I N F E C T I O U S D I S E A S E
TarO-specific inhibitors of wall teichoic acid biosynthesis restore b-lactam efficacy against methicillin-resistant staphylococci
Sang Ho Lee,1*Hao Wang,1*Marc Labroli,2Sandra Koseoglu,1Paul Zuck,2Todd Mayhood,1 Charles Gill,1Paul Mann,1Xinwei Sher,3Sookhee Ha,1Shu-Wei Yang,1Mihir Mandal,1 Christine Yang,1Lianzhu Liang,1Zheng Tan,1Paul Tawa,1Yan Hou,1Reshma Kuvelkar,1 Kristine DeVito,1Xiujuan Wen,1Jing Xiao,1Michelle Batchlett,2Carl J.Balibar,1Jenny Liu,1 Jianying Xiao,1Nicholas Murgolo,1Charles G.Garlisi,1Payal R.Sheth,1Amy Flattery,1Jing Su,1?Christopher Tan,1?Terry Roemer1?
The widespread emergence of methicillin-resistant Staphylococcus aureus(MRSA)has dramatically eroded the efficacy of current b-lactam antibiotics and created an urgent need for new treatment options.We report an S.aureus phe-notypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis.This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with b-lactams.We demonstrated by genetic and biochemical means that each of the new chemical series discovered,herein named tarocin A and tarocin B,inhibited the first step in wall teichoic acid biosynthesis(TarO).Tarocins do not have intrinsic bioactivity but rather demonstrated potent bac-tericidal synergy in combination with broad-spectrum b-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA.Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal b-lactam combination agents active against methicillin-resistant staphylococci.
INTRODUCTION
Methicillin-resistant Staphylococcus aureus(MRSA)and methicillin-resistant S.epidermidis(MRSE)are a major cause of bloodstream in-
fections in hospitals and in the community(1–4).Indeed,MRSA has
recently been reported as the second leading cause of mortality by drug-resistant bacterial pathogens in the United States(www.cdc.
gov/drugresistance/biggest_threats.html).Consequently,we have
witnessed a dramatic erosion in the therapeutic efficacy of ostensibly
the entire class of b-lactam antibiotics,which include penicillins such as methicillin,cephalosporins,and the more powerful carbapenems
(for example,imipenem,ertapenem,and meropenem)(5–8).Com-
bating antibacterial drug resistance highlights a need to broaden our focus from exclusively adopting a single-agent antibiotic therapeutic
strategy to one more aligned with combination agents(9–11),as suc-
cessfully used with emerging therapies for hepatitis C virus as well as historically emphasized by cancer treatment strategies(12,13).Indeed,
such a combination agent strategy of pairing b-lactamase inhibitors with b-lactams has proven highly successful in restoring b-lactam efficacy against Gram-negative bacteria that have aquired diverse b-lactamase enzymes that otherwise inactivate this class of antibiotic(14).Clinically
relevant b-lactam resistance in MRSA and MRSE,however,is not pri-
marily mediated by b-lactamases.Instead,it is achieved by a horizon-tally acquired alternative penicillin-binding protein,Pbp2a,with reduced affinity for all classes of b-lactams,thus buffering bacteria from the bactericidal effect of b-lactams that normally inhibit endogenous and essential Pbps(15–19).A rational b-lactam combination agent strategy applied to methicillin-resistant staphylococci therefore requires the identification of new targets and pathways that normally buffer the drug-resistant pathogen against the effects of b-lactams(either directly or indirectly)and that,if inactivated by genetic or small-molecule inhi-bition,result in a restored susceptibility to this important class of anti-biotics(9,11,20–22).
Recently,a series of reports has shown that inactivation or alteration of wall teichoic acid biosynthesis renders MRSA highly susceptible to b-lactam antibiotics both in vitro and in a murine infection setting
(9,23–27).Wall teichoic acid is a Gram-positive–specific anionic glycophosphate polymer comprising nearly50%of the dry weight of the S.aureus cell wall that is cross-linked to the peptidoglycan and plays a critical role in cell growth,division,morphology,and in vivo virulence(24,28–30).The wall teichoic acid biosynthetic pathway is uniquely categorized into two phenotypically distinct groups:the non-essential wall teichoic acid early-stage genes tarO,tarA,and mnaA,and the conditionally essential wall teichoic acid late-stage genes tarB,tarD, tarF,tarI,tarJ,tarL,tarG,and tarH,which are responsible for wall tei-choic acid synthesis and eventual transport to the extracellular environment(see fig.S1A)(27–29,31–36).Although staphylococci lacking wall teichoic acid polymers are viable under laboratory growth conditions,inactivation of late-stage wall teichoic acid biosynthetic steps results in a growth inhibitory bacteriostatic effect(24,27,32,34,37).The essentiality of the late-stage genes can be suppressed by concomitant in-activation of one of the nonessential wall teichoic acid early-stage genes; this has been referred to as an essential gene paradox(31,32,34,35,38). We and others have exploited this phenomenon to develop phenotypic screens and to identify late-stage wall teichoic acid inhibitors whose an-tibacterial activity recapitulates the conditional essentiality of late-stage wall teichoic acid genes(27,37).Specifically,such compounds are expected to inhibit wild-type S.aureus growth,but their bioactivity is
1Merck Research Laboratories,Kenilworth,NJ07033,USA.2Merck Research Laboratories, West Point,PA19486,USA.3Merck Research Laboratories,Boston,MA02115,USA.
*These authors contributed equally to this work.
?Corresponding author.E-mail:jing.su2@https://www.doczj.com/doc/4414993724.html,(J.S.);christopher_tan@merck. com(C.T.);terry_roemer@https://www.doczj.com/doc/4414993724.html,(T.R.) on March 18, 2016 https://www.doczj.com/doc/4414993724.html,/ Downloaded from
specifically suppressed,provided that an early nonessential step in wall teichoic acid biosynthesis is also inactivated(Fig.1A).In this way, multiple classes of late-stage wall teichoic acid inhibitors have been identified,including targocil and L-638,which both inhibit polymer biogenesis by targeting the wall teichoic acid integral membrane trans-porter subunit,TarG(27,37,39,40).
Here,we leveraged the wall teichoic acid essential gene paradox to identify new wall teichoic acid inhibitors of early nonessential steps that
Cell death Cell survival
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Whole-cell assays:
? L638 dose titration
? β-lactam potentiation
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A B D C
Fig.1.Phenotypic whole-cell screen to identify wall teichoic acid inhibitors.(A)Sche-
matic representation of targeted phenotypic screening strategy.Pharmacological inhibition
of TarG leads to cell killing,which can be suppressed by concomitant inhibition of wall tei-
choic acid early step proteins.This led to the identification of inhibitors of the early steps of
the wall teichoic acid(WTA)biosynthetic pathway.(B)Dose-response suppression of MRSA COL killing by the TarG inhibitor L-638alone(black square)or with supplementation with increasing concentrations of tunicamycin(Tuni;0.016to 0.25m g/ml).(C)Specificity of L-638suppression when supplemented with various antibiotic classes as designated on the bottom;subinhibitory concentrations(0.25×minimum inhibitory concentration)of the antibiotics were used in combination with L-638.(D)A flow chart guideline established to triage potential hits. on March 18, 2016 https://www.doczj.com/doc/4414993724.html,/ Downloaded from
can suppress the inhibitory bioactivity of the wall teichoic acid late-stage TarG inhibitor L-638.We provide mechanistic characterization of two
inhibitor classes named,tarocin A and tarocin B,and demonstrate that they block TarO,the enzyme responsible for the first step in wall teichoic acid biosynthesis.Finally,we show that tarocins demonstrate robust
in vitro bactericidal chemical synergy with multiple b-lactams against a variety of methicillin-resistant clinical staphylococci isolates as well as efficacy in a murine infection model of MRSA.
RESULTS
Chemical suppression screen for early-stage wall teichoic acid inhibitors
Recent studies have shown that genetic or pharmacological inactivation
of early steps in wall teichoic acid biosynthesis renders MRSA highly susceptible to b-lactam antibiotics(9,23–27).To independently corrob-orate these conclusions,we evaluated the phenotypic consequences of genetically inactivating wall teichoic acid early-stage genes tarO and
tarA in MRSA strain COL(fig.S1A).As expected,genetic null muta-tions in tarO or tarA completely abrogate wall teichoic acid polymer production(fig.S1B,left panel).Similarly,this phenotype is faithfully
reproduced pharmacologically in a concentration-dependent manner using sublethal concentrations of tunicamycin,a known natural pro-duct inhibitor of TarO(24,41)(fig.S1B,right panel).Consistent with previous reports,genetic or pharmacological inactivation of TarO in MRSA COL restored in vitro susceptibility to diverse b-lactams (24,25,27)(fig.S1C).Extending this evaluation using a previously published murine deep-thigh infection model of MRSA(11,42),an MRSA COL D tarO::emtA null mutant demonstrated an attenuated vir-ulence reflecting~1.5log10lower bacterial burden compared to the wild-type MRSA COL parent(fig.S1D),supporting the requirement of wall teichoic acid for virulence during infection.Additionally,mice infected with the D tarO::emtA mutant and treated with a subefficacious dose of imipenem(10mg/kg)showed>3log10reduction in bacterial burden compared to the isogenic MRSA parent strain(fig.S1D).Col-lectively,these results corroborate previous studies demonstrating that tarO(and presumably other early nonessential steps in wall teichoic acid biosynthesis)serves as an attractive b-lactam potentiation target.
To identify inhibitors to any of the early steps in the wall teichoic acid biosynthetic pathway,we designed a phenotypic screen that ex-ploits the conditional essentiality of late-stage wall teichoic acid genes (Fig.1A)and uses the previously described TarG inhibitor L-638(27). L-638(and other TarG inhibitors)is bacteriostatic(27,37),implying that cells treated with this compound could resume growth(that is, the effects of L-638would be suppressed)specifically in the presence of a second compound that selectively inhibits one of the early non-essential steps in wall teichoic acid biosynthesis,such as TarO,TarA, or MnaA.Such a chemical suppression of L-638bioactivity recapitulates the essential gene paradox and mirrors the demonstrated conditional essentiality of late-stage wall teichoic acid genes(32,38).Further,the readout of this phenotypic whole-cell target-selective screen is restored cell growth(Fig.1A).
To demonstrate the screening approach,MRSA COL growth was inhibited at a2×minimal inhibitory concentration(2m g/ml)of L-638and concomitantly supplemented with tunicamycin at increasing drug concentrations that resulted in a correspondingly greater depletion of wall teichoic acid(fig.S1B).Indeed,a striking dose-dependent sup-pression of the growth inhibitory effect of L-638was observed at tuni-camycin concentrations of0.125to0.25m g/ml,which completely abolished wall teichoic acid synthesis(Fig.1B).The suppression of
L-638bioactivity was also highly specific to tunicamycin and its cognate target TarO because known antibiotics that target other biological pro-cesses,such as PC190723(cell division),vancomycin(peptidoglycan synthesis),tetracycline(protein synthesis),and ciprofloxacin(DNA synthesis),do not suppress L-638(Fig.1C).Adapting this chemical sup-pression screen to a1536-well format(see Materials and Methods),we performed a single-point ultrahigh-throughput screen(uHTS)against
the complete corporate synthetic chemical library to identify com-pounds(screened at20m M)that specifically suppress L-638activity against MRSA COL.
Identification of TarO inhibitors
Our chemical suppression screen resulted in an extremely low(<0.16%)
hit rate from a collection of2.8million synthetic small molecules.A se-
ries of additional wall teichoic acid pathway-specific secondary screens performed in MRSA COL was required to identify authentic early-stage
wall teichoic acid inhibitors(Fig.1D).Hit compounds were prioritized
for follow-up studies provided that they(i)demonstrated a dose-dependent suppression of inhibitor L-638,(ii)conferred resistance to
cell lysis mediated by the staphylococcal-specific lytic bacteriophage
?K that utilizes wall teichoic acid as its receptor for bacteriophage entry
into the cell(43),and(iii)were synergistic in combination with imipe-
nem below its clinical breakpoint(4m g/ml).Two synthetic compounds structurally distinct from each other as well as the positive control tu-nicamycin met all pathway-specific criteria,herein designated as an ox-azolidinone series(named tarocin A)and a benzimidazole series (named tarocin B)(Table1).Both series reflected chemical classes of existing therapeutically efficacious drugs(including antimicrobial)in clinical use(44,45).Whereas tunicamycin demonstrated potent whole-cell wall teichoic acid pathway-specific inhibitory effects in these assays at≤0.1m M,tarocin A and B were notably less active(3to26m M)
in each of the above assays.Neither tarocin A nor tarocin B demonstrated
any intrinsic growth inhibitory activity against MRSA COL or other bacterial or fungal pathogens tested(minimum inhibitory concentra-tion,>200m M),whereas tunicamycin exhibited broad antimicrobial activity(Table1).Further,tarocins lacked cytotoxicity against HeLa cells [inhibitory concentration(IC50),>100m M]versus tunicamycin(IC50,
0.2m M)(Table1).As an analog of uridine diphosphate–N-acetylglucosamine (UDP-GluNAc),tunicamycin is a highly cytotoxic and promiscuous in-hibitor of many bacterial glucosyltransferases involved in not only wall teichoic acid biosynthesis(TarO)(24)but also peptidoglycan biosynthesis (MraY)(24)as well as N-linked glycosylation in yeast(Alg7)(46)and in human(DPAGT1)(47,48).Therefore,whereas tunicamycin’s cyto-toxicity precluded it as a viable chemical starting point to consider as a
b-lactam potentiation agent,tarocins provided an attractive alternative therapeutic candidate because they lacked cytotoxicity and intrinsic bio-activity as a single agent.
Confirmation of genetic TarO target engagement
To directly demonstrate that tarocin A and B inhibited wall teichoic acid production,MRSA COL was incubated in the presence of each agent,
and wall teichoic acid polymers were extracted and visualized on an Al-
cian blue/silver–stained polyacrylamide gel electrophoresis(PAGE) gel.Tarocin A and B depleted the wall teichoic acid polymer,mirroring
the wall teichoic acid depletion effects of tunicamycin-treated cells
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(Fig.2A).In addition,a highly potent tarocin A derivative (tarocin A1;see fig.S2for structure and microbiological data)displayed complete depletion of the wall teichoic acid polymer with similar potency to tu-nicamycin (Fig.2A).
Forward genetics –based drug resistance and mutation mapping re-mains the most powerful means of linking an antibiotic to its cognate target (11,27,37,49).However,tarocin A or B lacked intrinsic antibac-terial activity as a single therapeutic agent.Therefore,to identify their wall teichoic acid pathway target by genetic means,we exploited their synergistic activity in combination with the b -lactam antibiotic,imipe-nem,to select for MRSA COL mutants that were refractory to the ta-rocin A –imipenem chemical synergy (Fig.2B,middle panel).Provided such mutants yielded a target-based drug resistance mechanism,they were also expected to reverse the antagonism between tarocin A and L-638observed in wild-type treated cells (Fig.2B,lower panel).In ad-dition,such mutants were expected to be resistant to the wall teichoic acid depletion effects of tarocin A (Fig.2C).On the basis of these crite-ria,multiple (n =22)independently derived target-based resistant mu-tants were isolated and subjected to whole-genome sequencing (Fig.3A).Indeed,all predicted target-based drug-resistant mutants contained a single nonsynonymous mutation mapping to tarO (Fig.3A).Because no additional nonsynonymous mutations were identified in any of these resistant isolates,we concluded that the tarO mutations were causal for the resistance to the tarocin A –imipenem synergy.Similarly,tarocin B –imipemen drug resistance selections and follow-up studies also re-vealed TarO to be the drug target,establishing it as a second structurally
Table 1.Microbiological whole-cell profiles of leading wall teichoic acid inhibitors identified in the uHTS.Shown on top are the chemical structures of oxazolidinone series (tarocin A),benzimidazole series (tarocin B),and natural product tunicamycin.Minimum inhibitory concentrations were determined by the broth microdilution method in accordance with the recommendations of CLSI in 96-well plates and were assayed visually.TarG inhibitor suppression represents effective concentration of wall teichoic acid inhibitor required to suppress L-638(4m g/ml).Phage K resistance represents effective concentra-tion of wall teichoic acid inhibitor required to prevent Phage K –induced lysis.Imipenem potentiation represents effective concentration of wall teichoic acid inhibitor required to synergize imipenem below the clinical susceptibility breakpoint (4m g/ml).HeLa cell cytotoxicity represents concentrations at which 50%of the cell count is reduced within 24hours of treatment.All concentra-tions are in micromolar,unless otherwise denoted as microgram per milliliter.NA,no activity;ND,not determined;EC 50,median effective concentration;SIC,synergistic inhibitory concentration;MSSA,methicillin-susceptible S.aureus
.
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distinct inhibitor to this enzyme (Fig.3A).Unexpectedly,although ta-rocin A and B are structurally unrelated to one another,multiple tarO drug-resistant mutations selected against each series were also cross-resistant to the other series (Fig.3B),implying that both tarocin A and B shared a common mechanism of action in inhibiting TarO.Con-versely,none of the tarO tarocin-resistant (tarocin R )mutations were cross-resistant with tunicamycin (Fig.3B),indicating that the mecha-nism of TarO inhibition by tarocin A and B is distinct from that of tunicamycin,which is believed to act as a competitive inhibitor of UDP-GlcNAc and bind to the catalytic active site of TarO (47,50).
To independently demonstrate that tarocin A and B directly and specifically inhibited TarO,in vitro biochemical assays to monitor the enzymatic activity of TarO,TarA,and MnaA were established,and tar-ocin inhibition studies were performed (fig.S2).Both tarocin A and B
effectively inhibited TarO enzymatic activity,demonstrating IC 50of 0.2and 0.4m M,respectively (Fig.3C).Consistent with the improved whole-cell potency of tarocin A1,its inhibitory activity against TarO in this cell-free assay was sevenfold lower (IC 50,0.03m M)than that of tarocin A,achieving an in vitro potency similar to that of tunicamycin (IC 50,0.01m M)(Fig.2B).In contrast,tarocin A,A1,and B did not inhibit TarA or MnaA in vitro at the highest (200m M)concentration tested (fig.S2),demon-strating their highly selective inhibitory activity toward TarO within the wall teichoic acid biosynthetic pathway.
TarO resistance mapping by three-dimensional protein modeling
To further investigate the potential mechanism of inhibition of TarO by tarocin A and B,we generated a three-dimensional (3D)protein model
D M S O
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Fig.2.Confirmation of wall teichoic acid pathway engagement and isolation of tarocin-resistant mutants.(A )Depletion of wall teichoic acid polymer from inhibitor-treated MRSA COL strain was visualized on an Alcian blue/silver –stained PAGE gel (27).Inhibitors were serially titrated twofold,and the highest tested concentration is designated in parentheses:tunicamycin (0.5m g/ml),tarocin A (8m g/ml),tarocin B (8m g/ml),and tarocin A1(0.5m g/ml).DMSO,dimethyl sulfoxide.(B )Phenotypic characterization of tarocin A –resistant mutants.Tenfold serial dilutions of wild-type (WT)MRSA COL or isogenic TarO mutants (G225V or F236I)were spotted on agar plates containing no drug (top panel),tarocin A (20m g/ml)in combination with imipenem (4m g/ml)(middle panel),and tarocin A (20m g/ml)in combination with L-638(4m g/ml)(lower panel).(C )Depletion of wall teichoic acid polymer of MRSA COL or isogenic TarO mutants (G225V or F236I)treated with DMSO alone or with tarocin A (10or 20m g/ml).
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No drugβ-Lactam only
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Fig.3.Genetic and biochemical analyses of TarO target engage-
ment.(A)Heat map of22tarocin-resistant MRSA COL mutants and
corresponding mutations that conferred resistance to tarocin inhibitors.
The corresponding nonsynonymous single-nucleotide polymorphisms
and amino acid substitutions are shown(top).(B)Cross-resistance study
of tarocin A and B–resistant mutants.Tenfold serial dilutions of WT
MRSA COL or isogenic mutants containing nonsynonymous mutations
in tarO were spotted onto agar plates containing DMSO,imipenem(4m g/ml)
alone,tarocin A(20m g/ml)in combination with imipenem(4m g/ml),
tarocin B(20m g/ml)in combination with imipenem(4m g/ml),or tunicamycin
(2m g/ml)in combination with imipenem(4m g/ml).(C)TarO biochemical
assay measuring inhibition of wall teichoic acid lipid III(C55-P-P-GluNAc)
production after treatment with tunicamycin or tarocin A,A1,or B.IC50is
the average of two independent experiments.
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of the TarO structure using the recent x-ray crystal structure of the Aquifex aeolicus MraY (51)protein as template.Our ratio-nale for selecting MraY to model the TarO protein structure was based on the signif-icant structural and functional similarities of the two plasma membrane glycosyltrans-ferases.They share (i)a similar number of transmembrane (TM)domains (fig.S3;10TM domains for MraY and 11TM do-mains for TarO),(ii)a conserved pre-dicted membrane topology (extracellular N-terminal domain/cytoplasmic C-terminal domain)(51),(iii)conserved Mg 2+ion (D87and D88)and UDP-GlcNAc (H269,L270,H271,and H272)substrate binding sites (fig.S4),and (iv)a common lipid carrier (bactoprenol)cosubstrate that each enzyme requires in their glycosyltransferase reaction to contribute to peptidoglycan and wall tei-choic acid polymer synthesis,respectively.Mapping TarO mutations that conferred resistance to tarocin A,A1,and B into the protein structural model of TarO re-vealed that all mutations resided within TM5,TM8,TM9,and TM11of the protein (Fig.4A).These mutations clustered around an extracellularly exposed hydro-phobic pocket formed by the affected transmembrane helices (Fig.4B)with suf-ficient spacing (~500?3)between the helices for either tarocin A or B to pre-sumably bind through multiple hydro-phobic interactions (Fig.4C).MraY crystal structure data predicted that this hydrophobic pocket likely serves as the bactoprenol binding site of the enzyme (51)(fig.S5).Tarocin A and B are pre-dicted to inhibit TarO interactions with the bactoprenol cosubstrate.In contrast,tunicamycin has been proposed to com-pete with UDP-GlucNAc binding to the cytosol-exposed catalytic site of TarO (Fig.4A).Consistent with these proposed mechanistic differences between TarO inhibitor classes,none of the tarO muta-tions conferring resistance to tarocin A and B were mapped to the proposed TarO catalytic site of the enzyme,and none of these mutations conferred cross-resistance to tunicamycin (Fig.3B),consistent with tarocins and tunicamycin having distinct mechanisms of action.
Tarocin A and B:Therapeutic proof-of-concept studies
To evaluate the b -lactam potentiation and spectrum that TarO inhibitors
exhibited
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Fig.4.3D TarO protein modeling to elucidate mechanism of inhibition.(A )TarO protein predicted topology with amino acid residues that confer resistance to wall teichoic acid inhibitors are highlighted (tarocin A,blue;tarocin B,brown;tarocin A1,red).Putative UDP-GlcNAc substrate binding site (black)and Mg 2+binding site (light blue)are designated.(B )Side and top views of predicted TarO 3D protein modeling based on homology to MraY crystal structure (51).Residues that confer resistance to specific inhibitors are highlighted (tarocin A,blue;tarocin B,brown;tarocin A1,red).(C )Side and top views of predicted tarocin B (yellow)binding to surface-exposed hydrophobic sites composed of TM5,TM8,TM9,and TM11.
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Fig.5.Tarocin A and B restore b -lactam susceptibility to clinical MRSA
and MRSE isolates.(A )Synergistic antibiotic susceptibility checkerboard analyses of tunicamycin and tarocin A and B in combination with imipenem against MRSA clinical isolates (left panel)and MRSE clinical isolates (right panel).The FIC of each antibiotic combination pair is plotted,and synergy is achieved with a combination of the two agents fully inhibiting growth with individual FIC values yielding a sum FIC index <0.5(indicated by diagonal dashed line);an FIC index ≥0.5indicates additive or no synergistic activity.(B )b -Lactam susceptibility coverage of expanded clinical panel of MRSA iso-lates (n =17)with tarocin A1combined with either imipenem or dicloxacillin (DCX)and the corresponding median minimum inhibitory concentration (MIC)indicated by a black line.Percent change (top)represents percentage of isolates that were susceptible to b -lactams.*P <0.0001,two-tailed un-paired t test.(C )Susceptibility coverage of tarocin A2in combination with dicloxacillin against an expanded panel (n =174)of MRSA (n =108)and MRSE (n =66)clinical isolates.The y axis represents percent of b -lactam –resistant strains with minimum inhibitory concentration of dicloxacillin (>8m g/ml;CLSI clinical breakpoint),and the x axis includes the median b -lactam minimum inhibitory concentration of dicloxacillin alone or in combination with tarocin A2.The percent change represents the percent of formerly dicloxacillin-resistant strains that are now susceptible to the tarocin A2–dicloxacillin combination.
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against MRSA and MRSE,we initially examined the in vitro activity of tarocin A or B in combination with imipenem against a modest panel of MRSA and MRSE clinical isolates by standard checkerboard analyses.Both tarocin A and B showed potent synergy with imipenem against MRSA and MRSE clinical isolates similar to what was observed for tunicamycin [frac-tional inhibitory concentration (FIC)index <0.5](Fig.5A).We expanded the spectrum study to include dicloxacillin (a Gram-positive –specific penicillin class b -lactam)against a broader panel of methicillin-resistant staphylococcal clinical isolates (see table S1for antibiogram).These highly drug-resistant staphylococcal isolates had median MRSA minimum inhibitory concentrations of 64m g/ml for imipenem and 256m g/ml for dicloxacillin.Addition of tarocin A1at a fixed concentration (16m g/ml)to each of the b -lactams resulted in substantially reduced median b -lactam minimum inhibitory concentrations of 1and 5m g/ml (Fig.5B),respectively,representing >50-fold reductions from their single b -lactam minimum inhibitory concentration values.The observed potentiation resulting in the increased susceptibility of MRSA to b -lactams was achieved by re-storing the bactericidal mode of action of the parent b -lactams (fig.S6).In addition,combining tarocin A1with either b -lactam resulted in a restored b -lactam clinical susceptibility profile as determined by the Clinical and Laboratory Standards Institute (CLSI)standard (<4m g/ml for imipenem and <8m g/ml for dicloxacillin)for 75%of the clinical MRSA isolates tested (Fig.5B).On the basis of these results,an extensive evaluation of the efficacious coverage possible for a TarO inhibitor/b -lactam combination in restoring MRSA and MRSE susceptibility was performed against 174clinical isolates with median dicloxacillin minimum inhibitory concentrations of 512and 256m g/ml (Fig.5C),https://www.doczj.com/doc/4414993724.html,bining dicloxacillin with tarocin A2,a second analog with improved
solubility (fig.S2,structure and biological data),restored susceptibility to dicloxacillin in 82%of MRSA clinical isolates and in 77%of MRSE clinical isolates (Fig.5C).Further,an acceptable frequency of spontane-ous resistance (FOR)was observed in MRSA COL,ranging from 3.2×10?7to 1.6×10?8,using 2×to 8×SIC of tarocin A2in combination with a fixed concentration of imipenem (4m g/ml)or dicloxacillin (8m g/ml)after 24hours of treatment (fig.S7).Finally,the addition of L-638at 2×minimum inhibitory concentration (4m g/ml)as a third component un-der otherwise identical conditions considerably reduced target-mediated spontaneous resistance to tarocin A2in combination with dicloxacillin with an FOR value of <3.9×10?9(fig.S7;see Discussion).Collectively,these data provide strong in vitro evidence that a b -lactam potentiation strategy based on inhibition of wall teichoic acid biosynthesis is effica-cious and largely unaffected by spontaneous resistance or the substantial heterogeneity observed among clinical isolates of MRSA and MRSE.On the basis of in vitro data that tarocin A2is broadly synergistic in combination with dicloxacillin against diverse clinically relevant methicillin-resistant staphylococci and displays an equivalent pharmacokinetic half-life of 1.8hours compared to its partner antibiotic (52)(tables S3and S4),we evaluated the efficacy of this combination when coadministered to a murine systemic infection model of MRSA (42).At all doses studied,neither dicloxacillin (125mg/kg)nor tarocin A2(12.5,25,or 50mg/kg)administered as a single agent provided any efficacious benefit in treating an MRSA COL infection (Fig.6)compared with vehicle treatment.Con-versely,coadministering tarocin A2and dicloxacillin at concentrations otherwise nonefficacious when administered singly provided a signifi-cant dose-dependent reduction in MRSA bacterial burden after 24hours of combination therapy [Fig.6;P <0.05,one-way analysis of variance
(ANOVA)].This reduction of up to 2.5log 10colony-forming units (CFU)(P <0.05,one-way ANOVA)paralleled that of the control antibiotic linezolid (Fig.6;P <0.05,one-way ANOVA).Further,no evidence of mortality or morbidity was observed among mice in any of the tarocin
A2single treatment or b -lactam combina-tion cohorts,consistent with the low in vitro cytotoxicity observed for tarocins and proven safety of b -lactam antibiotics.In addition,no tarocin A2–dicloxacillin –resistant mutants were identified among the CFU recovered from the in vivo study.Collectively,these data provide strong ev-idence supporting the hypothesis that tar-ocins (or other early-stage wall teichoic acid inhibitors)may provide an important new strategy to develop Gram-positive bac-tericidal b -lactam combination agents that are active against methicillin-resistant staphylococci.DISCUSSION
We report the discovery and characteriza-tion of two structurally distinct chemical series,the tarocins.Tarocins effectively and specifically abolish staphylococcal
L o g C F U /g k i d n e y
V e h i c l e
D i c l o x a c i l l i n 125 m g /k g
L i n e z o l i d 10 m g /k g
Tarocin A2 alone
(mg/kg)
Tarocin A2
+ dicloxacillin 125
(mg/kg)
Fig.6.The tarocin A2–dicloxacillin combination demonstrates in vivo efficacy.Murine systemic in vivo efficacy study (42)of the tarocin A2–dicloxacillin combination against MRSA COL (dicloxacillin alone;minimum inhibitory concentration,256m g/ml).Treatment was initiated 2hours after infection [three times a day (2,5,and 8hours after challenge)]by subcutaneous injection.Bacterial burden was enumerated 24hours after infection and compared among five groups:vehicle alone,tarocin A2alone,dicloxacillin alone,tarocin A2and dicloxacillin coadministration,and linezolid alone.*P <0.05,one-way ANOVA compared to the dicloxacillin-alone group.**P <0.05,one-way ANOVA compared to the vehicle-alone group.
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怎样在《Science》杂志上发表文章 佚名 一、《Science》杂志概况 美国的《Science》杂志为国际上著名的自然科学综合类学术期刊，在世界学术界享有盛誉，反映其被引文量的影响因子始终高居《SCI》收录的5700种科学期刊的前十位。据2001年最新统计，《Science》杂志年发表论文数901篇，被引用次数282431，影响因子为23.329，排名所有科学期刊的第8位。由于其独特的学术地位，国内许多科研院所为鼓励学术人员在该刊发表文章，都制定了优厚的奖励措施。 《Science》杂志创刊于1880年，目前在全球拥有16.5万个订户，超过《N ature》杂志三倍。《Science》杂志具有新闻杂志和学术期刊的双重特点，每周除向世界各地发布有关科学技术和科技政策的重要新闻外，还发表全球科技研究最显著突破的研究论文和报告。 《Science》杂志发表的论文涉及所有科学学科，特别是物理学、生命科学、化学、材料科学和医学中最重要的、最激动人心的研究进展。据统计，发表的论文中60%有关生命科学，40%是属于物理科学领域的（见附录1）。每年《Scien ce》杂志还出版大约15期专辑，展示某一专门领域的最新成果，例如生物技术、寄生虫学、纳米技术、计算机技术等。除高水平的论文外，每期专辑还发表有关科技职业的专题文章和以不同国家、地区为对象的专栏。 除了为发表全世界最好的科学论文和报道全球最好的科学新闻而努力外，《S cience》杂志还有三个特别重要的目标： ?将《Science》杂志和科学带入更多的发展中国家的科学工作者的家中和实验室里； ?帮助世界各地青年科技工作者更多地了解今后十年最重要的科技发展趋势、最新的科学仪器和技术以及科技职业的选择； ?用电子手段传播科技信息，进一步提高信息质量，并且通过与发展中国家和发达国家的团体合作利用计算机互联网传送杂志，降低发行成本。 1995年，《Science》杂志与时俱进，实现了上网，即科学在线《Science Online》,提供《Science》杂志全文、摘要和检索服务。特别要注意的是：网络版是印刷版的补充，而不是替代。网络版上许多内容是免费的，如今日科学（S cience Now）报道每日科学新闻；科学后浪（Science Next Wave）给未来科学家提供职业信息；科学事业（Science Careers）提供就职机会、会议和研究活
【原创】回答美国《科学》杂志提出的125个重大科学前沿问题（2） 文/简浩 据2018年01月12日07:44新浪科技载，北京时间1月12日消息，据国外媒体报道，目前，《科学》杂志提出125个重大问题，其中涉及到宇宙形成、地球演化、生命兴起和人类生理谜团等。以下分别回答125个其中的10个科学前沿问题： 30、是什么给类星体提供动力？答： 宇宙高速自转运动的中心，会不断积累热能，久而久之，形成宇宙大爆炸，本质就是“超能核聚变”。聚变出新一轮的质子、中子、电子、离子等轻物质，又会形成一轮又一轮的年轻的“类星体”，在宇宙空间自转运动的螺旋辐射动能推动下，仍然继续向外圆螺旋扩张。 所有星系的前半生，都曾经是“极端天体”中的“类星体”，银河系也不例外。 类星体看似星系，又不完全像是普通星系，看似恒星，又不完全像是普通恒星，所以被称作“类星体”。 新形成的类星体距宇宙中心最近，公转度最快，物质分子就会产生剧烈震荡，因此，类星体就像滚雪球一样，“公转特快、自转特慢、占空特小、密度特大、热能特大、亮度特大”，释放的能量却是普通星系的数千倍以上，亮度是正常星系的千倍以上。 类星体边公转、边螺旋、边扩张、边膨胀，前一轮扩张到外圆轨道的类星体公转运动开始减速，类星体内的空间开始伸展、密度变小、能量变小、亮度变小、占空变大，后来逐渐演变为正常星系。 宇宙中所有星系（包括类星体）的公转速度和自转速度，都有一个共同而普遍的规律，也是宇宙的基本规律：距离宇宙中心（重力源）越近的星体，位能会越小，自转速度则越慢，而动能会越大，公转速度则越快。反之，距离宇宙中心（重力源）越远的星体，位能会越大，自转速度则越快，而动能会越小，公转速度则越慢。 这就是类星体为什么会高速公转运动，能给类星体自身带来巨大动能的原因。 31、黑洞的本质是什么？答： 黑洞里面是中子或夸克。黑洞是实体天体，不是虚拟物质。所有星系中心都有黑洞存在，黑洞是“统领星系”的实体“极端天体”。 黑洞的特征：“质量特大、引力特大、磁场超强、密度超大、能量超大、热能超大、自转太快、体积太小”，就是光线也逃不脱黑洞的引力。 黑洞的运行机制：“边高速自转、边疯狂吞噬、边高温高压、边高能聚变，边增加自重、边超能喷射”。黑洞吞噬的天体物质，只有少数与黑洞是同类的物质被黑洞吸收，大多数非同类物质不能被黑洞吸收，都要从黑洞的两极喷射出去。因此，黑洞能使自身星系的总体质量逐渐增加，能使恒星、行星等天体物质也逐渐增加。 黑洞的本质：进行天体物质的“循环回炉”、“脱胎换骨”、“物质洗牌”，黑洞的本质就是一座强大的“高能核聚变工厂”。喷射散发的质子、中子、电子、离子，大多数又形成了新恒星，银河系外围边缘的年轻恒星就是这样的来历。 黑洞喷射的高能粒子：基本都是新生恒星的“原料”氢元素物质，而产生的重元素物质微乎其微，只能形成极少量的星际尘埃。 被黑洞吞噬的已经衰老的天体物质，经过黑洞“秘密”的聚变“深加工”，喷射出来的高能粒子，从此获得“重新做人”的机会，焕然一新，成为年轻的新粒子、新质子。 黑洞带着星系的公转运动，由于公转速度高，一般最低速度也有600km/s，这样一来，黑洞就会像“弯道超车”一样，黑洞就会发生倾斜。 黑洞倾斜的规律：距离宇宙中心越近的星系，黑洞倾斜度则越小，反之，距离宇宙中心越远的星系，黑洞的倾斜度则越大。
◎=◎“电气科学与工程”学科领域的国内外著名刊物◎=◎： ◆国际著名刊物： 1、IEEE TRANSACTIONS ON ENERGY CONVERSION 美国(各种能量转换理论,装置及控制领域等) 2、IEEE TRANSACTIONS ON POWER SYSTEMS 美国(电力系统领域) 3、IEEE TRANSACTIONS ON POWER ELECTRONICS 美国(电力电子器件,电路与系统等) 4、IEEE TRANSACTIONS ON DIELECTRICS AND ELECTRICAL INSULATION 美国(电解质与绝缘,高电压领域) 5、IEEE TRANSACTIONS ON MAGNETICS 美国(信息电磁场与波，强电的电机电磁装置与控制领域) 6、IEEE TRANSACTIONS ON POWER DELIVERY 美国(电力发配电等，电力系统领域) ◆相关的几大牛刊： 1、PROCEEDINGS OF THE IEEE 美国(含盖电气,计算机科学等领域, “电气与电子领域综合类”) 2、IEEE TRANSACTIONS ON INDUSTRY APPLICATIONS 美国(含盖面宽,电气,控制系统,工业电子等, 属于“电气、电子应用综合类”) 3、IEEE TRANSACTIONS ON INDUSTRIAL ELECTRONICS 美国(工业应用电子科学与技术, 检测与转换等) 4、IEEE TRANSACTIONS ON PLASMA SCIENCE 美国(等离子体科学，偏理科） ◆国内权威刊物： 1*.《中国电机工程学报》，领域：电气工程、能源动力工程等。 2*.《电工技术学报》，领域：电工技术领域。 3*.《电力系统自动化》，领域：电气工程学科的电力系统自动化领域。 4.《电机与控制学报》，领域：电气工程学科的电机、电力电子、电气传动。 5.《电网技术》，领域：电气工程学科的电力系统及其自动化。 6.《继电器》，领域：电气工程学科的电力系统及其自动化。 7.《电力自动化设备》，领域：电气工程学科的电力系统及其自动化装备。
《Science》 一、《Science》杂志概况 美国的《Science》杂志为国际上著名的自然科学综合类学术期刊，在世界学术界享有盛誉，反映其被引文量的影响因子始终高居《SCI》收录的5700种科学期刊的前十位。据2001年最新统计，《Science》杂志年发表论文数901篇，被引用次数282431，影响因子为23.329，排名所有科学期刊的第8位。由于其独特的学术地位，国内许多科研院所为鼓励学术人员在该刊发表文章，都制定了优厚的奖励措施。 《Science》杂志创刊于1880年，目前在全球拥有16.5万个订户，超过《N ature》杂志三倍。《Science》杂志具有新闻杂志和学术期刊的双重特点，每周除向世界各地发布有关科学技术和科技政策的重要新闻外，还发表全球科技研究最显著突破的研究论文和报告。 《Science》杂志发表的论文涉及所有科学学科，特别是物理学、生命科学、化学、材料科学和医学中最重要的、最激动人心的研究进展。据统计，发表的论文中60%有关生命科学，40%是属于物理科学领域的（见附录1）。每年《Scien ce》杂志还出版大约15期专辑，展示某一专门领域的最新成果，例如生物技术、寄生虫学、纳米技术、计算机技术等。除高水平的论文外，每期专辑还发表有关科技职业的专题文章和以不同国家、地区为对象的专栏。 除了为发表全世界最好的科学论文和报道全球最好的科学新闻而努力外，《S cience》杂志还有三个特别重要的目标： ?将《Science》杂志和科学带入更多的发展中国家的科学工作者的家中和实验室里； ?帮助世界各地青年科技工作者更多地了解今后十年最重要的科技发展趋势、最新的科学仪器和技术以及科技职业的选择； ?用电子手段传播科技信息，进一步提高信息质量，并且通过与发展中国家和发达国家的团体合作利用计算机互联网传送杂志，降低发行成本。 1995年，《Science》杂志与时俱进，实现了上网，即科学在线《Science Online》,提供《Science》杂志全文、摘要和检索服务。特别要注意的是：网络版是印刷版的补充，而不是替代。网络版上许多内容是免费的，如今日科学（S cience Now）报道每日科学新闻；科学后浪（Science Next Wave）给未来科学家提供职业信息；科学事业（Science Careers）提供就职机会、会议和研究活
怎样在《Science》杂志上发表文章 一、《Science》杂志概况 美国的《Science》杂志为国际上著名的自然科学综合类学术期刊，在世界学术界享有盛誉，反映其被引文量的影响因子始终高居《SCI》收录的5700种科学期刊的前十位。据2001年最新统计，《Science》杂志年发表论文数901篇，被引用次数282431，影响因子为23.329，排名所有科学期刊的第8位。由于其独特的学术地位，国内许多科研院所为鼓励学术人员在该刊发表文章，都制定了优厚的奖励措施。 《Science》杂志创刊于1880年，目前在全球拥有16.5万个订户，超过《N ature》杂志三倍。《Science》杂志具有新闻杂志和学术期刊的双重特点，每周除向世界各地发布有关科学技术和科技政策的重要新闻外，还发表全球科技研究最显著突破的研究论文和报告。 《Science》杂志发表的论文涉及所有科学学科，特别是物理学、生命科学、化学、材料科学和医学中最重要的、最激动人心的研究进展。据统计，发表的论文中60%有关生命科学，40%是属于物理科学领域的（见附录1）。每年《Scien ce》杂志还出版大约15期专辑，展示某一专门领域的最新成果，例如生物技术、寄生虫学、纳米技术、计算机技术等。除高水平的论文外，每期专辑还发表有关科技职业的专题文章和以不同国家、地区为对象的专栏。 除了为发表全世界最好的科学论文和报道全球最好的科学新闻而努力外，《S cience》杂志还有三个特别重要的目标： ?将《Science》杂志和科学带入更多的发展中国家的科学工作者的家中和实验室里； ?帮助世界各地青年科技工作者更多地了解今后十年最重要的科技发展趋势、最新的科学仪器和技术以及科技职业的选择； ?用电子手段传播科技信息，进一步提高信息质量，并且通过与发展中国家和发达国家的团体合作利用计算机互联网传送杂志，降低发行成本。 1995年，《Science》杂志与时俱进，实现了上网，即科学在线《Science Online》,提供《Science》杂志全文、摘要和检索服务。特别要注意的是：网络版是印刷版的补充，而不是替代。网络版上许多内容是免费的，如今日科学（S cience Now）报道每日科学新闻；科学后浪（Science Next Wave）给未来科学家提供职业信息；科学事业（Science Careers）提供就职机会、会议和研究活
极具权威性的美国科学杂志《今日心理学》 阅读答案 极具权威性的美国科学杂志《今日心理学》近日刊登了一篇惊人的文章，文章指出，原先人们认为海产品对大脑最有益，多吃海产品可以提高人的智力，但美国科学家最新研究的结果却大大出乎人们的预料。研究发现，森林中的野果比如红莓苔子、黑莓果等对大脑的益处远远超过海产品，排在第一位；占据第二位的是蔬菜，其次才是鱼等海产品。 研究人员发现，红莓苔子之所以排在排在第一位，是因为其中含有大量能与自由氧离子发生相互作用的抗氧化剂。抗氧化剂的存在几乎破坏了对血管和心脏有极大破坏性的胆醇激素。黑莓果里面含有的抗氧化剂要相对少一些，但含有对视力和听力非常有益的成分。大叶子的红甜菜和圆白菜含有一种能把发展成帕金森氏综合症的酶破坏掉的物质。菠菜能够延缓神经系统的衰老，还可以防止认知能力出现问题。相比之下，鱼的作用就小多了，只有鲑鳟鱼、金枪鱼、沙丁鱼和鲱鱼含有能分解有害酶的脂肪酸，此外，这些鱼中还有大量大脑所需要的磷。 俄罗斯医学科学院食品研究的教授波波夫也持这样的观点。他认为，野果不仅对大脑有益，对心脏也有好处。他们的研究发现，许多含有大量维生素C和蔗糖的蔬菜，对大脑的活动也特别有益。 但几乎所有的专家都认为，如果认为只吃了上述食品你就变得聪明了，那就大错特错了。这样的食品结构会引起营
养的失衡，食品应该是多种多样的。 还有一种观点认为巧克力可以提高智力。的确，巧克力中含有一些对大脑有益的物质。研究发现每天吃50克巧克力可以延缓机体的衰老，但这里所指的是黑色的苦巧克力。哪些非常甜的、含有奶制品的巧克力含有大量糖，过多食用这样的巧克力会产生许多不良问题，如糖尿病、肥胖症等。 食品专家指出，在日常饮食中，最重要的是保持一个良好习惯，每餐不能吃得太饱。饱满的午餐会降低大脑的活动能力，出现所谓的“食困”现象，但紧张的工作与低能量的饮食也是不相容的。因此，最合理的方法是多吃一些蔬菜、豆制品和液体，但不是啤酒和浓茶。 科学研究还发现，其实大脑最好的营养成分是葡萄糖，大脑细胞需要大量的葡萄糖。葡萄糖通常存在于谷物、土豆和豆角中，桃子、香蕉和梨中也含有丰富的葡萄糖。 研究人员指出，食品本身并不能提高智力。含有维生素B的食品，比如肉、鱼、花生等，可以帮助促进大脑思维的过程，消除疲劳。早晨吃上一个橙子可以一整天精神饱满。如果你不能利用这些食品恢复体质，还可以用合成维生素补充。但是要想开发智力，最好的方法是不断学习、读好书，与有文化有知识的人交流。 8．下列对美国科学家最新研究的结果表述正确的一项是（） A．蔬菜之所以排在鱼等海产品之前，是因为蔬菜比鱼等海产品含有更多的营养。
极具权威性的美国科学杂志《今日心理学》阅读答案 ：巧克力极具权威性的美国科学杂志《今日心理学》近日刊登了一篇惊人的文章，文章指出，原先人们认为海产品对大脑最有益，多吃海产品可以提高人的智力，但美国科学家最新研究的结果却大大出乎人们的预料。研究发现，森林中的野果比如红莓苔子、黑莓果等对大脑的益处远远超过海产品，排在第一位；占据第二位的是蔬菜，其次才是鱼等海产品。 研究人员发现，红莓苔子之所以排在排在第一位，是因为其中含有大量能与自由氧离子发生相互作用的抗氧化剂。抗氧化剂的存在几乎破坏了对血管和心脏有极大破坏性的胆醇激素。黑莓果里面含有的抗氧化剂要相对少一些，但含有对视力和听力非常有益的成分。大叶子的红甜菜和圆白菜含有一种能把发展成帕金森氏综合症的酶破坏掉的物质。菠菜能够延缓神经系统的衰老，还可以防止认知能力出现问题。相比之下，鱼的作用就小多了，只有鲑鳟鱼、金枪鱼、沙丁鱼和鲱鱼含有能分解有害酶的脂肪酸，此外，这些鱼中还有大量大脑所需要的磷。 俄罗斯医学科学院食品研究的教授波波夫也持这样的观点。他认为，野果不仅对大脑有益，对心脏也有好处。他们的研究发现，许多含有大量维生素C和蔗糖的蔬菜，对大脑的活动也特别有益。 但几乎所有的专家都认为，如果认为只吃了上述食品你就变得聪明了，那就大错特错了。这样的食品结构会引起营养的失衡，食品应该是多种多样的。 还有一种观点认为巧克力可以提高智力。的确，巧克力中含有一些对大脑有益的物质。研究发现每天吃50克巧克力可以延缓机体的衰老，但这里所指的是黑色的苦巧克力。哪些非常甜的、含有奶制品的巧克力含有大量糖，过多食用这样的巧克力会产生许多不良问题，如糖尿病、肥胖症等。 食品专家指出，在日常饮食中，最重要的是保持一个良好习惯，每餐不能吃得太饱。饱满的午餐会降低大脑的活动能力，出现所谓的”食困”现象，但紧张的工作与低能量的饮食也是不相容的。因此，最合理的方法是多吃一些蔬菜、豆制品和液体，但不是啤酒和浓茶。 科学研究还发现，其实大脑最好的营养成分是葡萄糖，大脑细胞需要大量的葡萄糖。葡萄糖通常存在于谷物、土豆和豆角中，桃子、香蕉和梨中也含有丰富的葡萄糖。
怎样在《科学》杂志上发表文章 (这是非正式译文，最近更新是在2001年5月，不一定包括编辑部最新的要求。请以英文原文为准。) 《科学》是一个周刊，是发表最好的原始研究论文、以及综述和分析当前研究和科学政策的同行评议的期刊。我们在美国首都华盛顿和英国剑桥的编辑部欢迎任何领域和任何地方的投稿。争取在《科学》发表文章的竞争很激烈，许多投稿在没有得到进一步的同行评议之前就被退回。我们对在有广泛兴趣的领域中有创新的文章优先。我们对投来的稿件坚定地履行快速评审、快速发表的原则。 下面介绍一下： 署名文章的栏目 稿件的选择 接受稿件的条件 文章的署名 曾经发表的文章 与《科学》联系 稿件的准备 在线的补充数据 投稿 《科学》周刊参考文献格式
署名文章的栏目 报告(Reports)栏目发表新的有广泛意义的重要研究成果。报告长度不超过2500单词或《科学》版面的3页。报告要包括摘要和引言。参考文献应在30条以内。 研究文章(Research Articles)栏目发表反映某一领域的重大突破的文章，文章长度不超过4500单词或5页，包括一个摘要、一个引言、和加有简短的小标题的内容部分。参考文献建议最多不超过40条。技术评论(Technical Comments)讨论《科学》周刊过去6个月内发表的论文，长度不超过500单词。原文章作者将被给与答复评论的机会。评论和答复都要得到评议和必要的编辑。讨论的提要刊登在印刷版，全文刊登在电子版。 《科学》指南(Science's Compass)栏目为广大读者提供由科学家或其他专家撰写的对当前科学问题的评论。除了读者来信，本栏目的文章都是由编辑们约稿的，但有时对未被邀请的稿件也予以考虑。来信(Letters)一般不超过300单词，讨论《科学》上已发表的内容或普遍感兴趣的问题。来信应该直接投到我们的网站(或以电子信形式投来().编辑不通知作者是否收到来信，而且可能对来信加以修改以求明了或满足版面的限制。来信发表时，编辑一般不再征求作者的意见。政策论坛(Policy Forum)(2000单词以下)讨论科学政策，科学与社会短文(Essays on Science and Society)(2000单词)着重于科学与
科学的发展往往出乎我们的意料——美《科学》杂志主编点评本年度 十大科技突破 被列为2011年十大科技突破榜首的是HPTN052的HIV研究项目——早期口服抗逆转录病毒药物(ARVs)预防HIV感染，研究对1700多对异性伴侣中其中一位感染了人类免疫缺陷病毒(HIV)的感染者进行了实验，其中一半感染者服用了这种抗逆转录病毒药物，而另一半人则当他们的免疫系统下降到危险的程度时才给予治疗，结果发现早期治疗者伴侣受感染的比例大为降低，受感染者本身的情况也有所改善。可以相信，ARVs与之前其他效果较好的临床治疗方法相结合，可以一年前不可想象的方式阻止全世界艾滋病疫情的泛滥。“在下一代人中消除艾滋病的远大目标可有望实现，”美国国务卿希拉里·克林顿在上个月对科学家们如此说道。 这并不是说，我们要放弃寻找艾滋病疫苗，ARVs作为一种预防性治疗手段，并无法承诺在一夜之间改变艾滋病疫情蔓延的严峻形势，但它让我们看到了攻克艾滋病的希望，并在2011年十大科技进展中名列榜首。 本年度榜上有名的另外九大科技突破也令人兴奋，大多数科技领域都取得了稳步进展，这也正符合了科技进步的总趋势。目前已有迹象表明，2012年将是一个令人兴奋的科学年，欧洲粒子物理研究所的科学家有可能发现一直以来令人难以捉摸的希格斯玻色子存在的迹象，这是一种解释其他粒子如何获得质量的假想中的基本粒子，它将成为来年科学界重大突破之一，我们期待这一成果的最新报道。但是，未来科学的发展往往总是出乎我们的意料，未来一年必定会给我们带来更多令人眼花缭乱的惊喜。 但是，今年科学界的新闻并非都是喜讯，遗憾的是，我们生活在一个“否定科学”已成为一种时尚的时代，例如在美国，许多政界人物迫于种种压力，不愿意公开支持关于气候变化的科学事实。为了应对这种“否定科学”现象，正如我一直反复强调的那样，科学界需要更重视科学教育，不是简单地将所知道的知识传授给学生，同时还要将科学家推理和解决问题的能力赋予所有的学生，也许有一天，科学教育在提高学生动手能力和探索世界能力方面所取得的显著成果也将成为年度重大科技突破之一。 ——布鲁斯·艾伯茨 相关链接2011年十大科学突破 近期美国《科学》杂志公布了其评选的本年度十大重要科学突破，一项大规模艾滋病临床试验成果被列为本年度最重要的科学突破，其他九项突破涉及行星科学、考古学、生命科学、天文学和化学等。 艾滋病防治获重大进展 令人信服的一些新证据显示，口服抗逆转录病毒药物(ARVs)可有效预防异性伴侣间的艾滋病传染。
◎=◎“电气科学与工程”学科领域的国内外著名刊物◎=◎： ◆国际著名刊物： 1、IEEE TRANSACTIONS ON ENERGY CONVERSION 美国(各种能量转换理论,装置及控制领域等) 2、IEEE TRANSACTIONS ON POWER SYSTEMS 美国(电力系统领域) 3、IEEE TRANSACTIONS ON POWER ELECTRONICS 美国(电力电子器件,电路与系统等) 4、IEEE TRANSACTIONS ON DIELECTRICS AND ELECTRICAL INSULATION 美国(电解质与绝缘,高电压领域) 5、IEEE TRANSACTIONS ON MAGNETICS 美国(信息电磁场与波，强电的电机电磁装置与控制领域) 6、IEEE TRANSACTIONS ON POWER DELIVERY 美国(电力发配电等，电力系统领域) ◆相关的几大牛刊： 1、PROCEEDINGS OF THE IEEE 美国(含盖电气,计算机科学等领域, “电气与电子领域综合类”) 2、IEEE TRANSACTIONS ON INDUSTRY APPLICATIONS 美国(含盖面宽,电气,控制系统,工业电子等, 属于“电气、电子应用综合类”) 3、IEEE TRANSACTIONS ON INDUSTRIAL ELECTRONICS 美国(工业应用电子科学与技术, 检测与转换等) 4、IEEE TRANSACTIONS ON PLASMA SCIENCE 美国(等离子体科学，偏理科） ◆国内权威刊物： 1*.《中国电机工程学报》，领域：电气工程、能源动力工程等。 2*.《电工技术学报》，领域：电工技术领域。 3*.《电力系统自动化》，领域：电气工程学科的电力系统自动化领域。 4.《电机与控制学报》，领域：电气工程学科的电机、电力电子、电气传动。 5.《电网技术》，领域：电气工程学科的电力系统及其自动化。 6.《继电器》，领域：电气工程学科的电力系统及其自动化。 7.《电力自动化设备》，领域：电气工程学科的电力系统及其自动化装备。