Pseudorabies virus gM and its homologous proteins in herpesviruses induce mitochondria-related apoptosis involved in viral pathogenicity.

Apoptosis is a critical host antiviral defense mechanism. But many viruses have evolved multiple strategies to manipulate apoptosis and escape host antiviral immune responses. Herpesvirus infection regulated apoptosis; however, the underlying molecular mechanisms have not yet been fully elucidated. Hence, the present study aimed to study the relationship between herpesvirus infection and apoptosis in vitro and in vivo using the pseudorabies virus (PRV) as the model virus. We found that mitochondria-dependent apoptosis was induced by PRV gM, a late protein encoded by PRV UL10, a virulence-related gene involved in enhancing PRV pathogenicity. Mechanistically, gM competitively combines with BCL-XL to disrupt the BCL-XL-BAK complex, resulting in BCL-2-antagonistic killer (BAK) oligomerization and BCL-2-associated X (BAX) activation, which destroys the mitochondrial membrane potential and activates caspase-3/7 to trigger apoptosis. Interestingly, similar apoptotic mechanisms were observed in other herpesviruses (Herpes Simplex Virus-1 [HSV-1], human cytomegalovirus [HCMV], Equine herpesvirus-1 [EHV-1], and varicella-zoster virus [VZV]) driven by PRV gM homologs. Compared with their parental viruses, the pathogenicity of PRV-ΔUL10 or HSV-1-ΔUL10 in mice was reduced with lower apoptosis and viral replication, illustrating that UL10 is a key virulence-related gene in PRV and HSV-1. Consistently, caspase-3 deletion also diminished the replication and pathogenicity of PRV and HSV-1 in vitro and in mice, suggesting that caspase-3-mediated apoptosis is closely related to the replication and pathogenicity of PRV and HSV-1. Overall, our findings firstly reveal the mechanism by which PRV gM and its homologs in several herpesviruses regulate apoptosis to enhance the viral replication and pathogenicity, and the relationship between gM-mediated apoptosis and herpesvirus pathogenicity suggests a promising approach for developing attenuated live vaccines and therapy for herpesvirus-related diseases.

African swine fever virus pB318L, a trans-geranylgeranyl-diphosphate synthase, negatively regulates cGAS-STING and IFNAR-JAK-STAT signaling pathways.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by the ASF virus (ASFV). ASFV has evolved multiple strategies to escape host antiviral immune responses. Here, we reported that ASFV pB318L, a trans-geranylgeranyl-diphosphate synthase, reduced the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs). Mechanically, pB318L not only interacted with STING to reduce the translocation of STING from the endoplasmic reticulum to the Golgi apparatus but also interacted with IFN receptors to reduce the interaction of IFNAR1/TYK2 and IFNAR2/JAK1. Of note, ASFV with interruption of B318L gene (ASFV-intB318L) infected PAMs produces more IFN-I and ISGs than that in PAMs infected with its parental ASFV HLJ/18 at the late stage of infection. Consistently, the pathogenicity of ASFV-intB318L is attenuated in piglets compared with its parental virus. Taken together, our data reveal that B318L gene may partially affect ASFV pathogenicity by reducing the production of IFN-I and ISGs. This study provides a clue to design antiviral agents or live attenuated vaccines to prevent and control ASF.

African swine fever virus pH240R enhances viral replication via inhibition of the type I IFN signaling pathway.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by ASF virus (ASFV) infection. At present, there are still no safe and effective drugs and vaccines to prevent ASF. Mining the important proteins encoded by ASFV that affect the virulence and replication of ASFV is the key to developing effective vaccines and drugs. In this study, ASFV pH240R, a capsid protein of ASFV, was found to inhibit the type I interferon (IFN) signaling pathway. Mechanistically, pH240R interacted with IFNAR1 and IFNAR2 to disrupt the interaction of IFNAR1-TYK2 and IFNAR2-JAK1. Additionally, pH240R inhibited the phosphorylation of IFNAR1, TYK2, and JAK1 induced by IFN-α, resulting in the suppression of the nuclear import of STAT1 and STAT2 and the expression of IFN-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induced more ISGs in porcine alveolar macrophages compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs expression. Taken together, our results clarify that pH240R enhances ASFV replication by inhibiting the JAK-STAT signaling pathway, which highlights the possibility of pH240R as a potential drug target.IMPORTANCEThe innate immune response is the host's first line of defense against pathogen infection, which has been reported to affect the replication and virulence of African swine fever virus (ASFV) isolates. Identification of ASFV-encoded proteins that affect the virulence and replication of ASFV is the key step in developing more effective vaccines and drugs. In this study, we found that pH240R interacted with IFNAR1 and IFNAR2 by disrupting the interaction of IFNAR1-TYK2 and IFNAR2-JAK1, resulting in the suppression of the expression of interferon (IFN)-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induces more ISGs' expression compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs' expression. Taken together, our findings showed that pH240R enhances ASFV replication by inhibiting the IFN-JAK-STAT axis, which highlights the possibility of pH240R as a potential drug target.

African Swine Fever Virus HLJ/18 CD2v Suppresses Type I IFN Production and IFN-Stimulated Genes Expression through Negatively Regulating cGMP-AMP Synthase-STING and IFN Signaling Pathways.

African swine fever is a fatal infectious disease caused by African swine fever virus (ASFV). The high mortality caused by this infectious disease is a significant challenge to the swine industry worldwide. ASFV virulence is related to its ability to antagonize IFN response, yet the mechanism of antagonism is not understood. Recently, a less virulent recombinant virus has emerged that has a EP402R gene deletion within the parental ASFV HLJ/18 (ASFV-ΔEP402R) strain. EP402R gene encodes CD2v. Hence we hypothesized that ASFV uses CD2v protein to evade type I IFN-mediated innate immune response. We found that ASFV-ΔEP402R infection induced higher type I IFN response and increased the expression of IFN-stimulated genes in porcine alveolar macrophages when compared with parental ASFV HLJ/18. Consistent with these results, CD2v overexpression inhibited type I IFN production and IFN-stimulated gene expression. Mechanistically, CD2v, by interacting with the transmembrane domain of stimulator of IFN genes (STING), prevented the transport of STING to the Golgi apparatus, and thereby inhibited the cGMP-AMP synthase-STING signaling pathway. Furthermore, ASFV CD2v disrupted IFNAR1-TYK2 and IFNAR2-JAK1 interactions, and thereby inhibited JAK-STAT activation by IFN-α. In vivo, specific pathogen-free pigs infected with the mutant ASFV-ΔEP402R strain survived better than animals infected with the parental ASFV HLJ/18 strain. Consistent with this finding, IFN-ß protein levels in the peripheral blood of ASFV-ΔEP402R-challenged pigs were significantly higher than in the blood of ASFV HLJ/18-challenged pigs. Taken together, our findings suggest a molecular mechanism in which CD2v inhibits cGMP-AMP synthase-STING and IFN signaling pathways to evade the innate immune response rendering ASFV infection fatal in pigs.

Pseudorabies Virus Infection Activates the TLR-NF-κB Axis and AIM2 Inflammasome To Enhance Inflammatory Responses in Mice.

Pseudorabies virus (PRV) infection activates inflammatory responses to release robust proinflammatory cytokines, which are critical for controlling viral infection and clearance of PRV. However, the innate sensors and inflammasomes involved in the production and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, we report that the transcription and expression levels of some proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α), are upregulated in primary peritoneal macrophages and in mice during PRV infection. Mechanistically, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR5 were induced by the PRV infection to enhance the transcription levels of pro-IL-1ß, pro-IL-18, and gasdermin D (GSDMD). Additionally, we found that PRV infection and transfection of its genomic DNA triggered AIM2 inflammasome activation, apoptosis-related speckle-like protein (ASC) oligomerization, and caspase-1 activation to enhance the secretion of IL-1ß and IL-18, which was mainly dependent on GSDMD, but not GSDME, in vitro and in vivo. Taken together, our findings reveal that the activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release, which resists the PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection. IMPORTANCE PRV can infect several mammals, including pigs, other livestock, rodents, and wild animals, causing huge economic losses. As an emerging and reemerging infectious disease, the emergence of PRV virulent isolates and increasing human PRV infection cases indicate that PRV is still a high risk to public health. It has been reported that PRV infection leads to robust release of proinflammatory cytokines through activating inflammatory responses. However, the innate sensor that activates IL-1ß expression and the inflammasome involved in the maturation and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, our findings reveal that, in mice, activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release during PRV infection, and it resists PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection.

African Swine Fever Virus H240R Protein Inhibits the Production of Type I Interferon through Disrupting the Oligomerization of STING.

African swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease in domestic pigs and wild boars. Domestic pigs infected with virulent African swine fever virus (ASFV) isolates have a high mortality, approaching 100%. Identification of ASFV genes related to virulence/pathogenicity and deletion of them are considered to be key steps in the development of live attenuated vaccines, because the ability of ASFV to escape host innate immune responses is related to viral pathogenicity. However, the relationship between the host antiviral innate immune responses and the pathogenic genes of ASFV has not been fully understood. In this study, the ASFV H240R protein (pH240R), a capsid protein of ASFV, was found to inhibit type I interferon (IFN) production. Mechanistically, pH240R interacted with the N-terminal transmembrane domain of stimulator of interferon genes (STING) and inhibited its oligomerization and translocation from the endoplasmic reticulum to the Golgi apparatus. Additionally, pH240R inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and TANK binding kinase 1 (TBK1), leading to reduced production of type I IFN. Consistent with these results, infection with H240R-deficient ASFV (ASFV-ΔH240R) induced more type I IFN than infection with its parental strain, ASFV HLJ/18. We also found that pH240R may enhance viral replication via inhibition of type I IFN production and the antiviral effect of interferon alpha (IFN-α). Taken together, our findings provide a new explanation for the reduction of ASFV's replication ability by knockout of the H240R gene and a clue for the development of live attenuated ASFV vaccines. IMPORTANCE African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly contagious and acute hemorrhagic viral disease with a high mortality, approaching 100% in domestic pigs. However, the relationship between viral pathogenicity and immune evasion of ASFV is not fully understood, which limits the development of safe and effective ASF vaccines, specifically, live attenuated vaccines. In this study, we found that pH240R, as a potent antagonist, inhibited type I IFN production by targeting STING and inhibiting its oligomerization and translocation from the endoplasmic reticulum to the Golgi apparatus. Furthermore, we also found that deletion of the H240R gene reduced viral pathogenicity by enhancing type I IFN production, which decreases ASFV replication. Taken together, our findings provide a clue for the development of an ASFV live attenuated vaccine via deleting the H240R gene.

In Silico Insights: QSAR Modeling of TBK1 Kinase Inhibitors for Enhanced Drug Discovery.

TBK1, or TANK-binding kinase 1, is an enzyme that functions as a serine/threonine protein kinase. It plays a crucial role in various cellular processes, including the innate immune response to viruses, cell proliferation, apoptosis, autophagy, and antitumor immunity. Dysregulation of TBK1 activity can lead to autoimmune diseases, neurodegenerative disorders, and cancer. Due to its central role in these critical pathways, TBK1 is a significant focus of research for therapeutic drug development. In this paper, we explore data from the CAS Content Collection regarding TBK1 and its implication in a large assortment of diseases and disorders. With the demand for developing efficient TBK1 inhibitors being outlined, we focus on utilizing a machine learning approach for developing predictive models for TBK1 inhibition, derived from the fragment-functional analysis descriptors. Using the extensive CAS Content Collection, we assembled a training set of TBK1 inhibitors with experimentally measured IC50 values. We explored several machine learning techniques combined with various molecular descriptors to derive and select the best TBK1 inhibitor QSAR models. Certain significant structural alerts that potentially contribute to inhibition of TBK1 are outlined and discussed. The merit of the article stems from identifying the most adequate TBK1 QSAR models and subsequent successful development of advanced positive training data to facilitate and enhance drug discovery for an important therapeutic target such as TBK1 inhibitors, based on an extensive, wide-ranging set of scientific information provided by the CAS Content Collection.

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic.

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

PEGylated Lipid Nanoparticle Formulations: Immunological Safety and Efficiency Perspective.

Lipid nanoparticles (LNPs) have been recognized as efficient vehicles to transport a large variety of therapeutics. Currently in the spotlight as important constituents of the COVID-19 mRNA vaccines, LNPs play a significant role in protecting and transporting mRNA to cells. As one of their key constituents, polyethylene glycol (PEG)-lipid conjugates are important in defining LNP physicochemical characteristics and biological activity. PEGylation has proven particularly efficient in conferring longer systemic circulation of LNPs, thus greatly improving their pharmacokinetics and efficiency. Along with revealing the benefits of PEG conjugates, studies have revealed unexpected immune reactions against PEGylated nanocarriers such as accelerated blood clearance (ABC), involving the production of anti-PEG antibodies at initial injection, which initiates accelerated blood clearance upon subsequent injections, as well as a hypersensitivity reaction referred to as complement activation-related pseudoallergy (CARPA). Further, data have been accumulated indicating consistent yet sometimes controversial correlations between various structural parameters of the PEG-lipids, the properties of the PEGylated LNPs, and the magnitude of the observed adverse effects. Detailed knowledge and comprehension of such correlations are of foremost importance in the efforts to diminish and eliminate the undesirable immune reactions and improve the safety and efficiency of the PEGylated medicines. Here, we present an overview based on analysis of data from the CAS Content Collection regarding the PEGylated LNP immunogenicity and overall safety concerns. A comprehensive summary has been compiled outlining how various structural parameters of the PEG-lipids affect the immune responses and activities of the LNPs, with regards to their efficiency in drug delivery. This Review is thus intended to serve as a helpful resource in understanding the current knowledge in the field, in an effort to further solve the remaining challenges and to achieve full potential.

The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress.

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.

Trends and Opportunities in Organic Synthesis: Global State of Research Metrics and Advances in Precision, Efficiency, and Green Chemistry.

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

Successful implantation of leadless pacemaker in a patient with giant right atrium and tricuspid valve stenosis.

With the steadily increasing amount of leadless pacemaker implantations performed worldwide, it has called attention to the delivery difficulty in patients with severe large right heart. Nevertheless, limited studies have reported leadless pacemaker implantation in patients with tricuspid stenosis. Here, we report the successful implantation of leadless pacemaker in a 60-year-old female patient with giant right atrium and tricuspid valve stenosis. It is highlighted that leadless pacemaker should not be discouraged even if there are tricuspid valve stenosis and giant right atrium.

Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury.

Autophagy plays a deleterious role in ischemic myocardial injury. The deacetylase SIRT1 is a well-established regulator of autophagy that can be modified by the ubiquitin-like protein SUMO1. Our previous work demonstrated that another ubiquitin-like protein, FAT10, exerts cardioprotective effects against myocardial ischemia by stabilizing the caveolin-3 protein; however, the effects of FAT10 on autophagy through SIRT1 are unclear. Here, we constructed a Fat10-knockout rat model to evaluate the role of FAT10 in autophagy. In vivo and in vitro assays confirmed that FAT10 suppressed autophagy to protect the heart from ischemic myocardial injury. Mechanistically, FAT10 was mainly involved in the regulation of the autophagosome formation process. FAT10 affected autophagy through modulating SIRT1 degradation, which resulted in reduced SIRT1 nuclear translocation and inhibited SIRT1 activity via its C-terminal glycine residues. Notably, FAT10 competed with SUMO1 at the K734 modification site of SIRT1, which further reduced LC3 deacetylation and suppressed autophagy. Our findings suggest that FAT10 inhibits autophagy by antagonizing SIRT1 SUMOylation to protect the heart from ischemic myocardial injury. This is a novel mechanism through which FAT10 regulates autophagy as a cardiac protector.

Bioorthogonal Chemistry and Its Applications.

Bioorthogonal chemistry is a set of methods using the chemistry of non-native functional groups to explore and understand biology in living organisms. In this review, we summarize the most common reactions used in bioorthogonal methods, their relative advantages and disadvantages, and their frequency of occurrence in the published literature. We also briefly discuss some of the less common but potentially useful methods. We then analyze the bioorthogonal-related publications in the CAS Content Collection to determine how often different types of biomolecules such as proteins, carbohydrates, glycans, and lipids have been studied using bioorthogonal chemistry. The most prevalent biological and chemical methods for attaching bioorthogonal functional groups to these biomolecules are elaborated. We also analyze the publication volume related to different types of bioorthogonal applications in the CAS Content Collection. The use of bioorthogonal chemistry for imaging, identifying, and characterizing biomolecules and for delivering drugs to treat disease is discussed at length. Bioorthogonal chemistry for the surface attachment of proteins and in the use of modified carbohydrates is briefly noted. Finally, we summarize the state of the art in bioorthogonal chemistry and its current limitations and promise for its future productive use in chemistry and biology.

Artificial Intelligence in Chemistry: Current Trends and Future Directions.

The application of artificial intelligence (AI) to chemistry has grown tremendously in recent years. In this Review, we studied the growth and distribution of AI-related chemistry publications in the last two decades using the CAS Content Collection. The volume of both journal and patent publications have increased dramatically, especially since 2015. Study of the distribution of publications over various chemistry research areas revealed that analytical chemistry and biochemistry are integrating AI to the greatest extent and with the highest growth rates. We also investigated trends in interdisciplinary research and identified frequently occurring combinations of research areas in publications. Furthermore, topic analyses were conducted for journal and patent publications to illustrate emerging associations of AI with certain chemistry research topics. Notable publications in various chemistry disciplines were then evaluated and presented to highlight emerging use cases. Finally, the occurrence of different classes of substances and their roles in AI-related chemistry research were quantified, further detailing the popularity of AI adoption in the life sciences and analytical chemistry. In summary, this Review offers a broad overview of how AI has progressed in various fields of chemistry and aims to provide an understanding of its future directions.

Knowledge Graph-Based Approaches to Drug Repurposing for COVID-19.

The COVID-19 pandemic has motivated researchers all over the world in trying to find effective drugs and therapeutics for treating this disease. To save time, much effort has focused on repurposing drugs known for treating other diseases than COVID-19. To support these drug repurposing efforts, we built the CAS Biomedical Knowledge Graph and identified 1350 small molecules as potentially repurposable drugs that target host proteins and disease processes involved in COVID-19. A computer algorithm-driven drug-ranking method was developed to prioritize those identified small molecules. The top 50 molecules were analyzed according to their molecular functions and included 11 drugs in clinical trials for treating COVID-19 and new candidates that may be of interest for clinical investigation. The CAS Biomedical Knowledge Graph provides researchers an opportunity to accelerate innovation and streamline the investigative process not just for COVID-19 but also in many other diseases.

Nuclear Factor Erythroid 2-Related Factor 2-Histone Deacetylase 2 Pathway in the Pathogenesis of Refractory Sudden Sensorineural Hearing Loss and Glucocorticoid Resistance.

INTRODUCTION: A significant number of sensorineural hearing loss (SSNHL) patients had no noticeable hearing improvement after glucocorticoid (GC) treatment. In the present study, we examined expression of the nuclear factor erythroid 2-related factor 2 (NRF2) and histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) of refractory SSNHL patients to study the role of NRF2-HDAC2 pathway in GC insensitivity hearing improvement after GC treatment, which is usually referred to as refractory SSNHL or GC insensitivity. MATERIALS AND METHODS: Forty-four refractory SSNHL patients were treated by intratympanic GC infusion. Hearing was tested in all patients before and after treatment by pure tone hearing test. NRF2/HDAC2 mRNA and protein levels were examined in PBMCs of refractory SSNHL patients before and after treatment. PBMCs from healthy volunteers were used as normal controls. RESULTS: According to the hearing improvement after treatment, patients were assigned into 2 groups: the intratympanic GC sensitive (IGCS) group (hearing recovery ≥15 dB HL) and the intratympanic GC insensitive (IGCI) group (hearing recovery <15 dB HL). Before treatment, the NRF2 mRNA level was lower in all patients than the normal control group. After treatment, NRF2 and HDAC2 mRNA and protein levels were increased in the IGCS group, while no significant change was observed in the IGCI group. CONCLUSION: Low response of NRF2/HDAC2 proteins is associated with GC insensitivity in SSNHL. We speculate that the NRF2-HDAC2 pathway affects GC sensitivity in SSNHL patients.

FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3.

FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin-proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions.

Transcriptomic analysis between self- and cross-pollinated pistils of tea plants (Camellia sinensis).

BACKGROUND: Self-incompatibility (SI) is a major barrier that obstructs the breeding process in most horticultural plants including tea plants (Camellia sinensis). The aim of this study was to elucidate the molecular mechanism of SI in tea plants through a high throughput transcriptome analysis. RESULTS: In this study, the transcriptomes of self- and cross-pollinated pistils of two tea cultivars 'Fudingdabai' and 'Yulv' were compared to elucidate the SI mechanism of tea plants. In addition, the ion components and pollen tube growth in self- and cross-pollinated pistils were investigated. Our results revealed that both cultivars had similar pollen activities and cross-pollination could promote the pollen tube growth. In tea pistils, the highest ion content was potassium (K+), followed by calcium (Ca2+), magnesium (Mg2+) and phosphorus (P5+). Ca2+ content increased after self-pollination but decreased after cross-pollination, while K+ showed reverse trend with Ca2+. A total of 990 and 3 common differentially expressed genes (DEGs) were identified in un-pollinated vs. pollinated pistils and self- vs. cross-pollinated groups after 48 h, respectively. Function annotation indicated that three genes encoding UDP-glycosyltransferase 74B1 (UGT74B1), Mitochondrial calcium uniporter protein 2 (MCU2) and G-type lectin S-receptor-like serine/threonine-protein kinase (G-type RLK) might play important roles during SI process in tea plants. CONCLUSION: Ca2+ and K+ are important signal for SI in tea plants, and three genes including UGT74B1, MCU2 and G-type RLK play essential roles during SI signal transduction.

Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages?

The benefits of implantable cardioverter defibrillator (ICD) implantation in chronic kidney disease (CKD) patients with high sudden cardiac death (SCD) risk are uncertain. To clarify the effects of receiving an ICD in CKD patients, we conducted this meta-analysis to identify the effects of ICDs on patients with CKD, including those on dialysis. We searched the Cochrane library, EMBASE, PubMed, and clinical trials for studies published before July 2016. Eleven studies including 20,196 CKD patients were considered for inclusion. The pooled analysis suggested that patients with an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m2 would benefit from receiving treatments with ICDs compared with patients without an ICD device (aHR = 0.74; 95% confidence interval [CI], 0.63 to 0.86). [corrected]. This is the first report of a subgroup analysis on the survival rate of ICD implantation in CKD patients according to an eGFR group. The subgroup analysis indicated a similar protective association of ICDs in stage 3 (aHR = 0.71; 95% CI, 0.61 to 0.82) and 5 (aHR = 0.71; 95% CI, 0.54 to 0.92) CKD patients [corrected] compared with the control group. However, there was no significant improvement in all-cause mortality in stage 4 CKD patients (aHR = 1.02; 95%CI, 0.75 to 1.37) [corrected]. This is the first meta-analysis reporting that ICD implantation reduces all-cause mortality in stage 3 and 5 [corrected] CKD patients. However, the data do not indicate there is any benefit to ICD implantation in stage 4 [corrected] CKD patients.