A sphingolipid message promotes neuronal health across generations

Maternal nutrition can affect brain function of offspring in later life(Fitzgerald et al.,2020).Emerging studies have also shown that the maternal environment can modify susceptibility to neurodegenerative disease(Boots et al.,2023).Transmission of environmental information from mother to offspring depends on maternal nutrient provisioning.In the nematode Caenorhabditis elegans,maternal yolk,which is synthesized in the intestine and transferred to nourish oocytes and early embryos,can provide extranuclear inheritance factors to mediate phenotypic plasticity across generations.However,the molecular mechanisms of regulating such intergenerational effects remain largely unknown.

AβPP^(Lon/Swe)转基因小鼠记忆缺陷逆转与甲醛水平降低相关

β淀粉样蛋白(Aβ)沉积形成斑块是阿尔茨海默病(AD)的病理标志之一.以β淀粉样前体蛋白(AβPP)为基础的转基因小鼠模型表现出斑块形成加速和记忆损伤.然而,在一些模型中,记忆丧失与斑块形成的相关性较差.我们实验室最近报道了AD患者和动物模型的认知障碍与其体内甲醛水平有很强的相关性.本研究发现,AβPP^(Lon/Swe)转基因小鼠3月龄时表现出记忆缺陷,而在6月龄时记忆正常,其工作记忆与甲醛水平变化相反.与对照组相比,3月龄小鼠记忆受损伴随着甲醛水平的增高和过度磷酸化tau的增加.腹腔注射甲醛清除剂白藜芦醇可通过降低甲醛水平和tau蛋白的过度磷酸化,挽回小鼠的记忆损伤.6月龄AβPP^(Lon/Swe)小鼠甲醛水平和工作记忆与对照组相似,伴随甲醛降解酶ALDH2和ADH3表达增加.结果显示,在AβPP^(Lon/Swe)转基因小鼠中,大脑甲醛水平与记忆变化进程显著相关,且记忆的恢复与甲醛水平下降相关.该研究为揭示阿尔茨海默病机制研究提供了新视角.

Amnion epithelial cells——a novel therapy for ischemic stroke?

Stroke is a leading cause of death and disability and new therapies are desperately needed. Given the complex nature of ischemic brain injury, it has been postulated that cell-based therapies may be useful. However, cell resources, invasive extraction procedures, immunological rejection, tumorigenesis and ethical challenges make it unlikely that many stem cell types could serve as a practical source for therapy. By contrast, these issues do not pertain to human amnion epithelial cells（h AECs）, which are placenta-derived stem cells. We recently assessed the effects of systemically delivered hAECs on stroke outcome using four animal models of stroke. We demonstrated that when injected intravenously after ischemia onset, hAECs migrate preferentially to the spleen and injured brain to limit apoptosis and inflammation, and attenuate early brain infiltration of immune cells, progression of infarction and systemic immunosuppression and to ultimately ameliorate functional deficits. When administration of hAECs is delayed by 1-3 days poststroke, long-term functional recovery can still be enhanced in young and aged mice of either sex. Moreover, our proof-of-principle findings suggest that h AECs are effective at limiting post-stroke infarct development in non-human primates. Overall, the results suggest that hAECs could be a viable clinical stroke therapy.

多黏菌素临床研究进展

1前言目前耐多药革兰阴性菌所致感染的治疗手段越来越少,新抗菌药物的紧缺导致多黏菌素类抗生素（多黏菌素E和多黏菌素B）越来越受到重视。多黏菌素类抗生素于20世纪50年代获准上市,当时药物研发的审查标准较简单,可用于指导其临床使用的信息很少。近年来,随着多黏菌素临床前研究和临床药理学研究的进展.

Rac GTPases:domain-specific functions in neuronal development

Understanding fundamental mechanisms governing axon outgrowth and guidance can inform the development of therapeutic strategies to restore neuronal function damaged though injury or disease. Axons navigate the extracellular environment by responding to guidance cues that bind to cell surface receptors to relay information intracellularly via Rho GTPase family members, including the Rac GTPases.

Cell-specific mineralocorticoid receptors:future therapeutic targets for stroke?

The mineralocorticoid receptor（MR）,well known to be expressed in renal epithelial cells where it is important in fluid and electrolyte homeostasis,has aldosterone as one of its main agonists.Much research in the last 10–15 years indicates that MRs are also expressed outside of the kidney,including in the brain,vasculature and heart,where they contribute to the pathophysiology of disease（Dinh et al.,2012;]aisser and Farman, 2016）.

Bridging the gap:axonal fusion drives rapid functional recovery of the nervous system

Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair.This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients.Compared to humans,a number of species possess far greater regenerative capabilities,and can therefore provide important insights into how our own nervous systems can be repaired.In particular,several invertebrate species have been shown to rapidly initiate regeneration post-injury,allowing separated axon segments to re-join.This process,known as axonal fusion,represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure.Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons.Moreover,we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion,and discovered that the level of axonal fusion can be enhanced by promoting a neuron＇s intrinsic growth potential.A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

Ghrelin is the metabolic link connecting calorie restriction to neuroprotection

Parkinson’s disease（PD）is the second most common neurodegenerative disease whereby the number of diagnosed patients rises by 3–4%each year creating an ever-expanding social,medical and financial burden.Symptoms such as rigidity,postural instability and bradykinesia are due to diminished levels of dopamine within the brain.

Thirteen years to get from b to a:one of the neglected isoforms of IL-37 enters the stage

Interleukin(IL)-37 is one of the few anti-inflammatory members of the predominantly pro-inflammatory IL-1 cytokine family.IL-37 possesses alarmin-like properties[1]and exerts its activities via intracellular[2]as well as cell surface receptor-dependent mechanisms,and the latter involves IL-1R8 and IL-18Rα[3].Because of its powerful and broad-spectrum“peacemaking”[4]functions,considerable efforts have been invested in developing IL-37-based anti-inflammatory therapeutics[5,6].

Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B,endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society

Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.

P450-mediated dehydrotyrosine formation during WS9326 biosynthesis proceeds via dehydrogenation of a specific acylated dipeptide substrate

WS9326A is a peptide antibiotic containing a highly unusual N-methyl-E-2-3-dehydrotyrosine(NMet-Dht)residue that is incorporated during peptide assembly on a non-ribosomal peptide synthetase(NRPS).The cytochrome P450 encoded by sas16(P450Sas)has been shown to be essential for the formation of the alkene moiety in NMet-Dht,but the timing and mechanism of the P450Sas-mediatedα,β-dehydrogenation of Dht remained unclear.Here,we show that the substrate of P450Sas is the NRPS-associated peptidyl carrier protein(PCP)-bound dipeptide intermediate(Z)-2-pent-1′-enyl-cinnamoyl-Thr-N-Me-Tyr.We demonstrate that P450Sas-mediated incorporation of the double bond follows N-methylation of the Tyr by the N-methyl transferase domain found within the NRPS,and further that P450Sas appears to be specific for substrates containing the(Z)-2-pent-1’-enyl-cinnamoyl group.A crystal structure of P450Sas reveals differences between P450Sas and other P450s involved in the modification of NRPS-associated substrates,including the substitution of the canonical active site alcohol residue with a phenylalanine(F250),which in turn is critical to P450Sas activity and WS9326A biosynthesis.Together,our results suggest that P450Sas catalyses the direct dehydrogenation of the NRPS-bound dipeptide substrate,thus expanding the repertoire of P450 enzymes that can be used to produce biologically active peptides.

CIS controls the functional polarization of GM-CSF-derived macrophages

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.

Corrigendum to“Absence of Serpinb6a causes progressive hair cell apoptosis and hearing loss in mice”[Journal of Genetics and Genomics(2023)50,122-125]

This corrigendum clarifies information in the article"Absence of Serpinb6a causes progressive hair cell apoptosis and hearing loss in mice"by Cheng et al.(2023).In the author list,the author"Cheng Cheng"should be corrected into"Cheng Cheng".

Absence of Serpinb6a causes progressive hair cell apoptosis and hearing loss in mice

Hearing impairment constitutes a global public health problem with severe social,political,and economic consequences,and the World Health Organization estimates that about 466 million individuals globally have some degree of hearing loss.Genetic factors account for about half of all deafness cases.Currently,more than 100 genes are known to be involved in hearing loss,but the underlying molecular mechanisms behind these deafness genes have not been fully characterized.The main clinical treatment for deafness is hearing aids and cochlear implants,but their efficacy depends heavily on the quantity and quality of residual hair cells(HCs)and spiral ganglion neurons and has only limited auditory effects.

中国多黏菌素类抗菌药物临床合理应用多学科专家共识

多黏菌素类抗菌药物问世于20世纪50年代末,后来因同样有效但更安全的新药不断问世而逐渐淡出临床。到了20世纪80年代,随着多重耐药革兰阴性菌的增多,此类药物重新受到重视而重返临床。但由于其上市时间早,至今仍有许多问题给临床造成困惑。因此,由中国医药教育协会感染疾病专业委员会牵头,联合多学科相关领域著名专家与权威学术组织共同编写本共识,全文以问答的方式展示,分为11个部分,37个问题,10条推荐意见,希望为临床医生合理应用多黏菌素类药物提供切实可行的参考。

Procleave: Predicting Protease-specific Substrate Cleavage Sites by Combining Sequence and Structural Information

Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins.Protease-controlled proteolysis plays a key role in the degradation and recycling of proteins,which is essential for various physiological processes.Thus,solving the substrate identification problem will have important implications for the precise understanding of functions and physiological roles of proteases,as well as for therapeutic target identification and pharmaceutical applicability.Consequently,there is a great demand for bioinformatics methods that can predict novel substrate cleavage events with high accuracy by utilizing both sequence and structural information.In this study,we present Procleave,a novel bioinformatics approach for predicting protease-specific substrates and specific cleavage sites by taking into account both their sequence and 3D structural information.Structural features of known cleavage sites were represented by discrete values using a LOWESS data-smoothing optimization method,which turned out to be critical for the performance of Procleave.The optimal approximations of all structural parameter values were encoded in a conditional random field(CRF)computational framework,alongside sequence and chemical group-based features.Here,we demonstrate the outstanding performance of Procleave through extensive benchmarking and independent tests.Procleave is capable of correctly identifying most cleavage sites in the case study.Importantly,when applied to the human structural proteome encompassing 17,628 protein structures,Procleave suggests a number of potential novel target substrates and their corresponding cleavage sites of different proteases.Procleave is implemented as a webserver and is freely accessible at http://procleave.erc.monash.edu/.

Graphene quantum dots rescue protein dysregulation of pancreatic β-cells exposed to human islet amyloid polypeptide

The amyloid aggregation of peptides and proteins is a hallmark of neurological disorders and type 2 diabetes.Human islet amyloid polypeptide(IAPP),co-secreted with insulin by pancreaticβ-cells,plays dual roles in both glycemic control and the pathology of type 2 diabetes.While IAPP can activate the NLRP3 inflammasome and modulate cellular autophagy,apoptosis and extracellular matrix metabolism,no data is available concerning intracellular protein expression upon exposure to the polypeptide.More surprisingly,how intracellular protein expression is modulated by nanoparticle inhibitors of protein aggregation remains entirely unknown.In this study,we first examined the changing proteomes ofβTC6,a pancreaticβ-cell line,upon exposure to monomeric,oligomeric and fibrillar IAPP,and detailed cellular protein expression rescued by graphene quantum dots(GQDs),an IAPP inhibitor.We found that 29 proteins were significantly dysregulated by the IAPP species,while majority of these proteins were nucleotide-binding proteins.Collectively,our liquid chromatography tandem-mass spectrometry,fluorescence quenching,helium ion microscopy,cytotoxicity and discreet molecular dynamics simulations data revealed a remarkable capacity of GQDs in regulating aberrant protein expression through H-bonding and hydrophobic interactions,pointing to nanomedicine as a new frontier against human amyloid diseases.

Pooled Plasmid Sequencing Reveals the Relationship Between Mobile Genetic Elements and Antimicrobial Resistance Genes in Clinically Isolated Klebsiella pneumoniae

Plasmids remain important microbial components mediating the horizontal gene transfer(HGT)and dissemination of antimicrobial resistance.To systematically explore the relationship between mobile genetic elements(MGEs)and antimicrobial resistance genes(ARGs),a novel strategy using single-molecule real-time(SMRT)sequencing was developed.This approach was applied to pooled conjugative plasmids from clinically isolated multidrug-resistant(MDR)Klebsiella pneumoniae from a tertiary referral hospital over a 9-month period.The conjugative plasmid pool was obtained from transconjugants that acquired antimicrobial resistance after plasmid conjugation with 53 clinical isolates.The plasmid pool was then subjected to SMRT sequencing,and 82 assembled plasmid fragments were obtained.In total,124 ARGs(responsible for resistance to b-lactam,fluoroquinolone,and aminoglycoside,among others)and 317 MGEs[including transposons(Tns),insertion sequences(ISs),and integrons]were derived from these fragments.Most of these ARGs were linked to MGEs,allowing for the establishment of a relationship network between MGEs and/or ARGs that can be used to describe the dissemination of resistance by mobile elements.Key elements involved in resistance transposition were identified,including IS26,Tn3,IS903 B,ISEcp1,and ISKpn19.As the most predominant IS in the network,a typical IS26-mediated multi-copy composite transposition event was illustrated by tracing its flanking 8-bp target site duplications(TSDs).The landscape of the pooled plasmid sequences highlights the diversity and complexity of the relationship between MGEs and ARGs,underpinning the clinical value of dominant HGT profiles.

Bystanders or real players:virtual memory T cells keep chronic infections in check

Jin et al.demonstrate that a recently defined T-cell population,known as virtual memory T cells,accumulate with human immunodeficiency virus(HIV),are inversely correlated with latent viral load and may be uniquely well suited to eliminate latently infected cells during chronic infections.Infection with HIV presents many challenges to the immune system,but viral reservoirs are one of the most intractable.Treatment of HIV has been revolutionized by antiretroviral therapy(ART),which effectively ablates viral replication in patients.Unfortunately,a real cure remains elusive,as HIV will persist in latently infected cells.The identification of immune mechanisms that can reduce this latent reservoir may improve treatment and progress cure strategies for HIV.In this issue,Jin et al.demonstrate that the activity of an unconventional immune cell,the virtual memory T(TVM)cell,may play a role.

SAHA attenuates Takotsubo-like myocardial injury by targeting an epigenetic Ac/Dc axis

Dear Editor,Takotsubo syndrome(TS)is a stress-induced non-ischaemic cardiomyopathy that is more common in women,but is associated with higher morbidity and mortality in males.Also known as broken-heart syndrome,TS is characterised by transient left ventricular(LV)dysfunction independent of obstructive coronary artery disease.TS is a polygenic condition and nowhere is this more evident than the use of positive inotropes,such as isoprenaline(ISO)in pre-clinical models.1 There is no standard therapy for broken-heart syndrome because the mechanisms underlying the condition remain unknown.Furthermore,there is no consensus on predisposition for Takotsubo2 and our goal was to better understand the regulatory mechanism as a first step towards improved treatment plans.Suberanilohydroxamic acid or SAHA,a drug approved for cancer treatment by the US Food and Drug Administration has previously been shown to improve cardiopulmonary function.3 We tested the hypothesis that the cardioprotective benefit of SAHA in a pre-clinical model of Takotsubo is conferred by an epigenetic acetylation/deacetylation(Ac/Dc)axis.