available online 29November 2012a b s t r a c tAnalysis of geometric parameters of butadiene and acrolein reveals the contradiction between the Csp 2–Csp 2bond length in acrolein and classical concept of conjugation degree in the polarized molecules.In this Letter the reasons of this contradiction have been investigated.It is concluded that the Csp 2–Csp 2bond length in acrolein is determined by inﬂuence of the bonding for it p –p conjugation and antibonding n ?r ⁄hyperconjugation between the oxygen lone pair and the antibonding orbital of the single bond.It was shown also this bond length depends on the difference in energy of conjugative and hyperconjuga-tive interactions.Ó2012Elsevier B.V.All rights reserved.1.IntroductionButadiene and acrolein belong to the most fundamental mole-cules in the organic chemistry.They are canonical objects for the investigation of phenomena of p –p conjugation between double bonds and polarization of p -system by heteroatom [1].According to many experimental [2–16]as well as theoretical studies [13,17–23]the molecular structure of butadiene is determined by conjugation between p -orbitals of two double bonds and may be described as superposition of two resonance structures (Scheme 1).The presence of zwitterionic structure causes the shortening of the central single Csp 2–Csp 2bond as compare with similar unconjugated bond [24].Acrolein differs from butadiene by presence of the oxygen atom instead terminal methylene group.According to classical concepts of organic chemistry such replacement should causes polarization of p -system due to presence of highly polar C @O bond [25].This leads to signiﬁcant increase of the contribution of the zwitterionic resonance structure (Scheme 1)reﬂecting strengthening of conju-gation between p -systems of double bonds.Therefore the central Csp 2–Csp 2bond must be shorter in acrolein as compared with one in butadiene.However numerous investigations of acrolein by experimental [26–28]and theoretical methods [26,27,29–36]demonstrate an opposite situation:the Csp 2–Csp 2bond length varies within the range 1.469Ä1.481Åin acrolein as compared with 1.454Ä1.467in butadiene.Based on these data one can conclude that conjugation between double bonds in acrolein is weaker than in butadiene.At that time the rotation barrier obtained from quan-tum-chemical calculations is higher in acrolein [26,27],conﬁrming stronger conjugation between double bonds.Thus,results of experimental and theoretical investigations demonstrate the con-tradiction between the strengthening of the conjugation in acrolein as compare with butadiene and the values of the Csp 2–Csp 2bond length in these molecules.Recently such illogical situation was observed also in derivatives of cyclohexene containing conjugated endocyclic and exocyclic double bonds [37].It was assumed that elongation of the Csp 2–Csp 2bond in cycloxen-2-enone as compare with one in 3-methylene-cyclohexene is caused by the inﬂuence of n ?r ⁄hyperconjugation.In this Letter we demonstrate the results of the investigation of intramolecular interactions in butadiene and acrolein which ex-plain the experimentally observed contradiction between the length of the Csp 2–Csp 2bond and degree of conjugation in acrolein.2.Method of calculationsThe structures of all investigated molecules were optimized using second-order Møller-Plesset perturbation theory [38].The standard aug-cc-pvtz basis set [39]was applied.The character of stationary points on the potential energy surface was veriﬁed by calculations of vibrational frequencies within the harmonic approximation using analytical second derivatives at the same level of theory.All stationary points possess zero (minima)or one (saddle points)imaginary frequencies.The veriﬁcation of the calculation method was performed using optimization of butadi-ene and acrolein by MP2/aug-cc-pvqz,CCSD(T)/cc-pvtz and CCSD(T)/6-311G(d,p)methods [40].The geometry of saddle points for the rotation process was lo-cated using standard optimization technique [41].The barrier of the rotation in all molecules was calculated as the difference be-tween the Gibbs free energies at 298K of the most stable s-trans0009-2614/$-see front matter Ó2012Elsevier B.V.All rights reserved./10.1016/j.cplett.2012.11.032Corresponding author.Fax:+3805723409339.E-mail address:sveta@ (S.V.Shishkina).conformer and saddle-point conformation.All calculations were performed using the G AUSSIAN 03program [42].The intramolecular interactions were investigated within the Natural Bonding Orbitals theory [43]with N BO 5.0program [44].Calculations were performed using B3LYP/aug-cc-pvtz wave func-tion obtained from single point calculations by G AUSSIAN 03program.The conjugation and hyperconjugation interactions are referred to as ‘delocalization’corrections to the zeroth-order natural Lewis structure.For each donor N BO (i )and acceptor N BO (j ),the stabiliza-tion energy E (2)associated with delocalization (‘2e-stabilization’)i ?j is estimated asE ð2Þ¼D E ij ¼q iF ði ;j Þ22j À2i;where q i is the donor orbital occupancy,e j and e i are the diagonal elements (orbital energies),and F (i,j )is the off-diagonal N BO Fock matrix element.3.Results and discussionThe equilibrium geometry of s-trans and s-cis conformers of butadiene and acrolein calculated by MP/aug-cc-pvtz method (Ta-ble 2)agrees very well with obtained earlier results [2–23,25–34]and data of higher and more computationally expensive methods (Table 1).It can be noted that the C–C bond length in acrolein(Tables 1and 2)is longer as compared with butadiene in all sta-tionary points on the potential energy surface.Such relation does not agree with the conception of the resonance theory [45–47].Analysis of intramolecular interactions in both molecules using N BO theory indicates that acrolein differs from butadiene by pres-ence of intramolecular interaction between lone pair of the oxygen atom and antibonding orbital of the C–C bond (Figure 1)as well as the polarization of one double bond containing more electronega-tive ually the interactions between lone pair and antibonding orbital of single bond are stronger than the interac-tions between the C–H bond and antibonding orbital [48]and they can inﬂuence geometrical characteristics.Such type of interactions is named by anomeric effect and it is studied very well for the case when the central bond between interacted orbitals is single [48,49].It is investigated in details [49]an inﬂuence of classical anomeric effect on conformation of the substituents about central single bond as well as on values of bond lengths.In the case of hyperconjugation interactions along double bond in acrolein orien-tation of substituents around it is determined by its double charac-ter.Therefore,n ?r ⁄hyperconjugative interaction can inﬂuence on the bond lengths of interacted ones only.It can assume the dou-ble character of the central bond must also promote some strengthening of this inﬂuence due to shorter distance between the lone pair of the oxygen atom and antibonding orbital of the C–C bond.Results of N BO analysis of intramolecular interactions in butadi-ene and acrolein demonstrate that the energy of n ?r ⁄interaction between lone pair of the oxygen atom and antibonding orbital of the C–C bond in acrolein is twice as high of the energy of r ?r ⁄interaction between the C–H bond and antibonding orbital of the C–C bond in butadiene (Table 2).At that time the energy of n ?r ⁄interaction is close enough to the energy of p –pTable 2The equilibrium geometries (bond lengths,Åand C @C–C @X (X =CH 2,O)torsion angle,deg.),transition state of the rotation process,bond length alternation (BLA)parameter,related energy (D E rel ,kcal/mol),related stability (D G 298,kcal/mol)and energy of strongest intramolecular interactions (E (2),kcal/mol)for butadiene and acrolein optimized by MP2/aug-cc-pvtz method.The wave function calculated by b3lyp/aug-cc-pvtz method was used for N BO analysis.ConformerBond lengths (Å)C @C–C @X torsion angle deg.BLA (Å)D E rel(kcal/mol)D G 298(kcal/mol)E (2)(kcal/mol)C @CC–C C @X p –pn ?r ⁄(C–C)r ?r ⁄(C–C)Butadiene s-trans 1.341 1.453 1.340180.0+0.1120030.74–8.67gauche 1.340 1.465 1.34036.8+0.125 2.83 2.8921.04–8.94TS 1.3361.4801.336101.8+0.1446.446.102.32–10.66Acrolein s-trans 1.339 1.469 1.219180.0+0.1300027.7518.06–s-cis 1.338 1.481 1.2190.0+0.143 2.26 2.2224.6319.05–TS1.334 1.492 1.21692.5+0.1588.017.46–18.78–Acrolein +BH 3s-trans 1.341 1.449 1.235180.0+0.1080033.12 2.4511.43s-cis 1.340 1.460 1.2340.0+0.120 2.45 2.3829.61 2.6011.43TS1.334 1.476 1.23193.7+0.1429.258.61–2.3911.55Table 1The Csp 2–Csp 2bond length in butadiene and acrolein optimized by different quantum-chemical methods.Method of calculationCsp 2–Csp 2bond length (Å)D (Csp 2–Csp 2)(Å)ButadieneAcrolein MP2/aug-cc-pvtz 1.453 1.4690.016MP2/aug-cc-pvqz 1.451 1.4670.016CCSD(T)/cc-pvtz1.461 1.4780.017CCSD(T)/6–311G(d,p)1.4681.4870.019S.V.Shishkina et al./Chemical Physics Letters 556(2013)18–2219conjugation between two double bonds.Therefore it can assume that the inﬂuence of p–p conjugation and n?r⁄hyperconjuga-tion on the C–C bond length should be comparable.However two strongest intramolecular interactions in the acrolein differ from each other:p–p conjugation between double bonds causes the shortening of the C–C bond in contrary to n?r⁄hyperconjugation which leads to the elongation of the C–C bond owing to the popu-lation of its antibonding orbital.Taking into account this situation it is possible to conclude that length of the Csp2–Csp2single bond in acrolein is determined by balance of two opposite factors namely p–p conjugation and n?r⁄hyperconjugation which may be considered as bonding and antibonding interactions for this bond(Figure1).In this case the length of the Csp2–Csp2bond in acrolein depends on the con-tribution of each of these factors.The changing of the delocaliza-tion of the structures due to inﬂuence of intramolecular interactions can be analyzed easier by mean of the bond length alternation(BLA)parameter(Table2).The analysis of BLA shows the presence of n?r⁄hyperconjugative interaction in acrolein what results in the increasing of alternation of double bonds as compare with butadiene.Clear estimation of inﬂuence of both interactions on geometri-cal parameters of molecule may be performed by comparison of properties of single C–C bond and BLA parameter in equilibrium s-trans conformation and in situations where one or both intramo-lecular interactions are absent.It is well known that p–p conjugation between double bonds decreases appreciably up to disappearing(in acrolein)in the tran-sition state for the rotation around single bond process(Figure2). The data of N BO analysis for butadiene and acrolein in the transition state conﬁrm this evidence(Table2).As expected the absence of p–p conjugation results in the elongation of the Csp2–Csp2bond and increasing of BLA as compare with equilibrium geometry.At that time single C–C bond remains longer in the transition state for acrolein as compare with one for butadiene’s transition state.1.4921.4691.4491.476π−π is present n σ* is presentπ−π is absentn σ* is absent without π−πwithout n σ∗Figure2.Inﬂuence of p–p⁄conjugation and n?r⁄hyperconjugation on the C–Cbond length in acrolein.Table3The energy(E(2),kcal/mol)of the conjugative(bonding)and hyperconjugative(antibonding)intramolecular interactions inﬂuencing the Csp2–Csp2bond length in butadiene, acrolein and its complex with BH3.Molecule Bonding interactions E(2)(kcal/mol)Antibonding interactions E(2)(kcal/mol)Butadienes-trans BD(2)C1-C2–BD(2)C3-C430.74BD(1)C1-H5–BD(1)C2-C38.67 BD(1)C2-H7–BD(1)C3-H87.68BD(1)C4-H9–BD(1)C2-C38.67 gauche BD(2)C1-C2–BD(2)C3-C421.04BD(1)C1-H5–BD(1)C2-C38.94 BD(1)C2-H7–BD(1)C3-C4 5.36BD(1)C4-H9–BD(1)C2-C39.01BD(1)C3-H8–BD(1)C1-C2 5.36TS BD(1)C1-C2–BD(1)C3-C4 3.5BD(1)C1-H5–BD(1)C2-C310.66 BD(1)C1-C2–BD(2)C3-C4 3.46BD(1)C4-H9–BD(1)C2-C310.66BD(1)C3-C4–BD(2)C1-C2 3.46BD(2)C1-C2–BD(2)C3-C4 2.32BD(1)C3-H8–BD(2)C1-C29.57BD(1)C2-H7–BD(2)C3-C49.57Acroleins-trans BD(1)C1-C2–BD(1)C3-O4 2.73BD(1)C1-H5–BD(1)C2-C38.25 BD(2)C1-C2–BD(2)C3-O427.75LP(2)O4–BD(1)C2-C318.06BD(1)C2-H7–BD(1)C3-H8 5.95s-cis BD(2)C1-C2–BD(2)C3-O424.63BD(1)C1-H5–BD(1)C2-C38.76 BD(1)C2-H7–BD(1)C3-O4 4.05LP(2)O4–BD(1)C2-C319.05BD(1)C3-H8–BD(1)C1-C2 5.01TS BD(1)C1-C2–BD(2)C3-O4 2.98BD(1)C1-H5–BD(1)C2-C39.07 BD(1)C3-O4–BD(2)C1-C2 4.48LP(2)O4–BD(1)C2-C318.78BD(1)C3-H8–BD(2)C1-C2 5.85BD(1)C2-H7–BD(2)C3-O4 6.16Acrolein+BH3s-trans BD(1)C1-C2–BD(1)C3-O4 3.07BD(1)C1-H6–BD(1)C2-C38.09 BD(2)C1-C2–BD(2)C3-O433.12BD(1)C2-C3–BD(1)O4-B511.43BD(1)C2-H8–BD(1)C3-H9 5.97LP(1)O4–BD(1)C2-C3 2.45 s-cis BD(1)C1-C2–BD(1)C3-H9 4.98BD(1)C1-H6–BD(1)C2-C38.51 BD(2)C1-C2–BD(2)C3-O429.61BD(1)C2-C3–BD(1)O4-B511.43BD(1)C2-H8–BD(1)C3-O4 4.41LP(1)O4–BD(1)C2-C3 2.60 TS BD(1)C1-C2–BD(1)C3-O40.55BD(1)C1-H6–BD(1)C2-C39.05 BD(1)C1-C2–BD(2)C3-O4 3.01BD(1)C2-C3–BD(1)O4-B511.55BD(2)C1-C2–BD(1)C3-O4 4.90LP(1)O4–BD(1)C2-C3 2.39BD(1)C3-H9–BD(2)C1-C2 6.13BD(1)C2-H8–BD(2)C3-O4 6.8820S.V.Shishkina et al./Chemical Physics Letters556(2013)18–22It is additional argument about the inﬂuence of n?r⁄hypercon-jugation on the C–C bond length through the C@O double bond.In contrary to p–p conjugation n?r⁄hyperconjugation is present in all stationary points on the potential energy surface for acrolein(Table2).But this interaction can be shielded by for-mation of dative bond involving lone pair of the oxygen atom and unoccupied orbital of Lewis acid,for example,BH3.The formed O–B bond has r-character and the energy of its interaction with antibonding orbital of the central C–C bond is very close to the en-ergy of similar C–H?r⁄(C–C)interaction in butadiene(Table2). The absence of n?r⁄hyperconjugation results signiﬁcant short-ening of the Csp2–Csp2bond and decreasing of BLA in all stationary points for acrolein.It is more interesting that the C–C bond in acro-lein becomes shorter and p–p conjugation becomes stronger as compare with ones in butadiene in the case of absence of n?r⁄hyperconjugative interaction(Table2)what agrees well with the resonance theory.This evidence is conﬁrmed also by values of BLA parameter.It is very interesting the situation when both strong intramolec-ular interactions are absent namely acrolein with shielded by BH3 lone pair in the transition state for the rotation process.In absence of p–p conjugative and n?r⁄hyperconjugative interactions the C–C bond length is almost equal to mean value for length of this bond for s-trans and s-cis conformers of acrolein with both interac-tions(Table2).This fact conﬁrms that the C–C bond length in acro-lein in the equilibrium state is determined by balance of p–p conjugation and n?r⁄hyperconjugation.Taking into account the opposite inﬂuence of two types of intra-molecular interactions on the C–C bond one may assume that its length depends on the difference in energy of bonding and antibonding interactions for this bond.In such case all bonding for C–C bond and antibonding for it interactions(Table3)must be taken into account.Specially,this is important for transition states where p–p conjugative interaction is minimal and r(c-H)–p interaction appears instead it.This interaction has bond-ing for Csp2–Csp2bond character and it is weaker as compare with p–p interaction.Analysis of relation between C–C bond length and total energy of intramolecular interaction inﬂuencing on it demon-strates good correlation between them(Figure3)with correlation coefﬁcient aboutÀ0.93.The barrier of the rotation around ordinary C–C bond is also sensitive to intramolecular interactions.The absence of n?r⁄hyperconjugation in acrolein results the increase of conjugation in molecule what leads to the increase of the rotation barrier (Table2).4.ConclusionsResults of quantum-chemical calculations demonstrate the structure of acrolein does not correspond to conventional views about inﬂuence of the polarization of p-system by the oxygen atom.According to classic viewpoint this effect should lead to in-crease of conjugation between double bonds and shortening of central single C–C bond as compared to butadiene.However,anal-ysis of intramolecular interactions shows that the geometry of acrolein is determined by counteraction of p–p conjugation and n?r⁄hyperconjugation.The energies of these interactions are very close but ones inﬂuence on the C–C bond lengths in opposite directions.Conjugation promotes the shortening of the central sin-gle bond due to the overlapping of the p-orbitals of two double bonds.In the contrary the n?r⁄hyperconjugation causes the elongation of the C–C bond due to the population of its antibonding orbital.The absence of conjugation in the 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C.parvum全基因组序列

DOI: 10.1126/science.1094786, 441 (2004);304Science et al.Mitchell S. Abrahamsen,Cryptosporidium parvum Complete Genome Sequence of the Apicomplexan, (this information is current as of October 7, 2009 ):The following resources related to this article are available online at/cgi/content/full/304/5669/441version of this article at:including high-resolution figures, can be found in the online Updated information and services,/cgi/content/full/1094786/DC1 can be found at:Supporting Online Material/cgi/content/full/304/5669/441#otherarticles , 9 of which can be accessed for free: cites 25 articles This article 239 article(s) on the ISI Web of Science. cited by This article has been /cgi/content/full/304/5669/441#otherarticles 53 articles hosted by HighWire Press; see: cited by This article has been/cgi/collection/genetics Genetics: subject collections This article appears in the following/about/permissions.dtl in whole or in part can be found at: this article permission to reproduce of this article or about obtaining reprints Information about obtaining registered trademark of AAAS.is a Science 2004 by the American Association for the Advancement of Science; all rights reserved. The title Copyright American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the Science o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m3.R.Jackendoff,Foundations of Language:Brain,Gram-mar,Evolution(Oxford Univ.Press,Oxford,2003).4.Although for Frege(1),reference was established rela-tive to objects in the world,here we follow Jackendoff’s suggestion(3)that this is done relative to objects and the state of affairs as mentally represented.5.S.Zola-Morgan,L.R.Squire,in The Development andNeural Bases of Higher Cognitive Functions(New York Academy of Sciences,New York,1990),pp.434–456.6.N.Chomsky,Reﬂections on Language(Pantheon,New York,1975).7.J.Katz,Semantic Theory(Harper&Row,New York,1972).8.D.Sperber,D.Wilson,Relevance(Harvard Univ.Press,Cambridge,MA,1986).9.K.I.Forster,in Sentence Processing,W.E.Cooper,C.T.Walker,Eds.(Erlbaum,Hillsdale,NJ,1989),pp.27–85.10.H.H.Clark,Using Language(Cambridge Univ.Press,Cambridge,1996).11.Often word meanings can only be fully determined byinvokingworld knowledg e.For instance,the meaningof “ﬂat”in a“ﬂat road”implies the absence of holes.However,in the expression“aﬂat tire,”it indicates the presence of a hole.The meaningof“ﬁnish”in the phrase “Billﬁnished the book”implies that Bill completed readingthe book.However,the phrase“the g oatﬁn-ished the book”can only be interpreted as the goat eatingor destroyingthe book.The examples illustrate that word meaningis often underdetermined and nec-essarily intertwined with general world knowledge.In such cases,it is hard to see how the integration of lexical meaning and general world knowledge could be strictly separated(3,31).12.W.Marslen-Wilson,C.M.Brown,L.K.Tyler,Lang.Cognit.Process.3,1(1988).13.ERPs for30subjects were averaged time-locked to theonset of the critical words,with40items per condition.Sentences were presented word by word on the centerof a computer screen,with a stimulus onset asynchronyof600ms.While subjects were readingthe sentences,their EEG was recorded and ampliﬁed with a high-cut-off frequency of70Hz,a time constant of8s,and asamplingfrequency of200Hz.14.Materials and methods are available as supportingmaterial on Science Online.15.M.Kutas,S.A.Hillyard,Science207,203(1980).16.C.Brown,P.Hagoort,J.Cognit.Neurosci.5,34(1993).17.C.M.Brown,P.Hagoort,in Architectures and Mech-anisms for Language Processing,M.W.Crocker,M.Pickering,C.Clifton Jr.,Eds.(Cambridge Univ.Press,Cambridge,1999),pp.213–237.18.F.Varela et al.,Nature Rev.Neurosci.2,229(2001).19.We obtained TFRs of the single-trial EEG data by con-volvingcomplex Morlet wavelets with the EEG data andcomputingthe squared norm for the result of theconvolution.We used wavelets with a7-cycle width,with frequencies ranging from1to70Hz,in1-Hz steps.Power values thus obtained were expressed as a per-centage change relative to the power in a baselineinterval,which was taken from150to0ms before theonset of the critical word.This was done in order tonormalize for individual differences in EEG power anddifferences in baseline power between different fre-quency bands.Two relevant time-frequency compo-nents were identiﬁed:(i)a theta component,rangingfrom4to7Hz and from300to800ms after wordonset,and(ii)a gamma component,ranging from35to45Hz and from400to600ms after word onset.20.C.Tallon-Baudry,O.Bertrand,Trends Cognit.Sci.3,151(1999).tner et al.,Nature397,434(1999).22.M.Bastiaansen,P.Hagoort,Cortex39(2003).23.O.Jensen,C.D.Tesche,Eur.J.Neurosci.15,1395(2002).24.Whole brain T2*-weighted echo planar imaging bloodoxygen level–dependent(EPI-BOLD)fMRI data wereacquired with a Siemens Sonata1.5-T magnetic reso-nance scanner with interleaved slice ordering,a volumerepetition time of2.48s,an echo time of40ms,a90°ﬂip angle,31horizontal slices,a64ϫ64slice matrix,and isotropic voxel size of3.5ϫ3.5ϫ3.5mm.For thestructural magnetic resonance image,we used a high-resolution(isotropic voxels of1mm3)T1-weightedmagnetization-prepared rapid gradient-echo pulse se-quence.The fMRI data were preprocessed and analyzedby statistical parametric mappingwith SPM99software(http://www.ﬁ/spm99).25.S.E.Petersen et al.,Nature331,585(1988).26.B.T.Gold,R.L.Buckner,Neuron35,803(2002).27.E.Halgren et al.,J.Psychophysiol.88,1(1994).28.E.Halgren et al.,Neuroimage17,1101(2002).29.M.K.Tanenhaus et al.,Science268,1632(1995).30.J.J.A.van Berkum et al.,J.Cognit.Neurosci.11,657(1999).31.P.A.M.Seuren,Discourse Semantics(Basil Blackwell,Oxford,1985).32.We thank P.Indefrey,P.Fries,P.A.M.Seuren,and M.van Turennout for helpful discussions.Supported bythe Netherlands Organization for Scientiﬁc Research,grant no.400-56-384(P.H.).Supporting Online Material/cgi/content/full/1095455/DC1Materials and MethodsFig.S1References and Notes8January2004;accepted9March2004Published online18March2004;10.1126/science.1095455Include this information when citingthis paper.Complete Genome Sequence ofthe Apicomplexan,Cryptosporidium parvumMitchell S.Abrahamsen,1,2*†Thomas J.Templeton,3†Shinichiro Enomoto,1Juan E.Abrahante,1Guan Zhu,4 Cheryl ncto,1Mingqi Deng,1Chang Liu,1‡Giovanni Widmer,5Saul Tzipori,5GregoryA.Buck,6Ping Xu,6 Alan T.Bankier,7Paul H.Dear,7Bernard A.Konfortov,7 Helen F.Spriggs,7Lakshminarayan Iyer,8Vivek Anantharaman,8L.Aravind,8Vivek Kapur2,9The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals,and causes an unrelenting infection in immuno-compromised individuals such as AIDS patients.We report the complete ge-nome sequence of C.parvum,type II isolate.Genome analysis identiﬁes ex-tremely streamlined metabolic pathways and a reliance on the host for nu-trients.In contrast to Plasmodium and Toxoplasma,the parasite lacks an api-coplast and its genome,and possesses a degenerate mitochondrion that has lost its genome.Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected.Elu-cidation of the core metabolism,including enzymes with high similarities to bacterial and plant counterparts,opens new avenues for drug development.Cryptosporidium parvum is a globally impor-tant intracellular pathogen of humans and animals.The duration of infection and patho-genesis of cryptosporidiosis depends on host immune status,ranging from a severe but self-limiting diarrhea in immunocompetent individuals to a life-threatening,prolonged infection in immunocompromised patients.Asubstantial degree of morbidity and mortalityis associated with infections in AIDS pa-tients.Despite intensive efforts over the past20years,there is currently no effective ther-apy for treating or preventing C.parvuminfection in humans.Cryptosporidium belongs to the phylumApicomplexa,whose members share a com-mon apical secretory apparatus mediating lo-comotion and tissue or cellular invasion.Many apicomplexans are of medical or vet-erinary importance,including Plasmodium,Babesia,Toxoplasma,Neosprora,Sarcocys-tis,Cyclospora,and Eimeria.The life cycle ofC.parvum is similar to that of other cyst-forming apicomplexans(e.g.,Eimeria and Tox-oplasma),resulting in the formation of oocysts1Department of Veterinary and Biomedical Science,College of Veterinary Medicine,2Biomedical Genom-ics Center,University of Minnesota,St.Paul,MN55108,USA.3Department of Microbiology and Immu-nology,Weill Medical College and Program in Immu-nology,Weill Graduate School of Medical Sciences ofCornell University,New York,NY10021,USA.4De-partment of Veterinary Pathobiology,College of Vet-erinary Medicine,Texas A&M University,College Sta-tion,TX77843,USA.5Division of Infectious Diseases,Tufts University School of Veterinary Medicine,NorthGrafton,MA01536,USA.6Center for the Study ofBiological Complexity and Department of Microbiol-ogy and Immunology,Virginia Commonwealth Uni-versity,Richmond,VA23198,USA.7MRC Laboratoryof Molecular Biology,Hills Road,Cambridge CB22QH,UK.8National Center for Biotechnology Infor-mation,National Library of Medicine,National Insti-tutes of Health,Bethesda,MD20894,USA.9Depart-ment of Microbiology,University of Minnesota,Min-neapolis,MN55455,USA.*To whom correspondence should be addressed.E-mail:abe@†These authors contributed equally to this work.‡Present address:Bioinformatics Division,Genetic Re-search,GlaxoSmithKline Pharmaceuticals,5MooreDrive,Research Triangle Park,NC27009,USA.R E P O R T S SCIENCE VOL30416APRIL2004441o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mthat are shed in the feces of infected hosts.C.parvum oocysts are highly resistant to environ-mental stresses,including chlorine treatment of community water supplies;hence,the parasite is an important water-and food-borne pathogen (1).The obligate intracellular nature of the par-asite ’s life cycle and the inability to culture the parasite continuously in vitro greatly impair researchers ’ability to obtain purified samples of the different developmental stages.The par-asite cannot be genetically manipulated,and transformation methodologies are currently un-available.To begin to address these limitations,we have obtained the complete C.parvum ge-nome sequence and its predicted protein com-plement.(This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the project accession AAEE00000000.The version described in this paper is the first version,AAEE01000000.)The random shotgun approach was used to obtain the complete DNA sequence (2)of the Iowa “type II ”isolate of C.parvum .This isolate readily transmits disease among numerous mammals,including humans.The resulting ge-nome sequence has roughly 13ϫgenome cov-erage containing five gaps and 9.1Mb of totalDNA sequence within eight chromosomes.The C.parvum genome is thus quite compact rela-tive to the 23-Mb,14-chromosome genome of Plasmodium falciparum (3);this size difference is predominantly the result of shorter intergenic regions,fewer introns,and a smaller number of genes (Table 1).Comparison of the assembled sequence of chromosome VI to that of the recently published sequence of chromosome VI (4)revealed that our assembly contains an ad-ditional 160kb of sequence and a single gap versus two,with the common sequences dis-playing a 99.993%sequence identity (2).The relative paucity of introns greatly simplified gene predictions and facilitated an-notation (2)of predicted open reading frames (ORFs).These analyses provided an estimate of 3807protein-encoding genes for the C.parvum genome,far fewer than the estimated 5300genes predicted for the Plasmodium genome (3).This difference is primarily due to the absence of an apicoplast and mitochondrial genome,as well as the pres-ence of fewer genes encoding metabolic functions and variant surface proteins,such as the P.falciparum var and rifin molecules (Table 2).An analysis of the encoded pro-tein sequences with the program SEG (5)shows that these protein-encoding genes are not enriched in low-complexity se-quences (34%)to the extent observed in the proteins from Plasmodium (70%).Our sequence analysis indicates that Cryptosporidium ,unlike Plasmodium and Toxoplasma ,lacks both mitochondrion and apicoplast genomes.The overall complete-ness of the genome sequence,together with the fact that similar DNA extraction proce-dures used to isolate total genomic DNA from C.parvum efficiently yielded mito-chondrion and apicoplast genomes from Ei-meria sp.and Toxoplasma (6,7),indicates that the absence of organellar genomes was unlikely to have been the result of method-ological error.These conclusions are con-sistent with the absence of nuclear genes for the DNA replication and translation machinery characteristic of mitochondria and apicoplasts,and with the lack of mito-chondrial or apicoplast targeting signals for tRNA synthetases.A number of putative mitochondrial pro-teins were identified,including components of a mitochondrial protein import apparatus,chaperones,uncoupling proteins,and solute translocators (table S1).However,the ge-nome does not encode any Krebs cycle en-zymes,nor the components constituting the mitochondrial complexes I to IV;this finding indicates that the parasite does not rely on complete oxidation and respiratory chains for synthesizing adenosine triphosphate (ATP).Similar to Plasmodium ,no orthologs for the ␥,␦,or εsubunits or the c subunit of the F 0proton channel were detected (whereas all subunits were found for a V-type ATPase).Cryptosporidium ,like Eimeria (8)and Plas-modium ,possesses a pyridine nucleotide tran-shydrogenase integral membrane protein that may couple reduced nicotinamide adenine dinucleotide (NADH)and reduced nico-tinamide adenine dinucleotide phosphate (NADPH)redox to proton translocation across the inner mitochondrial membrane.Unlike Plasmodium ,the parasite has two copies of the pyridine nucleotide transhydrogenase gene.Also present is a likely mitochondrial membrane –associated,cyanide-resistant alter-native oxidase (AOX )that catalyzes the reduction of molecular oxygen by ubiquinol to produce H 2O,but not superoxide or H 2O 2.Several genes were identified as involved in biogenesis of iron-sulfur [Fe-S]complexes with potential mitochondrial targeting signals (e.g.,nifS,nifU,frataxin,and ferredoxin),supporting the presence of a limited electron flux in the mitochondrial remnant (table S2).Our sequence analysis confirms the absence of a plastid genome (7)and,additionally,the loss of plastid-associated metabolic pathways including the type II fatty acid synthases (FASs)and isoprenoid synthetic enzymes thatTable 1.General features of the C.parvum genome and comparison with other single-celled eukaryotes.Values are derived from respective genome project summaries (3,26–28).ND,not determined.FeatureC.parvum P.falciparum S.pombe S.cerevisiae E.cuniculiSize (Mbp)9.122.912.512.5 2.5(G ϩC)content (%)3019.43638.347No.of genes 38075268492957701997Mean gene length (bp)excluding introns 1795228314261424ND Gene density (bp per gene)23824338252820881256Percent coding75.352.657.570.590Genes with introns (%)553.9435ND Intergenic regions (G ϩC)content %23.913.632.435.145Mean length (bp)5661694952515129RNAsNo.of tRNA genes 454317429944No.of 5S rRNA genes 6330100–2003No.of 5.8S ,18S ,and 28S rRNA units 57200–400100–20022Table parison between predicted C.parvum and P.falciparum proteins.FeatureC.parvum P.falciparum *Common †Total predicted proteins380752681883Mitochondrial targeted/encoded 17(0.45%)246(4.7%)15Apicoplast targeted/encoded 0581(11.0%)0var/rif/stevor ‡0236(4.5%)0Annotated as protease §50(1.3%)31(0.59%)27Annotated as transporter ࿣69(1.8%)34(0.65%)34Assigned EC function ¶167(4.4%)389(7.4%)113Hypothetical proteins925(24.3%)3208(60.9%)126*Values indicated for P.falciparum are as reported (3)with the exception of those for proteins annotated as protease or transporter.†TBLASTN hits (e Ͻ–5)between C.parvum and P.falciparum .‡As reported in (3).§Pre-dicted proteins annotated as “protease or peptidase”for C.parvum (CryptoGenome database,)and P.falciparum (PlasmoDB database,).࿣Predicted proteins annotated as “trans-porter,permease of P-type ATPase”for C.parvum (CryptoGenome)and P.falciparum (PlasmoDB).¶Bidirectional BLAST hit (e Ͻ–15)to orthologs with assigned Enzyme Commission (EC)numbers.Does not include EC assignment numbers for protein kinases or protein phosphatases (due to inconsistent annotation across genomes),or DNA polymerases or RNA polymerases,as a result of issues related to subunit inclusion.(For consistency,46proteins were excluded from the reported P.falciparum values.)R E P O R T S16APRIL 2004VOL 304SCIENCE 442 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o mare otherwise localized to the plastid in other apicomplexans.C.parvum fatty acid biosynthe-sis appears to be cytoplasmic,conducted by a large(8252amino acids)modular type I FAS (9)and possibly by another large enzyme that is related to the multidomain bacterial polyketide synthase(10).Comprehensive screening of the C.parvum genome sequence also did not detect orthologs of Plasmodium nuclear-encoded genes that contain apicoplast-targeting and transit sequences(11).C.parvum metabolism is greatly stream-lined relative to that of Plasmodium,and in certain ways it is reminiscent of that of another obligate eukaryotic parasite,the microsporidian Encephalitozoon.The degeneration of the mi-tochondrion and associated metabolic capabili-ties suggests that the parasite largely relies on glycolysis for energy production.The parasite is capable of uptake and catabolism of mono-sugars(e.g.,glucose and fructose)as well as synthesis,storage,and catabolism of polysac-charides such as trehalose and amylopectin. Like many anaerobic organisms,it economizes ATP through the use of pyrophosphate-dependent phosphofructokinases.The conver-sion of pyruvate to acetyl–coenzyme A(CoA) is catalyzed by an atypical pyruvate-NADPH oxidoreductase(Cp PNO)that contains an N-terminal pyruvate–ferredoxin oxidoreductase (PFO)domain fused with a C-terminal NADPH–cytochrome P450reductase domain (CPR).Such a PFO-CPR fusion has previously been observed only in the euglenozoan protist Euglena gracilis(12).Acetyl-CoA can be con-verted to malonyl-CoA,an important precursor for fatty acid and polyketide biosynthesis.Gly-colysis leads to several possible organic end products,including lactate,acetate,and ethanol. The production of acetate from acetyl-CoA may be economically beneficial to the parasite via coupling with ATP production.Ethanol is potentially produced via two in-dependent pathways:(i)from the combination of pyruvate decarboxylase and alcohol dehy-drogenase,or(ii)from acetyl-CoA by means of a bifunctional dehydrogenase(adhE)with ac-etaldehyde and alcohol dehydrogenase activi-ties;adhE first converts acetyl-CoA to acetal-dehyde and then reduces the latter to ethanol. AdhE predominantly occurs in bacteria but has recently been identified in several protozoans, including vertebrate gut parasites such as Enta-moeba and Giardia(13,14).Adjacent to the adhE gene resides a second gene encoding only the AdhE C-terminal Fe-dependent alcohol de-hydrogenase domain.This gene product may form a multisubunit complex with AdhE,or it may function as an alternative alcohol dehydro-genase that is specific to certain growth condi-tions.C.parvum has a glycerol3-phosphate dehydrogenase similar to those of plants,fungi, and the kinetoplastid Trypanosoma,but(unlike trypanosomes)the parasite lacks an ortholog of glycerol kinase and thus this pathway does not yield glycerol production.In addition to themodular fatty acid synthase(Cp FAS1)andpolyketide synthase homolog(Cp PKS1), C.parvum possesses several fatty acyl–CoA syn-thases and a fatty acyl elongase that may partici-pate in fatty acid metabolism.Further,enzymesfor the metabolism of complex lipids(e.g.,glyc-erolipid and inositol phosphate)were identified inthe genome.Fatty acids are apparently not anenergy source,because enzymes of the fatty acidoxidative pathway are absent,with the exceptionof a3-hydroxyacyl-CoA dehydrogenase.C.parvum purine metabolism is greatlysimplified,retaining only an adenosine ki-nase and enzymes catalyzing conversionsof adenosine5Ј-monophosphate(AMP)toinosine,xanthosine,and guanosine5Ј-monophosphates(IMP,XMP,and GMP).Among these enzymes,IMP dehydrogenase(IMPDH)is phylogenetically related toε-proteobacterial IMPDH and is strikinglydifferent from its counterparts in both thehost and other apicomplexans(15).In con-trast to other apicomplexans such as Toxo-plasma gondii and P.falciparum,no geneencoding hypoxanthine-xanthineguaninephosphoribosyltransferase(HXGPRT)is de-tected,in contrast to a previous report on theactivity of this enzyme in C.parvum sporo-zoites(16).The absence of HXGPRT sug-gests that the parasite may rely solely on asingle enzyme system including IMPDH toproduce GMP from AMP.In contrast to otherapicomplexans,the parasite appears to relyon adenosine for purine salvage,a modelsupported by the identification of an adeno-sine transporter.Unlike other apicomplexansand many parasitic protists that can synthe-size pyrimidines de novo,C.parvum relies onpyrimidine salvage and retains the ability forinterconversions among uridine and cytidine5Ј-monophosphates(UMP and CMP),theirdeoxy forms(dUMP and dCMP),and dAMP,as well as their corresponding di-and triphos-phonucleotides.The parasite has also largelyshed the ability to synthesize amino acids denovo,although it retains the ability to convertselect amino acids,and instead appears torely on amino acid uptake from the host bymeans of a set of at least11amino acidtransporters(table S2).Most of the Cryptosporidium core pro-cesses involved in DNA replication,repair,transcription,and translation conform to thebasic eukaryotic blueprint(2).The transcrip-tional apparatus resembles Plasmodium interms of basal transcription machinery.How-ever,a striking numerical difference is seenin the complements of two RNA bindingdomains,Sm and RRM,between P.falcipa-rum(17and71domains,respectively)and C.parvum(9and51domains).This reductionresults in part from the loss of conservedproteins belonging to the spliceosomal ma-chinery,including all genes encoding Smdomain proteins belonging to the U6spliceo-somal particle,which suggests that this par-ticle activity is degenerate or entirely lost.This reduction in spliceosomal machinery isconsistent with the reduced number of pre-dicted introns in Cryptosporidium(5%)rela-tive to Plasmodium(Ͼ50%).In addition,keycomponents of the small RNA–mediatedposttranscriptional gene silencing system aremissing,such as the RNA-dependent RNApolymerase,Argonaute,and Dicer orthologs;hence,RNA interference–related technolo-gies are unlikely to be of much value intargeted disruption of genes in C.parvum.Cryptosporidium invasion of columnarbrush border epithelial cells has been de-scribed as“intracellular,but extracytoplas-mic,”as the parasite resides on the surface ofthe intestinal epithelium but lies underneaththe host cell membrane.This niche may al-low the parasite to evade immune surveil-lance but take advantage of solute transportacross the host microvillus membrane or theextensively convoluted parasitophorous vac-uole.Indeed,Cryptosporidium has numerousgenes(table S2)encoding families of putativesugar transporters(up to9genes)and aminoacid transporters(11genes).This is in starkcontrast to Plasmodium,which has fewersugar transporters and only one putative ami-no acid transporter(GenBank identificationnumber23612372).As a first step toward identification ofmulti–drug-resistant pumps,the genome se-quence was analyzed for all occurrences ofgenes encoding multitransmembrane proteins.Notable are a set of four paralogous proteinsthat belong to the sbmA family(table S2)thatare involved in the transport of peptide antibi-otics in bacteria.A putative ortholog of thePlasmodium chloroquine resistance–linkedgene Pf CRT(17)was also identified,althoughthe parasite does not possess a food vacuole likethe one seen in Plasmodium.Unlike Plasmodium,C.parvum does notpossess extensive subtelomeric clusters of anti-genically variant proteins(exemplified by thelarge families of var and rif/stevor genes)thatare involved in immune evasion.In contrast,more than20genes were identified that encodemucin-like proteins(18,19)having hallmarksof extensive Thr or Ser stretches suggestive ofglycosylation and signal peptide sequences sug-gesting secretion(table S2).One notable exam-ple is an11,700–amino acid protein with anuninterrupted stretch of308Thr residues(cgd3_720).Although large families of secretedproteins analogous to the Plasmodium multi-gene families were not found,several smallermultigene clusters were observed that encodepredicted secreted proteins,with no detectablesimilarity to proteins from other organisms(Fig.1,A and B).Within this group,at leastfour distinct families appear to have emergedthrough gene expansions specific to the Cryp-R E P O R T S SCIENCE VOL30416APRIL2004443o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mtosporidium clade.These families —SKSR,MEDLE,WYLE,FGLN,and GGC —were named after well-conserved sequence motifs (table S2).Reverse transcription polymerase chain reaction (RT-PCR)expression analysis (20)of one cluster,a locus of seven adjacent CpLSP genes (Fig.1B),shows coexpression during the course of in vitro development (Fig.1C).An additional eight genes were identified that encode proteins having a periodic cysteine structure similar to the Cryptosporidium oocyst wall protein;these eight genes are similarly expressed during the onset of oocyst formation and likely participate in the formation of the coccidian rigid oocyst wall in both Cryptospo-ridium and Toxoplasma (21).Whereas the extracellular proteins described above are of apparent apicomplexan or lineage-specific in-vention,Cryptosporidium possesses many genesencodingsecretedproteinshavinglineage-specific multidomain architectures composed of animal-and bacterial-like extracellular adhe-sive domains (fig.S1).Lineage-specific expansions were ob-served for several proteases (table S2),in-cluding an aspartyl protease (six genes),a subtilisin-like protease,a cryptopain-like cys-teine protease (five genes),and a Plas-modium falcilysin-like (insulin degrading enzyme –like)protease (19genes).Nine of the Cryptosporidium falcilysin genes lack the Zn-chelating “HXXEH ”active site motif and are likely to be catalytically inactive copies that may have been reused for specific protein-protein interactions on the cell sur-face.In contrast to the Plasmodium falcilysin,the Cryptosporidium genes possess signal peptide sequences and are likely trafficked to a secretory pathway.The expansion of this family suggests either that the proteins have distinct cleavage specificities or that their diversity may be related to evasion of a host immune response.Completion of the C.parvum genome se-quence has highlighted the lack of conven-tional drug targets currently pursued for the control and treatment of other parasitic protists.On the basis of molecular and bio-chemical studies and drug screening of other apicomplexans,several putative Cryptospo-ridium metabolic pathways or enzymes have been erroneously proposed to be potential drug targets (22),including the apicoplast and its associated metabolic pathways,the shikimate pathway,the mannitol cycle,the electron transport chain,and HXGPRT.Nonetheless,complete genome sequence analysis identifies a number of classic and novel molecular candidates for drug explora-tion,including numerous plant-like and bacterial-like enzymes (tables S3and S4).Although the C.parvum genome lacks HXGPRT,a potent drug target in other api-complexans,it has only the single pathway dependent on IMPDH to convert AMP to GMP.The bacterial-type IMPDH may be a promising target because it differs substan-tially from that of eukaryotic enzymes (15).Because of the lack of de novo biosynthetic capacity for purines,pyrimidines,and amino acids,C.parvum relies solely on scavenge from the host via a series of transporters,which may be exploited for chemotherapy.C.parvum possesses a bacterial-type thymidine kinase,and the role of this enzyme in pyrim-idine metabolism and its drug target candida-cy should be pursued.The presence of an alternative oxidase,likely targeted to the remnant mitochondrion,gives promise to the study of salicylhydroxamic acid (SHAM),as-cofuranone,and their analogs as inhibitors of energy metabolism in the parasite (23).Cryptosporidium possesses at least 15“plant-like ”enzymes that are either absent in or highly divergent from those typically found in mammals (table S3).Within the glycolytic pathway,the plant-like PPi-PFK has been shown to be a potential target in other parasites including T.gondii ,and PEPCL and PGI ap-pear to be plant-type enzymes in C.parvum .Another example is a trehalose-6-phosphate synthase/phosphatase catalyzing trehalose bio-synthesis from glucose-6-phosphate and uridine diphosphate –glucose.Trehalose may serve as a sugar storage source or may function as an antidesiccant,antioxidant,or protein stability agent in oocysts,playing a role similar to that of mannitol in Eimeria oocysts (24).Orthologs of putative Eimeria mannitol synthesis enzymes were not found.However,two oxidoreductases (table S2)were identified in C.parvum ,one of which belongs to the same families as the plant mannose dehydrogenases (25)and the other to the plant cinnamyl alcohol dehydrogenases.In principle,these enzymes could synthesize protective polyol compounds,and the former enzyme could use host-derived mannose to syn-thesize mannitol.References and Notes1.D.G.Korich et al .,Appl.Environ.Microbiol.56,1423(1990).2.See supportingdata on Science Online.3.M.J.Gardner et al .,Nature 419,498(2002).4.A.T.Bankier et al .,Genome Res.13,1787(2003).5.J.C.Wootton,Comput.Chem.18,269(1994).Fig.1.(A )Schematic showing the chromosomal locations of clusters of potentially secreted proteins.Numbers of adjacent genes are indicated in paren-theses.Arrows indicate direc-tion of clusters containinguni-directional genes (encoded on the same strand);squares indi-cate clusters containingg enes encoded on both strands.Non-paralogous genes are indicated by solid gray squares or direc-tional triangles;SKSR (green triangles),FGLN (red trian-gles),and MEDLE (blue trian-gles)indicate three C.parvum –speciﬁc families of paralogous genes predominantly located at telomeres.Insl (yellow tri-angles)indicates an insulinase/falcilysin-like paralogous gene family.Cp LSP (white square)indicates the location of a clus-ter of adjacent large secreted proteins (table S2)that are cotranscriptionally regulated.Identiﬁed anchored telomeric repeat sequences are indicated by circles.(B )Schematic show-inga select locus containinga cluster of coexpressed large secreted proteins (Cp LSP).Genes and intergenic regions (regions between identiﬁed genes)are drawn to scale at the nucleotide level.The length of the intergenic re-gions is indicated above or be-low the locus.(C )Relative ex-pression levels of CpLSP (red lines)and,as a control,C.parvum Hedgehog-type HINT domain gene (blue line)duringin vitro development,as determined by semiquantitative RT-PCR usingg ene-speciﬁc primers correspondingto the seven adjacent g enes within the CpLSP locus as shown in (B).Expression levels from three independent time-course experiments are represented as the ratio of the expression of each gene to that of C.parvum 18S rRNA present in each of the infected samples (20).R E P O R T S16APRIL 2004VOL 304SCIENCE 444 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m。

A highly ordered nanostructured carbon–sulphur cathode for lithium–sulphur batteries

A highly ordered nanostructured carbon–sulphur cathode for lithium–sulphur batteriesXiulei Ji,Kyu Tae Lee and Linda F.Nazar *The Li–S battery has been under intense scrutiny for over two decades,as it offers the possibility of high gravimetric capacities and theoretical energy densities ranging up to a factor of ﬁve beyond conventional Li-ion systems.Herein,we report the feasibility to approach such capacities by creating highly ordered interwoven composites.The conductive mesoporous carbon framework precisely constrains sulphur nanoﬁller growth within its channels and generates essential electrical contact to the insulating sulphur.The structure provides access to Li +ingress/egress for reactivity with the sulphur,and we speculate that the kinetic inhibition to diffusion within the framework and the sorption properties of the carbon aid in trapping the polysulphides formed during redox.Polymer modiﬁcation of the carbon surface further provides a chemical gradient that retards diffusion of these large anions out of the electrode,thus facilitating more complete reaction.Reversible capacities up to 1,320mA h g −1are attained.The assembly process is simple and broadly applicable,conceptually providing new opportunities for materials scientists for tailored design that can be extended to many different electrode materials.Safe,low-cost,high-energy-density and long-lasting recharge-able batteries are in high demand to address pressing environmental needs for energy storage systems that can be coupled to renewable sources 1,2.These include wind,wave and solar energy,as well as regenerative braking from vehicular transport.With production of oil predicted to decline,and the number of vehicles and their pollution impact increasing globally,a transformation in transportation economy is inevitable given that we live in a carbon-constrained world.One of the most promising candidates for storage devices is the lithium–sulphur cell.Under intense scrutiny for well over two decades,the cell in its simplest configuration consists of sulphur as the positive electrode and lithium as the negative electrode 3,4.It differs from conventional lithium-ion cells,which operate on the basis of topotactic inter-calation reactions:reversible uptake of Li ions and electrons in a solid with minimal change to the structure.They typically use a lithium transition-metal oxide or phosphate as a positive electrode (cathode)that de/re-intercalates Li +at a high potential with respect to the carbon negative electrode (anode).As the reaction is topotac-tic at both electrodes,the charge storage capability is inherently limited to about 300mA h g −1for any prospective system,and maximum capacities observed so far are 180mA h g −1with high power characteristics having been reported 5.The lithium–sulphur cell operates quite differently.The redox couple,described by the reaction S 8+16Li ↔8Li 2S lies near 2.2V with respect to Li +/Li o ,a potential about 2/3of that exhibited by conventional positive electrodes 6.However,this is offset by the very high theoretical capacity afforded by the non-topotactic ‘assimilation’process,of 1,675mA h g −1.Thus,compared with intercalation batteries,Li–S cells have the opportunity to provide a significantly higher energy density (a product of capacity and voltage).Values can approach 2,500W h kg −1or 2,800W h l −1on a weight or volume basis respec-tively,assuming complete reaction to Li 2S (refs 7,8).Despite its considerable advantages,the Li–S cell is plagued with problems that have hindered its widespread practical realization.These arise from the fact that all components of the cell must be addressed as a whole,including the interfaces betweenUniversity of Waterloo,Department of Chemistry,Waterloo,Ontario N2L 3G1,Canada.*e-mail:lfnazar@uwaterloo.ca.them.Sulphur or sulphur-containing organic compounds are highly electrically and ionically insulating 9.To enable a reversible electrochemical reaction at high current rates,the sulphur must maintain intimate contact with an electrically conductive additive.Various carbon–sulphur composites have been used for this purpose,but they have limitations owing to the scale of the contact area.Typical reported capacities are between 300and 550mA h g −1at moderate rates 10.To make a sulphur-containing cathode ionically conductive,liquid electrolytes are used that act not only as a charge transport medium but also as ionic conductors within the sulphur-containing cathode 11.This presents difficulties of electrolyte access.Another major hurdle is capacity degradation on repeated discharge–charge of the cell.This is mainly due to the high solubility of the polysulphide anions formed as reaction intermediates in both discharge and charge processes in the polar organic solvents used in electrolytes 12.During cycling,the polysulphide anions can migrate through the separator to the Li negative electrode whereupon they are reduced to solid precipitates (Li 2S 2and/or Li 2S),causing active mass loss.In addition,the solid product that extensively precipitates on the surface of the positive electrode during discharge becomes electrochemically irreversible,which also contributes to active mass loss 13.In response to these considerable challenges,novel advances in materials design such as new electrolytes 14–17and protective films for the lithium anode have been developed 18–binations of electrolyte modification,additives and anode protection have resulted in some promising results,although rates are not given 21.Much of the difficulty still remains at the cathode,where the lack of breakthroughs has led to some cell configurations in which all of the sulphides are solubilized (so-called ‘catholyte’cells)22.In the opposite approach,that is,to contain the sulphides,some interesting cathode developments have been reported recently 23–26.However,they still fall short of the mark for practical electrochemical performance.They include,for example,the fabrication of disordered mesoporous carbon/sulphur 50:50composites in conjunction with ionic liquid electrolytes;systems that achieve high initial capacity,but suffer extensive capacity0.20.40.60.81.01.21.4x in Li x S CMK¬3+S mixtureCMK¬3/S 155 °CV o l t a g e (V ) v e r s u s L i /L i +V o l t a g e (V ) v e r s u s L i /L i +Specific capacity (mA h g ¬1)2004006008001,0001,200Specific capacity (mA h g ¬1)02004006008001,0001,2001.52.02.53.01.52.02.53.0Sab cd2 µm2 µmFigure 1|SEM images of CMK-3/sulphur,and its electrochemical characterization.a ,Mixture of CMK-3and elemental sulphur before heating.b ,CMK-3/S heated at 155◦C,showing the disappearance of the sulphur mass indicated by the red rectangle in a .c ,d ,Comparison of the galvanostatic discharge–charge proﬁles of the ﬁrst cycles of the carbon–sulphur composites shown in a ,b ,at a current rate of 168mAg −1.The marked increase in capacity in d is due to the encapsulation effect.fading posites with sulphur embedded in conducting polymers have shown some promising results 27.However,a large polarization was observed,resulting in a very low operating voltage that reduces the energy density of cells.The loading of active mass in the S-polymer composite is also limited (less than 55wt%)owing to the low surface area of the conducting polymer.Here,we demonstrate that cathodes based on nanostructured sulphur/mesoporous carbon materials can overcome these challenges to a large degree,and exhibit stable,high,reversible capacities (up to 1,320mA h g −1)with good rate properties and cycling efficiency.Our proof-of-concept studies are based on CMK-3,the most well-known member of the mesoporous carbon family,although they are not limited to this material.Highly ordered mesoporous carbons exhibit a uniform pore diameter,very high pore volume,interconnected porous structure and can exhibit high conductivity 28,29.They,and their oxide analogues 30,31,have attracted much attention recently as nanoscale electrode materials in Li batteries 32,33,as supercapacitors and as supports for proton-exchange-membrane fuel-cell catalysts 34.CMK-3was synthesized by a nanocasting method that uses silaceous SBA-15as a hard template.The resulting replica comprises an assembly of hollow 6.5-nm-thick carbon rods separated by empty 3–4-nm-wide channel voids 35.The channel space is spanned by carbon microfibres that prevent the collapse of the nano-architecture of the two-dimensional hexagonally ordered carbon rods.We tuned the synthesis of the CMK-3to produce a short rod-like morphology,to optimize access to the mesoporous channels 36.The CMK-3/sulphur composite was prepared following a simple melt-diffusion strategy.A 3:7weight ratio mixture of CMK-3and sulphur was heated just above the melting point of sulphur,where the viscosity is lowest 37.The melt is imbibed into the channels by capillary forces,whereupon it solidifies and shrinks to form sulphur nanofibres that are in intimate contact with the conductive carbon walls.The scanning electron microscopy (SEM)images in Fig.1reveal the changes in the mixture of CMK-3and sulphur before and after heating.The bulk sulphur evident in the SEM image of the composite on initial mixing (Fig.1a)largely disappears at 145◦C (see Supplementary Fig.S1),and completely disappears after heat treatment at 155◦C (Fig.1b).Full incorporation of sulphur into the channels of CMK-3occurs at this latter temperature.CMK-3and sulphur are both hydrophobic materials,which accounts for the ready absorption of sulphur into the channel structure.The filling of the carbon channels with sulphur is corroborated by the transmission electron microscopy (TEM)image shown in Fig.2a,along with the magnified image shown in Fig.2b.The fibres have a similar diameter to that of the channels of the mesoporous carbon (3.3nm),and a comparable diameter to the carbon nanorods that enclose them (6–7nm).The filling of the pores with sulphur,of similar density to carbon,is also evident from the decrease in contrast in relation to CMK-3itself (shown in the inset in Fig.2b).The sulphur and carbon elemental maps (Fig.2c,d)clearly demonstrate that sulphur is homogeneously distributed in the framework of the mesoporous carbon,with no significant fraction on the external surface.The marked diminution3 nm6.5 nmC Ka1_2S Ka1S meltS xtalx abc def30 nmFigure 2|TEM image and elemental maps of a CMK-3/S-155composite particle and schematic diagrams of the structure and redox processes.a ,CMK-3/S-155composite particle.b ,Image expansion corresponding to the area outlined by the red square in a ,where the inset shows the TEM image for pristine CMK-3at the same magniﬁcation.c ,d ,Corresponding carbon and sulphur elemental maps showing the homogeneous distribution of sulphur.e ,A schematic diagram of the sulphur (yellow)conﬁned in the interconnected pore structure of mesoporous carbon,CMK-3,formed from carbon tubes that are propped apart by carbon nanoﬁbres.f ,Schematic diagram of composite synthesis by impregnation of molten sulphur,followed by its densiﬁcation on crystallization.The lower diagram represents subsequent discharging–charging with Li,illustrating the strategy of pore-ﬁlling to tune for volume expansion/contraction.of the X-ray diffraction (XRD)peak (low-angle diffraction pattern,Fig.3a)due to long-range order in CMK-3is further proof of pore-filling,which is the result of the decrease in the scattering contrast (Fig.3a)paring the wide-angle XRD patterns in Fig.3b,the well-resolved peaks corresponding to bulk crystalline sulphur completely disappear after sulphur impregnation,and thermogravimetric analysis (TGA;Supplementary Fig.S2)shows the composites range up to 70wt%sulphur.A schematic diagram illustrating the impregnation of the CMK-3with sulphur is shown in Fig.2e,showing the alignment of the channels in comparison with the inset of Fig.2b.Note that most of the sulphur is contained within the interior of the pore structure,as the particles span hundreds of carbon channels in width.The average CMK-3particle size is of the order of 1µm (Fig.1b).Table 1summarizes the physical characteristics of the CMK-3and the CMK-3/S composite derived from Brunauer–Emmett–Teller (BET)and conductivity measurements.After imbibition of the sulphur in the channels,the pore size of the CMK-3/S composite decreases markedly,indicating that the channels of CMK-3are partially filled.Along with the presence of residual micropores in the carbon wall structure 39,this allows ingress of electrolyte within the structure.Empty volume within the pores is also necessary to accommodate the uptake of Liions,I n t e n s i t y2 (°)I n t e n s i t yi abθ2 (°)θFigure 3|XRD patterns of CMK-3/S before and after heating.a ,Low-angle XRD patterns of a mixture of CMK-3and sulphur before heating (i)and after heating at 155◦C (ii).The disappearance of the ﬁrst peak is due to the loss of contrast on sulphur imbibition.b ,Wide-angle XRD patterns of a mixture of CMK-3and sulphur before heating (i)and after heating at 155◦C (ii),showing the complete incorporation of crystalline sulphur within the framework.given by the reaction S +2Li →Li 2S,because of the lower density of Li 2S (1.66g cm −3)compared with sulphur.Note that the 70wt%sulphur/composite ratio is less than the theoretical limit of 79wt%sulphur/composite based on the pore volume of CMK-3(2.1cm 3g −1)and the density of liquidized sulphur (1.82g cm −3),and is precisely tuned for the volume expansion (see the Methods section).Using even lower S/carbon ratios provides less ‘stuffed’structures and extra porosity,but at the expense of reduced active mass.Most importantly,the electrical conductivity of the composites (∼0.2S cm −1for 70wt%sulphur/composite)is the same as its mesoporous carbon counterpart.The insulating sulphur merely occupies the empty channels in the mesoporous carbon and does not block the electrical current transporting paths.Three-dimensional,multiple electronic contacts are provided by the numerous carbon interconnects that span the channels,as illustrated schematically in Fig.2e,f (ref.35).Coin cells using a metallic Li anode were assembled to evaluate the materials.All of the capacity values in this article are calculated on the basis of sulphur mass.The first discharge–charge curve for a typical nanostructured CMK-3/S cathode is shown in Fig.1d alongside its SEM image,and is compared with a simple physical (unheated)mixture of 7:3weight ratio of sulphur and CMK-3in Fig.1c.The nanostructured composite exhibits an impressive capacity of 1,005mA h g −1.In contrast,the ‘macro-mixture’exhibited a reversible capacity of 390mA h g −1(on average between 300and 420mA h g −1),similar to that reported in the literature for C–S composites 10.The capacity of CMK-3/S was3.02.52.01.5V o l t a g e (V ) v e r s u s L i +/L i3.02.52.01.5V o l t a g e (V ) v e r s u s L i +/L i3006009001,2001,500Specific capacity (mA h g ¬1)S p e c i f i c c a p a c i t y (m A h g ¬1)CMK¬3/S at 55 °C with C/10 + C/10000.20.40.60.81.01.21.41.6x in Li x S Cycle numberCycle number200406080100S u l p h u r i n e l e c t r o l y t e /t o t a l s u l p h u r (%)1,0001,400abcFigure 4|Electrochemical characterization of PEG-coated CMK-3/S and comparison to reference materials.a ,Lower panel:galvanostaticdischarge–charge proﬁle of PEG-modiﬁed CMK-3/S-155recorded at room temperature at 168mA g −1.The reversible capacity of 1,320mA h g −1at room temperature is very close to that obtained for unmodiﬁed CMK-3/S obtained at elevated temperature under ‘quasi-equilibrium’conditions shown in the upper panel (CMK-3/S-155recorded at 55◦C at 168mA g −1on discharge to 1.0V followed by quasi-equilibrium discharge at 16.8mA g −1).The slight overcharge in the latter case is due to dissolution of some polysulphide,which is minor even at these conditions.This also indicates that storage of the cell at partial or full discharge does not lead to signiﬁcant capacity loss.b ,Cycling stability comparison of CMK-3/S-PEG (upper points,in black)versus CMK-3/S (lower points,in red)at 168mA g −1at room temperature.c ,Percentage of sulphur dissolution into the electrolyte from:the CMK-3/S-PEGcomposite cathode (black curve);from the CMK-3/S composite cathode (blue curve);a cathode made of a mixture of acetylene black carbon and sulphur with the exact same C /S ratio (red curve).highly reproducible over many cells.The coulombic efficiency for CMK-3/S in the first discharge–charge cycle is 99.94%without any overcharge,with virtually no irreversibility.This indicates that a very low fraction of polysulphide anions diffuse into the electrolyte.The polarization was decreased by more than a factor of three,owing to the greatly enhanced electrical contact achieved in the nanostructure.Further unequivocal proof of the effectiveness of the contact arises from experiments in which the degree of S incorporation was varied.Nanostructured composites (CMK-3/S-145)with the same S/C ratio,but heated at 145◦C instead of 155◦C result in less complete diffusion of sulphur into the channels because of the higher viscosity at the lower temperature.These composites showed less utilization of sulphur (capacity of 780mA h g −1)in the first discharge sweep (see Supplementary Fig.S3),and an irreversible capacity of 50mA h g −1on plete imbibition prevents sulphur agglomerates on the externalsurface of the mesoporous framework that would have poorer electrical wiring of the conductive carbon phase.These results are superior to those reported for sulphur in contact with multi-walled carbon nanotubes.Such composites exhibit lower capacities and a large electrochemical hysteresis 23.Although the sulphur is apparently confined in the carbon,the contact is limited owing to the relatively large diameter (∼50nm)of the multi-walled carbon nanotubes,and hence of the sulphur fibres within them.Thus,the efficiency of electron transfer to the sulphur mass and accessibility to the Li +electrolyte has a vitally important role in determining the electrochemical behaviour.As seen in Fig.1d,there are two plateaux in the discharge process.The first,which contributes a minor part to the overall capacity from 2.4to 2.0V,corresponds to the conversion from elemental sulphur (S 8)to Li polysulphide anions (Li 2S x ;where x is typically 4–5).The kinetics of this reaction is fast 40.The second plateau atHeat flow (W g ¬1)W e i g h t (%)Temperature (°C)Figure 5|TGA of PEG-modiﬁed CMK-3.TGA and differential scanning calorimetry curves recorded in air with a heating rate of 20◦C min −1,for PEG-CMK-3(solid lines),compared with PEG itself (dashed lines),showing the shift to higher temperature of the PEG release on bonding to the CMK-3framework.around 2.0V is due to the conversion of polysulphides to Li 2S 2and then to Li 2S,which occurs at a much slower rate.As we achieve a nominal reversible capacity of Li 1.2S in the nanostructured composite,we wanted to explore the limitations to full conversion.To gain a measure of the reversible capacity under conditions where the kinetics should be a minimal concern,we carried out discharge of the CMK-3/S cathode at 55◦C at 168mA g −1to a cutoff of 1.0V,and allowed the voltage to relax to equilibrium.We then switched the discharge current to a rate of 16.8mA g −1to the end of discharge,and completed charge at 168mA g −1.The electrochemical profile is presented in Fig.4a (upper panel).Under these close-to-equilibrium conditions of full discharge,we achieve a reversible capacity of 1,400mA h g −1—84%of the theoretical capacity (1,675mA h g −1)—indicating that indeed,the kinetics of the last reaction step has a role in capacity limitation.The other factor could be a transport problem.There is progressively more limited accessibility of Li +ions and electrolyte to the sulphur mass towards the end of discharge because the pores become filled with insoluble Li x S (x =1–2)—even though at 70wt%sulphur loading,there is sufficient space for the volume expansion based on the conversion of S to Li 2S.However,we observed that in doubling the rate from 168to 336mA g −1(equivalent to C/5rate),the capacity is reduced by only a small amount to 930mA h g −1(see Supplementary Fig.S4).The mesoporous carbon clearly performs very well as a sulphur container.This is apparent from the small degree of overcharge even under rigorous (55◦C;C/100discharge)conditions as shown in Fig.4a.The complete lack of a sharp minimum in the discharge curve between the two plateaux,as observed by others and ascribed to supersaturation of the electrolyte with S 2−(refs 21,41),is also indicative of the strong extent of sulphide containment in our case.Experiments were carried out to evaluate the degree of self-discharge,by taking the cell to a voltage of 2.1V,holding it at the open-circuit voltage for 24h and then completing discharge.The discharge capacity after relaxation was 5%less than the cell taken to full discharge without the open-circuit voltage step.However,this suggests that the framework still allows for some egress of dissolved sulphur species.We propose that the complex inner pathway and porous,absorptive carbon greatly retard the diffusion of the bulky polysulphide anions out from the channels into the electrolyte,butcannot entirelyprevent it.This is evident by the very slow capacity fading shown in Fig.4b(upperred points).To further trapthe highly polar polysulphide species,we adjusted the hydrophilicity of the carbon external surface afterabcd300 nmFigure 6|Changes in surface morphology of CMK-3/S-155versusPEG-modiﬁed CMK-3/S-155on cycling.a ,b ,SEM images of CMK-3/S-155before (a )and after (b )the 15th charge.c ,d ,SEM images of PEG-modiﬁed CMK-3/S before (c )and after (d )the 15th charge.Images show the effects of ‘polymer protection’in inhibiting surface deposition.sulphur imbibition by functionalizing the surface with polyethylene glycol (PEG)chains of varying molecular weight.The attachment of the PEG to CMK-3is evident by TGA (Fig.5).The release of the PEG tethered to the CMK-3occurs at 50◦C higher than in PEG itself owing to the ester bonds.The discharge–charge profile of CMK-3/S-PEG is shown in Fig.4a (lower panel).Not only is the initial discharge capacity increased to 1,320mA h g −1(approaching the ‘equilibrium’limit for CMK-3/S of 1,400mA h g −1),and the polarization decreased to low values,but no fading is observed in the second 10cycles and the capacity is stabilized at 1,100mA h g −1on cycling (Fig.4b,upper black points).The entrapment of sulphur active mass on cycling in the polymer-modified CMK-3/S composite is demonstrated in Fig.4c.To measure the degree of sulphur retention in the cathode,a 1.0M LiPF 6solution in a sulphur-free solvent,tetra(ethylene glycol)dimethyl ether (TEGDME),was used as the electrolyte.Glyme solvents are known for their excellent ability to dissolve polysulphides,and hence represent an ‘aggressive’pared with the cathode made of a mixture of sulphur and acetylene black that loses 96%of the total active mass into the electrolyte after 30cycles,the polymer-modified composite shows significant retention of sulphur.Only 25%of the total active mass is solubilized in the electrolyte after 30cycles.The polysulphide retention is also improved in relation to CMK-3/S.We believe that the effect of the PEG-functionalized surface is twofold.First,it serves to trap the polysulphide species by providing a highly hydrophilic surface chemical gradient that preferentially solubilizes them in relation to the electrolyte.Second,by limiting the concentration of the polysulphide anions in the electrolyte,the redox shuttle mechanism is curtailed to a large degree.Deposition of insoluble sulphur species on the surface of the Li electrode and formation of irreversible Li 2S on the cathode surface are strongly inhibited.The last point is clearly demonstrated in SEM images of the PEG-functionalized CMK-3/S cathode before and after cycling,which exhibit very little change in surface morphology (Fig.6),compared with CMK-3/S,which clearly shows precipitation of insoluble products on the surface of the mesoporous carbon particles.In summary,we demonstrate that the strategy illustrated here provides a versatile route to nanostructured polymer-modified mesoporous carbon–sulphur composites that display all of the benefits of confinement effects at a small length scale.Intimate contact of the insulating sulphur and discharge-product sulphides with the retaining conductive carbon framework at nanoscaledimensions affords excellent accessibility of the active material. The carbon framework not only acts as an electronic conduit to the active mass encapsulated within,but also serves as a mini-electrochemical reaction chamber.The entrapment ensures that a more complete redox process takes place,and results in enhanced utilization of the active sulphur material.This is vital to the success of all conversion reactions to ensure full reversibility of the back-reaction.The polymer coating on the external surface of the composite further helps retard diffusion of polysulphide out of the cathode structure,minimize the loss of the active mass in the cathode and improve the cycling stability.The composite materials reported here can supply up to nearly80%of the theoretical capacity of sulphur(1,320mA h g−1),representing more than three times the energy density of lithium transition-metal oxide cathodes,at reasonable rates with good cycling stability.In our laboratory,mesoporous carbon frameworks with various wall thicknesses,conductivities and connectivities have recently been prepared to take advantage of structural and electronic variation of the constraining support.The three-dimensional variants such as CMK-1and CMK-8are particularly promising in this respect42. We will report those results in a forthcoming paper.Owing to the flexibility of the method,the high capacity of the carbon for active material incorporation and facile functionalization of the surface,we believe that a wide variety of nanostructured‘imbibed’composites could find broad application in many areas of materials science,not only as advanced electrode materials that rely on assimilation and conversion reactions.MethodsSynthesis.For the synthesis of SBA-15with controlled morphology43,2g of Pluronic P123(EO20PPO70EO20)was dissolved in60ml of2M HCl at38◦C. Tetraethylorthosilicate(4.2g)was added to the above solution with vigorous stirring.The mixture was stirred for only6min and remained quiescent for24h at38◦C.The mixture was subsequently heated at100◦C for another24h in an autoclave.The as-synthesized SBA-15with short-rod morphology was collected by filtration,dried and calcined at550◦C in air.A nanocasting method was used to fabricate CMK-3from SBA-15as a hard template44.Sucrose(1.25g)was dissolved in5.0ml of water containing0.14g H2SO4.Surfactant-free SBA-15(1.0g)was then dispersed in the above solution and the mixture was sonicated for1h;heated at100◦C for12h and at160◦C for another12h.The impregnation process was repeated once with another5.0ml aqueous solution containing0.8g sucrose and 0.09g H2SO4.The composite was completely carbonized at900◦C for5h in an argon atmosphere.To remove the SBA-15silica template,the composite was stirred in a5%HF solution at room temperature for4h,although NaOH can also be used to dissolve the silica.The CMK-3/S nanocomposite was prepared following a melt-diffusion strategy.CMK-3(1.0g)and sulphur(2.33g)were ground together,and heatedto155◦C.The weight ratio of sulphur/carbon was adjusted to be equal to or less than7:3,to allow for expansion of the pore content on full lithiation to Li2S.For example,1.0g of CMK-3can accommodate3.486g of Li2S(1.66g cm−3(density of Li2S)×2.1cm3g−1,the pore volume of the CMK-3),which corresponds to a maximum of2.425g of sulphur.To prepare the CMK-3/S-PEG composite,CMK-3was first functionalized with carboxylic groups by oxidization treatment in concentrated HNO3solution for half an hour at80◦C,before incorporation of the sulphur.To tether the PEG chains to the surface of the CMK-3/S composite,the composite was dispersedin a PEG aqueous solution and the solution was heated at58◦C and stirred continuously overnight to ensure complete reaction of the carboxylic groups on the carbon particles with the hydroxyl groups on the PEG.The mixture was sonicated for20min to completely remove physically absorbed PEG on the composite,and the CMK-3/S-PEG composite was collected by filtration and dried. Characterization.X-ray diffraction patterns at low-angle(0.75◦to4◦2θ)and wide-angle(from10◦to80◦2θ)were collected on a D8-ADVANCE powderX-ray diffractometer operating at40kV and30mA and using Cu-Kαradiation (λ=0.15406nm).Nitrogen adsorption and desorption isotherms were obtained using a Micromeritics Gemini2735system at−196◦C.Before measurement of CMK-3,the sample was degassed at150◦C on a vacuum line following a standard protocol.It was not possible to carry this out for CMK-3/S owing to the volatility of the sulphur,and so no pretreatment was used.The BET method was usedto calculate the surface area45.The total pore volumes were calculated fromthe amount adsorbed at a relative pressure of0.99.The pore size distributions were calculated by means of the Barrett–Joyner–Halenda method applied to the desorption branch46.As the mesopores of CMK-3/S are decreased to micropores on(partial)filling with sulphur,the possibility of water entrapment,and/or pore blockage means that the values represent lower estimates.The morphology of the sulphur/CMK-3composites were examined by SEM using a LEO1530field-emission SEM instrument or a Hitachi S-5200 instrument.TEM was carried out on a Hitachi HD-2000STEM.Conductivity measurements were carried out at room temperature using the four-point method.Sample bars for the measurement were cut from the pellets and then cold pressed using a force of45kN.Elemental analyses were carried out at M-H-W Laboratories,Phoenix,USA.Electrochemistry.Positive electrodes were comprised84wt%CMK-3/S composite,8wt%Super-S carbon and8wt%poly(vinylidene fluoride)binder. The cathode materials were slurry-cast from cyclopentanone onto a carbon-coated aluminium current collector(Intelicoat).The electrolyte is composed of a1.2M LiPF6solution in ethyl methyl sulphone47.Lithium metal foil was used as the counter electrode.The equivalent current density for the168mA g−1rate is0.19 and0.37mA cm−2for the336mA g−1rate.To measure the degree of sulphur retention in the cathode,a1.0M LiPF6solution in TEGDME was used as the electrolyte.Cathodes comprising CMK-3/S-PEG were compared with simple mixtures of sulphur and acetylene black at the exact same S/C ratio.We used large Swagelok-type cells that accommodate a sufficient excess of the electrolyte to dissolve sulphur species.Swagelok cells were disassembled and immersed into TEGDME to completely extract sulphur species from the electrolyte.Sulphur analysis was carried out by Galbraith Laboratories(Tennessee,USA).Received10September2008;accepted17April2009; published online17May2009References1.Winter,M.&Brodd,R.Batteries,fuel cells and supercapacitors.Chem.Rev.104,4245–4269(2004).2.Bruce,P.G.Energy storage beyond the horizon:Rechargeable lithium batteries.Solid State Ion.179,752–760(2008).3.Rauh,R.D.,Abraham,K.M.,Pearson,G.F.,Surprenant,J.K.&Brummer,S.B.A lithium/dissolved sulfur battery with an organic electrolyte.J.Electrochem.Soc.126,523–527(1979).4.Shim,J.,Striebel,K.A.&Cairns,E.J.The lithium/sulfur rechargeable cell.J.Electrochem.Soc.149,A1321–A1325(2002).5.Kang,K.,Meng,Y.S.,Bréger,J.,Grey,C.P.&Ceder,G.Electrodes withhigh power and high capacity for rechargeable lithium batteries.Science311, 977–980(2006).6.Peled,E.&Yamin,H.Lithium/sulfur organic battery.Prog.Batteries Sol.Cells5,56–58(1984).7.Chu,M.-Y.Rechargeable positive Patent US5686201(1997).8.Peramunage,D.&Licht,S.A solid sulfur cathode for aqueous batteries.Science261,1029–1032(1993).9.Dean,J.A.(ed.)Lange’s Handbook of Chemistry3rd edn,3–5(McGraw-Hill,1985).10.Cunningham,P.T.,Johnson,S.A.&Cairns,E.J.Phase equilibria inlithium–chalcogen systems:Lithium–sulfur.J.Electrochem.Soc.119,1448–1450(1972).11.Choi,J.-W.et al.Rechargeable lithium/sulfur battery with suitable mixedliquid electrolytes.Electrochim.Acta52,2075–2082(2007).12.Rauh,R.D.,Shuker,F.S.,Marston,J.M.&Brummer,S.B.Formationof lithium polysulfides in aprotic media.J.Inorg.Nucl.Chem.39,1761–1766(1977).13.Cheon,S.-E.et al.Rechargeable lithium sulfur battery II.Rate capability andcycle characteristics.J.Electrochem.Soc.150,A800–A805(2003).14.Shin,J.H.&Cairns,E.J.Characterization of N-methyl-N-butylpyrrolidiniumbis(trifluoromethanesulfonyl)imide-LiTFSI-tetra(ethylene glycol)dimethyl ether mixtures as a Li metal cell electrolyte.J.Electrochem.Soc.155,A368–A373(2008).15.Yuan,L.X.et al.Improved dischargeability and reversibility of sulfur cathodein a novel ionic liquid mun.8,610–614(2006).16.Ryu,H.-S.et al.Discharge behavior of lithium/sulfur cell with TEGDME basedelectrolyte at low temperature.J.Power Sources163,201–206(2006).17.Wang,J.et al.Sulfur-mesoporous carbon composites in conjunction with anovel ionic liquid electrolyte for lithium rechargeable batteries.Carbon46, 229–235(2008).18.Chung,K.-I.,Kim,W.-S.&Choi,Y.-K.Lithium phosphorous oxynitride as apassive layer for anodes in lithium secondary batteries.J.Electroanal.Chem.566,263–267(2004).19.Visco,S.J.,Nimon,Y.S.&Katz,B.D.Ionically conductive composites forprotection of active metal Patent7,282,296,October16(2007). 20.Skotheim,T.A.,Sheehan,C.J.,Mikhaylik,Y.V.&Affinito,J.Lithium anodesfor electrochemical patent7247,408,July24(2007).21.Akridge,J.R.,Mikhaylik,Y.V.&White,N.Li/S fundamental chemistry andapplication to high-performance rechargeable batteries.Solid State Ion.175, 243–245(2004).。

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植物干细胞调控研究新进展

植物干细胞调控研究新进展中国细胞生物学学报Chinese Journal of Cell Biology 2015, 37(7): 1021–1028DOI: 10.11844/cjcb.2015.07.0024收稿日期: 2015-01-15 接受日期: 2015-04-07973计划前期研究专项(批准号: 2014CB160306)、重庆市教委创新团队建设基金(批准号: KJTD201307)和重庆师范大学引进人才启动基金项目(批准号: 12XLR36)资助的课题*通讯作者。

Tel: 023-********, E-mail: hanmazhang@/doc/f017810486.html, Received: January 15, 2015 Accepted: April 7, 2015This work was supported by the National Grand Fundamental Research Pre-973 Program of China (Grant No.2014CB160306), the Innovation T eam Fund of the Education Department of Chongqing Municipality (Grant No.KJTD201307) and a Start-Up Fund from Chongqing Normal University (Grant No.12XLR36)*Corresponding author. Tel: +86-23-65912976, E-mail: hanmazhang@/doc/f017810486.html, 网络出版时间: 2015-07-01 16:53 URL: /doc/f017810486.html,/kcms/detail/31.2035.Q. 20150701.1653.001.html植物干细胞调控研究新进展赵中华南文斌梁永书张汉马*(植物环境适应分子生物学重庆市重点实验室, 重庆师范大学生命科学学院, 重庆 401331)摘要植物干细胞是植物胚后发育形成各种组织和器官的细胞来源和信号调控中心, 其调控机理是植物学研究的重要内容。

2014年SCI大类分区及小类分区

期刊全称JCR期刊简称ISSN所属小类ACM COMPUTING SURVEYS ACM COMPUT SURV0360-0300C OMPUTER SC ACM Transactions on Intelligent Systems and Te ACM T INTEL SYST TEC2157-6904C OMPUTER SC ACM Transactions on Intelligent Systems and Te ACM T INTEL SYST TEC2157-6904C OMPUTER SC ACS Applied Materials & Interfaces ACS APPL MATER INTER1944-8244M ATERIALS S ACS Applied Materials & Interfaces ACS APPL MATER INTER1944-8244N ANOSCIENC ACS Macro Letters ACS MACRO LETT2161-1653P OLYMER SCI ACS Nano ACS NANO1936-0851M ATERIALS S ACS Nano ACS NANO1936-0851C HEMISTRY, MACS Nano ACS NANO1936-0851N ANOSCIENCACS Nano ACS NANO1936-0851C HEMISTRY, P Acta Biomaterialia ACTA BIOMATER1742-7061M ATERIALS S Acta Biomaterialia ACTA BIOMATER1742-7061E NGINEERING ADVANCES IN APPLIED MECHANICS ADV APPL MECH0065-2156E NGINEERING ADVANCES IN APPLIED MECHANICS ADV APPL MECH0065-2156M ECHANICS Advanced Energy Materials ADV ENERGY MATER1614-6832M ATERIALS S Advanced Energy Materials ADV ENERGY MATER1614-6832E NERGY & FU Advanced Energy Materials ADV ENERGY MATER1614-6832P HYSICS, CON Advanced Energy Materials ADV ENERGY MATER1614-6832P HYSICS, APP Advanced Energy Materials ADV ENERGY MATER1614-6832C HEMISTRY, P ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X M ATERIALS S ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X C HEMISTRY, M ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X N ANOSCIENC ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X P HYSICS, CON ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X P HYSICS, APP ADVANCED FUNCTIONAL MATERIALS ADV FUNCT MATER1616-301X C HEMISTRY, P Advanced Healthcare Materials ADV HEALTHC MATER2192-2640M ATERIALS SADVANCED MATERIALS ADV MATER0935-9648M ATERIALS S ADVANCED MATERIALS ADV MATER0935-9648C HEMISTRY, M ADVANCED MATERIALS ADV MATER0935-9648N ANOSCIENC ADVANCED MATERIALS ADV MATER0935-9648P HYSICS, CON ADVANCED MATERIALS ADV MATER0935-9648P HYSICS, APP ADVANCED MATERIALS ADV MATER0935-9648C HEMISTRY, PANNU REV BIOMED ENG1523-9829E NGINEERING 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多环芳烃暴露的生物标志物――尿中羟基多环芳烃

Haddad[17] 采用药物动力学模型对白鼠口服和静脉注射芘时的动力学进行了模拟。口服代表对肝脏的输入 ,符合一级模型。通过对预测值和实验值的比较 ,当芘剂量为 15 mgΠkg(7412μmolΠkg) 时 ,吸收效率低于剂量为 2 、4 、6 和 9 mgΠkg(919 、1918 、2917 和 4415μmolΠkg) 时的效率。 214 尿中 PAHs 代谢物的存在形式
收稿 : 2005 年 11 月 , 收修改稿 : 2006 年 2 月 3 国家重点基础研究发展规划 (973) 项目、国家自然科学基金项目 (No. 20577058 ,20475060) 、中国科学院重要方向性项目
( KZCX32SW423) 资助 3 3 通讯联系人 e2mail :caiyaqi @rcees. ac. cn
摘要多环芳烃 ( PAHs) 是典型的持久性有机污染物 ,在职业高 PAHs 暴露环境下 ,容易诱发肺癌、皮肤癌等癌症。对 PAHs 的暴露评价可为流行病学研究和污染物风险评价等提供有效的数据。由于暴露途径的复杂化 ,采用尿样中 PAHs 的代谢产物 ———羟基多环芳烃作为标志物来综合评价人体对 PAHs 的内暴露情况已经成为研究的热点。本文系统介绍了多环芳烃的吸收、代谢、尿中 PAHs 代谢产物的主要存在形式、主要的生物标志物以及它们的主要影响因素。
Niu Hongyun1 Cai Yaqi1 3 Wei Fusheng1 ,2 3 Mou Shifen1 Jiang Guibin1 (11State Key Laboratory of Environmental Chemistry and Ecotoxicology , Research Center for Eco2Environmental Science ,

2014最新SCI影响因子_JCR Impact Factor_(8431种完整版)

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LETTERSEnantioselectivehalocyclizationofpolyprenoidsinducedbynucleophilicphosphoramidites

AkiraSakakura1,AtsushiUkai1&KazuakiIshihara1Polycyclicbio-activenaturalproductsthatcontainhalogenatomshavebeenisolatedfromanumberofdifferentmarineorganisms1.Thebiosynthesisofthesenaturalproductsappearstobeinitiatedbyanelectrophilichalogenationreactionatacarbon–carbondou-blebond2–4viaamechanismthatissimilartoaproton-induced

olefinpolycyclization5–8.Enzymessuchashaloperoxidasesgen-

erateanelectrophilichaloniumion(oritsequivalent),whichreactswiththeterminalcarbon–carbondoublebondofthepoly-prenoid,enantioselectivelyinducingacyclizationreactionthatproducesahalogenatedpolycyclicterpenoid.Useofanenantio-selectivehalocyclizationreactionisonepossiblewaytochemicallysynthesizethesehalogenatedcyclicterpenoids;althoughseveralbrominatedcyclicterpenoidshavebeensynthesizedviaadia-stereoselectivehalocyclizationreactionthatusesstoichiometricquantitiesofabrominatingreagent9–12,theenantioselectivehalo-

cyclizationofisoprenoidsinducedbyachiralpromoterhasnotyetbeenreported.Herewereporttheenantioselectivehalocyclizationofsimplepolyprenoidsusinganucleophilicpromoter.Achiralnucleophilicphosphoruscompoundsareabletopromotethedia-stereoselectivehalocyclizationreactiontogiveahalogenatedcyc-licproductinexcellentyields.Moreover,chiralphosphoramiditespromotetheenantioselectivehalocyclizationofsimplepolypre-noidswithN-iodosuccinimidetogiveiodinatedcyclicproductsinupto99%enantiomericexcessanddiastereomericexcess.Tothebestofourknowledge,thisisthefirstsuccessfulexampleoftheenantioselectivehalopolycyclizationofpolyprenoids.Toachievehighenantioselectivityinelectrophilichalocyclization,wefocusedonthemethodusedtoactivatethehalogenatingreagentsbychiralpromoters(Fig.1).IntheLewisacidapproach(methodA)13,14,theactivatedhalogenatom(X)wouldbeplacedfarfromthe

chiralenvironmentoftheLewisacid(LA*)intheactivespecies,andthereforeitisdifficulttoobtainhighenantioselectivity.Incontrast,ifchiralnucleophilicpromoters(Nu*)canactivatethehalogenatingreagents(methodB),Xcouldbeplacedclosetothechiralenvir-onmentofthenucleophilicpromoterintheactivespecies,andthehalogenatedproductswouldbeobtainedwithhighenantioselectiv-ity.However,nosuccessfulmethodsforenantioselectivehalocycliza-tionsofpolyprenoidsinducedbynucleophilicpromotershavebeenreported,althoughtherehavebeenseveralexamplesofhalocycliza-tionsusingchiralaminepromoterswithquitelowenantioselectiv-ity15–18.Therefore,weinitiallyinvestigatednucleophilicpromoters

fortheactivationofhalogenatingreagents.First,weexaminedtheactivitiesofvariousachiralnucleophilesthatpromotedthehalocyclizationof4-(homogeranyl)toluene(1)withN-iodosuccinimide(NIS)orN-bromosuccinimide(NBS).Thereac-tionwascatalyticallyconductedwithoneequivalentofNISorNBSinthepresenceof30mol.%ofnucleophilicpromoterindichloro-methane(CH2Cl2)(Table1).Thereactiongavethedesiredtrans-

fusedAB-ringproducts2,togetherwithendo-andexo-isomeric

A-ringproducts3(2:35,7:3inallcases).cis-A-ringproductsandcis-fusedAB-ringproductswerenotobtained.Fortunately,treatmentofamixtureof2and3withchlorosulphonicacid(ClSO3H)in

2-nitropropane(i-PrNO2)gave2asasingletrans-diastereomer5.Therefore,theyieldof2wasevaluatedaftersubsequentdiastereo-selectivecyclizationwithClSO3H.Asaresult,tributylphosphine

(PBu3),triphenylphosphine(PPh3),tris(p-methoxyphenyl)pho-

sphine(P[C6H4(p-OMe)]3),andtriphenylphosphite[P(OPh)3]

showedgoodcatalyticactivities(entries124inTable1).Inparticular,theuseofhighlynucleophilictributylphosphinegavethebestresults(99%forNISand81%forNBS,entry1).Whenthereactionwasconductedintoluene,thecatalyticactivityoftriphenylphosphineunexpectedlydecreased(entry3).NISandNBSshowedcomparablereactivityinthepresentreaction.Incontrast,unexpectedly,nucleo-philicaminessuchas1,4-diazabicyclo[2.2.2]octane(DABCO)and4-(N,N-dimethylamino)pyridine(DMAP)werecompletelyinert(entries5and6).Thus,nucleophilicphosphoruscompoundscata-lysedtheelectrophiliciodination/brominationoftheterminalolefinof1,andthisefficientlyinduceddiastereoselectivecyclizationtogivethehalogenatedtricyclicproduct2asasinglediastereomer.Encouragedbytheseresults,wenextinvestigatedtheenantio-selectiveiodocyclizationof1withNISusingchiralnucleophilicpro-moters(Table2).Commerciallyavailablechiralphosphoramidite13

1GraduateSchoolofEngineering,NagoyaUniversity,Furo-cho,Chikusa,Nagoya464-8603,Japan.

N – XOONu*LA*method B N– X – Nu*OON – X δ+OO

LA* δ–

method A

*Nu – X

NOO

Nu*NH

O+

Figure1|NucleophilicpromotersversusLewisacidpromotersfortheactivationofN-halosuccinimides,andhalocyclizationof4-(homogeranyl)toluene(1)to2.LA*representsachiralLewisacidpromoter;Nu*representsachiralnucleophilicpromoter;Xrepresentsanactivatedhalogenatom.Inthenucleophilicpromoterapproach,XisexpectedtobeplacedclosetothechiralenvironmentofNu*intheactivespecies,whileXwouldbeplacedfarfromthechiralenvironmentofLA*intheLewisacidapproach.