Notch信号通路——对健康和疾病的机械论观点

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes.The Notch receptor is activated by two families of canonical ligands(Deltalike and Serrate/Jagged)where both ligands and receptors are single-pass transmembrane proteins usually with large extracellular domains,relative to their intracellular portions.Upon interaction of the core binding regions,presented on opposing cell surfaces,formation of the receptor/ligand complex initiates force-mediated proteolysis,ultimately releasing the transcriptionally-active Notch intracellular domain.This review focuses on structural features of the extracellular receptor/ligand complex,the role of posttranslational modifications in tuning this complex,the contribution of the cell membrane to ligand function,and insights from acquired and genetic diseases.

Optimizing nitrogen management can improve stem lodging resistance and stabilize the grain yield of japonica rice in rice-crayfish coculture systems

Nitrogen(N)significantly affects rice yield and lodging resistance.Previous studies have primarily investigated the impact of N management on rice lodging in conventional rice monoculture(RM);however,few studies have performed such investigations in rice-crayfish coculture(RC).We hypothesized that RC would increase rice lodging risk and that optimizing N application practices would improve rice lodging resistance without affecting food security.We conducted a two-factor(rice farming mode and N management practice)field experiment from2021 to 2022 to test our hypothesis.The rice farming modes included RM and RC,and the N management practices included no nitrogen fertilizer,conventional N application,and optimized N treatment.The rice yield and lodging resistance characteristics,such as morphology,mechanical and chemical characteristics,anatomic structure,and gene expression levels,were analyzed and compared among the treatments.Under the same N application practice,RC decreased the rice yield by 11.1-24.4% and increased the lodging index by 19.6-45.6% compared with the values yielded in RM.In RC,optimized N application decreased the plant height,panicle neck node height,center of gravity height,bending stress,and lodging index by 4.0-4.8%,5.2-7.8%,0.5-4.5%,5.5-10.5%,and 1.8-19.5%,respectively,compared with those in the conventional N application practice.Furthermore,it increased the culm diameter,culm wall thickness,breaking strength,and non-structural and structural carbohydrate content by 0.8-4.9%,2.2-53.1%,13.5-19.2%,2.2-24.7%,and 31.3-87.2%,respectively.Optimized N application increased sclerenchymal and parenchymal tissue areas of the vascular bundle at the culm wall of the base second internode.Furthermore,optimized N application upregulated genes involved in lignin and cellulose synthesis,thereby promoting lower internodes on the rice stem and enhancing lodging resistance.Optimized N application in RC significantly reduced the lodging index by 1.8-19.5%and stabilized the rice yield(>8,570 kg ha~(-1)on average).This study systematically analyzed and compared the differences in lodging characteristics between RM and RC.The findings will aid in the development of more efficient practices for RC that will reduce N fertilizer application.

An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

Antibacterial resistance is a global health threat that requires further concrete action on the part of all countries.In this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and developed.Although several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in China.In this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since 2019.Information was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other reviews.As of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and updated.Among them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in phase-1.Most of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial protein.Overall,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in China.Hopefully,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

Antibodies Targeting a Conserved Surface Polysaccharide Are Protective Against a Wide Range of Microbial Pathogens Producing β-1-6-Linked Poly-N-Acetylglucosamine(PNAG)

The b-1-6-linked poly-N-acetylglucosamine(PNAG)polymer is a conserved surface polysaccharide produced by many bacteria,fungi,and protozoan(and even filarial)parasites.This wide-ranging expression makes PNAG an attractive target for vaccine development,as it potentially encompasses a broad range of microorganisms.Significant progress has been made in discovering important properties of the biology of PNAG expression in recent years.The molecular characterization and regulation of operons for the production of PNAG biosynthetic proteins and enzymes have been studied in many bacteria.In addition,the physiological function of PNAG has been further elucidated.PNAG-based vaccines and PNAG-targeting antibodies have shown great efficacy in preclinical research.Furthermore,clinical tests for both vaccines and antibodies have been carried out in humans and economically important animals,and the results are promising.Although it is not destined to be a smooth road,we are optimistic about new vaccines and immunotherapeutics targeting PNAG becoming validated and eventually licensed for clinical use against multiple infectious agents.

Identification of potential anti-pneumonia pharmacological components of Glycyrrhizae Radix et Rhizoma after the treatment with Gan An He Ji oral liquid

Glycyrrhizae Radix et Rhizoma,a traditional Chinese medicine also known as Gan Cao(GC),is frequently included in clinical prescriptions for the treatment of pneumonia.However,the pharmacological components of GC for pneumonia treatment are rarely explored.Gan An He Ji oral liquid(GAHJ)has a simple composition and contains GC liquid extracts and paregoric,and has been used clinically for many years.Therefore,GAHJ was selected as a compound preparation for the study of GC in the treatment of pneumonia.We conducted an in vivo study of patients with pneumonia undergoing GAHJ treatments for three days.Using the intelligent mass spectrometry data-processing technologies to analyze the metabolism of GC in vivo,we obtained 168 related components of GC in humans,consisting of 24 prototype components and 144 metabolites,with 135 compounds screened in plasma and 82 in urine.After analysis of the metabolic transformation relationship and relative exposure,six components(liquiritin,liquiritigenin,glycyrrhizin,glycyrrhetinic acid,daidzin,and formononetin)were selected as potential effective components.The experimental results based on two animal pneumonia models and the inflammatory cell model showed that the mixture of these six components was effective in the treatment of pneumonia and lung injury and could effectively downregulate the level of inducible nitric oxide synthase(iNOS).Interestingly,glycyrrhetinic acid exhibited the strongest inhibition on iNOS and the highest exposure in vivo.The following molecular dynamic simulations indicated a strong bond between glycyrrhetinic acid and iNOS.Thus,the current study provides a pharmaceutical basis for GC and reveals the possible corresponding mechanisms in pneumonia treatment.

Phosphine-free synthesis of FeTe2 nanoparticles and self-assembly into tree-like nanoarchitectures

Manipulating the self-assembly of transition metal telluride nanocrystals(NCs) creates opportunities for exploring new properties and device applications. Iron ditelluride(FeTe2) has recently emerged as a new class of magnetic semiconductor with three-dimensional(3D) magnetic ordering and narrow band gap structure, yet the self-assembly of FeTe2 NCs has not been achieved. Herein, the tree-like FeTe2 nanoarchitectures with orthorhombic crystal structure have been successfully synthesized by hot-injection solvent thermal approach using phosphine-free Te precursor. The morphology, size, and crystal structure have been investigated using transmission electron microscopy(TEM), high-resolution TEM(HRTEM),and powder x-ray diffraction(XRD). We study the formation process of tree-like FeTe2 NCs according to trace the change of the sample morphology with the reaction time. It was found that the FeTe2 nanoparticles show oriented aggregation and self-assembly behavior with the increase of reaction time, which is attributed to size-dependent magnetism properties of the samples. The magnetic interaction is thought to be the driving force of nanoparticle self-organization.

A rational design of bimetallic PdAu nanoflowers as efficient catalysts for methanol oxidation reaction

Methanol fuel cells have been intensively developed as clean and high-efficiency energy conversion system due to their high efficiency and low emission of pollutants.Here,we developed a simple aqueous synthetic method to prepare bimetallic PdAu nanoflowers catalysts for methanol oxidation reaction(MOR)in alkaline environment.Their composition can be directly tuned by changing the ratio between Pd and Au precursors.Compared with commercial Pd/C catalyst,all of the PdAu nanoflowers catalysts show the enhanced catalytic activity and durability.In particular,the PdAu nanoflowers specific activity reached 0.72 mA/cm^(2),which is 14 times that of commercial Pd/C catalyst.The superior MOR activity could be attributed to the unique porous structure and the shift of the d-band center of Pd.

Practice and Study of Training Model for Professional Master Degree in Software Engineering

The culture of professional degree graduate students is a new form of postgraduate education in China. It focuses on cultivating high-level and applied talents compared with original academic degree graduate students. Considering about the source of full-time professional degree graduate students in domain of software engineering and the current college educational system, this paper makes a few beneficial explorations about curriculum, practice teaching, process management and puts forward the mode and method to improve full-time professional degree graduate education in domain of Software Engineering.

基于铬离子掺杂镓酸锌的近红外化学发光纳米探针制备及其过氧化氢传感研究

化学发光法因其灵敏度高、选择性好、响应速度快等优异性能在分析传感领域引起广泛关注.然而目前发展发光性能优异且发射波长长的新型化学发光体系仍面临严峻挑战.本文通过将具有优异反应活性和近红外光学发射信号的铬离子掺杂镓酸锌(Cr^(3+)-doped ZGC)纳米材料引入新型化学发光体的构建中,发展了基于ZGC-Fe^(2+)-H_(2)O_(2)的新型近红外化学发光体系,成功用于H_(2)O_(2)的高效传感研究.更进一步地,通过对ZGC-Fe^(2+)-H_(2)O_(2)体系的化学发光光谱及活性氧自由基清除实验研究,提出了一种可能的基于活性氧注入式的“电子-空穴复合”发光机制.得益于化学发光信号强度高且免背景信号干扰的独特优势,该ZGC-Fe^(2+)-H_(2)O_(2)近红外化学发光法在检测H_(2)O_(2)时具有宽线性范围(10-100μM),高灵敏度、检测限低至4.68μM以及优异的抗干扰性和选择性,为其他化学发光检测平台的构建提供了新思路.

Pressure effects on metal/covalent-organic frameworks:structural and optical properties

Metal-organic frameworks(MOFs)and covalent organic frameworks(COFs)with highly ordered porous structure,tunable bandgap,large specific surface area and structural diversity,provide an appealing platform for the development of stimulus response,sensing,imaging and optoelectronics.Among various tuning methods,pressure engineering using the diamond anvil cell is a highly powerful in-situ technique,which can efficiently modulate the structural and optical properties of MOFs/COFs.This is beyond the realization of traditional chemical methods.This review outlines the research progress in the experimentoriented discovery of new phases or unique properties under high pressure,including phase transition,abnormal compression,photoluminescence(PL)discoloration and enhancement.Notably,the improvement of PL quantum yield in MOFs could be achieved by pressure-treated engineering and hydrogen-bonding cooperativity effect.We also propose and establish the relationship between structure and optical properties under high pressure.Finally,the challenge and outlook of the current fields are summarized.We hope that this review will supply guidance for comprehending the development of high-pressure MOF/COF-related research fields,and offer novel strategies for designing more high-performance MOF/COF materials to ultimately expand their applications.

Safety Profile of COVID-19 Vaccines in HIV Patients Undergoing ART and Their Impact on Immune Recovery and HIV Reservoirs

Background:While some studies have reported the impact of COVID-19 vaccines on immune recovery and human immunodeficiency virus(HIV)reservoirs in persons living with HIV(PLWH),their findings remain inconsistent.Furthermore,limited data exist on the safety of multiple COVID-19 vaccines among PLWH.This study aimed to investigate the safety of heterological COVID-19 vaccine administration in PLWH receiving antiretroviral treatment(ART)and its effects on HIV reservoirs and immune recovery.Such an investigation can help provide a basis for vaccinations against COVID-19 in PLWH.Methods:In this cross-sectional study,PLWH receiving ART were recruited from the outpatient clinic of the Department of Infectious Diseases at the Fifth Medical Center of the Chinese PLA General Hospital from September 1,2021 to December 31,2021.Fifty-three PLWH receiving ART were vaccinated against COVID-19,with 35 receiving an inactivated vaccine(IN group)and 18 receiving a recombinant protein(CHO cells)vaccine(CHO group)as the third dose.We assessed the changes in liver and kidney functions,blood lipids,and other laboratory parameters at 0,1,2,4,7,8,10,and 13 months after the first vaccination dose.We also monitored CD4^(+)and CD8^(+)T cell counts using flow cytometry at 0,1,2,4,7,8,10,and 13 months after the first vaccination dose,as well as levels of cell-associated HIV DNA(CA HIV DNA)and cell-associated HIV RNA(CA HIV RNA)in peripheral blood using the corresponding quantitative detection kits at 0,2,and 8 months after the first vaccination dose.Results:No severe adverse events related to either type of COVID-19 vaccine were observed in HIV patients,irrespective of their CD4^(+)T cell levels.Both the IN and CHO groups showed significant increases in CD4^(+)T cell counts during follow-up,CD4^(+)T cells increased from 438±45 cells/μL to 557±48 cells/μL in the CHO group,while in the IN group,it increased from 448±34 cells/μL to 572±39 cells/μL(both P<0.001).CA HIV DNA initially decreased and then increased in both groups.CA HIV RNA levels showed significantly decreased in both group after three doses of vaccination(P<0.01 in CHO group and P<0.001 in IN group).CD8^(+)T cells increased from 608±77 cells/μL to 812±116 cells/μL in the CHO group(P<0.01),while in the IN group,it increased from 702±71 cells/μL to 852±68 cells/μL(P<0.001)from baseline to the 13 month of following up.Conclusion:Our data suggest that the SARS-CoV-2 booster vaccine is safe for PLWH on ART,although it may affect HIV reservoirs and CD8^(+)T cell counts.

Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes multi-organ damage,which includes hepatic dysfunction,as observed in over 50%of COVID-19 patients.Angiotensin I converting enzyme(peptidyl-dipeptidase A)2(ACE2)is the primary receptor for SARS-CoV-2 entry into host cells,and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2,but at extremely low levels.Consequently,we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells.To address this question,we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1(ASGR1)promoted SARS-CoV-2 pseudovirus infection of HeLa cells.In Huh-7 cells,simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection.In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells,both of which barely expressed ACE2,SARSCoV-2 pseudovirus could successfully establish an infection.However,after treatment with ASGR1 antibody or siRNA targeting ASGR1,the infection rate significantly dropped,suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism.We confirmed that ASGR1 could interact with Spike protein,which depends on receptor binding domain(RBD)and N-terminal domain(NTD).Finally,we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells.After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA,the infection efficiency of the live virus decreased significantly.Collectively,these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

Application of graph-curvature features in computer-aided diagnosis for histopathological image identification of gastric cancer

Background Histopathology diagnosis is often regarded as the final diagnostic method for malignant tumors;however,it has some drawbacks.This study explored a computer-aided diagnostic method that can be used to identify benign and malignant gastric cancer using histopathological images.Methods The most suitable process was selected through multiple experiments by comparing multiple meth-ods and features for classification.First,the U-net was applied to segment the image.Next,the nucleus was extracted from the segmented image,and the minimum spanning tree(MST)diagram structure that can cap-ture the topological information was drawn.The third step was to extract the graph-curvature features of the histopathological image according to the MST image.Finally,by inputting the graph-curvature features into the classifier,the recognition results for benign or malignant cancer can be obtained.Results During the experiment,we used various methods for comparison.In the image segmentation stage,U-net,watershed algorithm,and Otsu threshold segmentation methods were used.We found that the U-net method,combined with multiple indicators,was the most suitable for segmentation of histopathological images.In the feature extraction stage,in addition to extracting graph-edge and graph-curvature features,several basic im-age features were extracted,including the red,green and blue feature,gray-level co-occurrence matrix feature,histogram of oriented gradient feature,and local binary pattern feature.In the classifier design stage,we exper-imented with various methods,such as support vector machine(SVM),random forest,artificial neural network,K nearest neighbors,VGG-16,and inception-V3.Through comparison and analysis,it was found that classifica-tion results with an accuracy of 98.57%can be obtained by inputting the graph-curvature feature into the SVM classifier.

Optimizing iodine capture performance by metal-organic framework containing with bipyridine units

Radioactive iodine exhibits medical values in radiology,but its excessive emissions can cause environmental pollution.Thus,the capture of radioiodine poses significant engineering for the environment and medical radiology.The adsorptive capture of radioactive iodine by metal-organic frameworks(MOFs)has risen to prominence.In this work,a Th-based MOF(denoted as Th-BPYDC)was structurally designed and synthesized,consisting of[Th_(6)(μ_(3)-O)_(4)(μ_(3)-OH)_(4)(H_(2)O)6]^(12+)clusters,abundant bipyridine units,and large cavities that allowed guest molecules diffusion and transmission.Th-BPYDC exhibited the uptake capacities of 2.23 g·g^(-1) and 312.18 mg·g^(-1) towards I_(2) vapor and I_(2) dissolved in cyclohexane,respectively,surpassing its corresponding analogue Th-UiO-67.The bipyridine units boosted the adsorption performance,and Th-BPYDC showed good reusability with high stability.Our work thus opened a new way for the synthesis of MOFs to capture radioactive iodine.

Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae

Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Acinetobacter baumannii,and Klebsiella pneumoniae.Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing.Polymyxin S2(S2)is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin.To predict the possible resistant mechanism of S2for wide clinical application,we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms.Mut-S,a resistant mutant of K.pneumoniae ATCC BAA-2146(Kpn2146)induced by S2,was analyzed by whole genome sequencing,transcriptomics,mass spectrometry and complementation experiment.Surprisingly,large-scale genomic inversion(LSGI)of approximately 1.1 Mbp in the chromosome caused by IS26mediated intramolecular transposition was found in Mut-S,which led to mgrB truncation,lipid A modification and hence S2resistance.The resistance can be complemented by plasmid carrying intact mgrB.The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146(Mut-B and Mut-E,respectively).This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K.pneumoniae.The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Envt cells in vivo

HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications.Here,we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27(3BE)CAR construct that enabled the expression of programmed cell death protein(PD-1)-blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env.Compared with T cells expressing 3BNC117-CAR alone,3BE CAR-T cells showed greater cytotoxic activity against HIV Envt cells with stronger proliferation capability,higher killing efficiency,and enhanced cytokine secretion in the presence of HIV Env-expressing cells.Furthermore,we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env^(+) cells in vivo without the occurrence of severe graft-versus-host disease(GvHD)in NSG mice.These data suggest that we have provided a feasible approach to the generation of“off-theshelf”anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy,which can be a powerful therapeutic candidate for the functional cure of HIV.

洋底深部裂褶菌在不同环境条件的生长行为

【目的】了解洋底深部真菌适应原位环境的生长特征。【方法】在模拟洋底原位环境因子(压力除外)的培养条件(温度,pH,盐度,Fe2+,木质素和NH4+)下,比较了4株分离自洋底约2 km深处含煤沉积物的裂褶菌和2株分离自海洋及陆地生境的裂褶菌的生长速率。【结果】在本实验所设置的温度(20,30,40,45℃)、氧气(有氧和无氧)、pH(6,8,10)、盐度(淡水,原位水,人工海水)、Fe^2+(0.27,8.93,89.28μmol/L)、木质素(1,5,10 g/L)和NH4+(0.5,1.0,5.0 g/L)条件下,洋底菌株均比陆地菌株(CFCC7252)和海洋菌株(MCCC 3A00233)生长快,但不同洋底菌株之间也存在生长差异,菌株6R-2-F01和24R-3-F01在厌氧条件下的生长速率显著高于其在有氧条件下的生长速率。【结论】洋底真菌(如裂褶菌)可能拥有独特的生物学特性,以帮助其适应洋底极端环境,相关研究值得进一步探讨。

Repurposing carrimycin as an antiviral agent against human coronaviruses,including the currently pandemic SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

In vitro and in vivo activity of D-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical strains.Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.

Genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii from Beijing,China

The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 A.baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance(HLAR,MIC to gentamicin and amikacin>512 mg/mL)phenotype selection by broth microdilution method.The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes(aac(3)-Ⅰ,aac(3)-Ⅱc,aac(60)-Ⅰb,aac(60)-Ⅱ,aph(4)-Ⅰa,aph(30)-Ⅰ,aph(30)-Ⅱb,aph(30)-Ⅲa,aph(30)-Ⅵa,aph(2″)-Ⅰb,aph(2″)-Ⅰc,aph(2″)-Ⅰd,ant(2″)-Ⅰa,ant(3″)-Ⅰand ant(40)-Ⅰa)and the 16S rRNA methylase genes(armA,rmtB and rmtC).Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS.Totally 102(58.96%)HLAR isolates were selected.The HLAR rates for year 2006,2007,2008 and 2009 were 52.63%,65.22%,51.11%and 70.83%,respectively.Five modifying enzyme genes(aac(3)-Ⅰ,detection rate of 65.69%;aac(60)-Ⅰb,detection rate of 45.10%;aph(30)-Ⅰ,detection rate of 47.06%;aph(30)-Ⅱb,detection rate of 0.98%;ant(3″)-Ⅰ,detection rate of 95.10%)and one methylase gene(armA,detection rate of 98.04%)were detected in the 102 A.baumannii with aac(3)-Ⅰ+aac(60)-Ⅰ+þant(3″)-Ⅰ+armA(detection rate of 25.49%),aac(3)-Ⅰ+aph(30)-Ⅰ+ant(3″)-Ⅰ+armA(detection rate of 21.57%)and ant(3″)-Ⅰ+armA(detection rate of 12.75%)being the most prevalent gene profiles.The values of chi-square tests showed correlation of armA,ant(3″)-Ⅰ,aac(3)-Ⅰ,aph(30)-Ⅰand aac(60)-Ⅰb with HLAR.armA had significant correlation(contingency coefficient 0.685)and good contingency with HLAR(kappa 0.940).The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A.baumannii infections.As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides(gentamicin,amikacin,tobramycin,etc),the function of aminoglycoside modifying enzyme gene(s)in A.baumannii carrying armA deserves further investigation.