In closed mitotic systems such as Saccharomyces cerevisiae, the nuclear envelope (NE) does not break down during mitosis, so microtubule-organizing centers such as the spindle-pole body (SPB) must be inserted into the NE to facilitate bipolar spindle formation and chromosome segregation. The mechanism of SPB insertion has been linked to NE insertion of nuclear pore complexes (NPCs) through a series of genetic and physical interactions between NPCs and SPB components. To identify new genes involved in SPB duplication and NE insertion, we carried out genome-wide screens for suppressors of deletion alleles of SPB components, including Mps3 and Mps2. In addition to the nucleoporins POM152 and POM34, we found that elimination of SEC66/SEC71/KAR7 suppressed lethality of cells lacking MPS2 or MPS3. Sec66 is a nonessential subunit of the Sec63 complex that functions together with the Sec61 complex in import of proteins into the endoplasmic reticulum (ER). Cells lacking Sec66 have reduced levels of Pom152 protein but not Pom34 or Ndc1, a shared component of the NPC and SPB. The fact that Sec66 but not other subunits of the ER translocon bypass deletion mutants in SPB genes suggests a specific role for Sec66 in the control of Pom152 levels. Based on the observation that sec66∆ does not affect the distribution of Ndc1 on the NE or Ndc1 binding to the SPB, we propose that Sec66-mediated regulation of Pom152 plays an NPC-independent role in the control of SPB duplication.

Dwarfism is one of the most valuable traits in banana breeding because semi-dwarf cultivars show good resistance to damage by wind and rain. Moreover, these cultivars present advantages of convenient cultivation, management, and so on. We obtained a dwarf mutant '8818-1' through EMS (ethyl methane sulphonate) mutagenesis of Williams banana 8818 (Musa spp. AAA group). Our research have shown that gibberellins (GAs) content in 8818-1 false stems was significantly lower than that in its parent 8818 and the dwarf type of 8818-1 could be restored by application of exogenous GA3. Although GA exerts important impacts on the 8818-1 dwarf type, our understanding of the regulation of GA metabolism during banana dwarf mutant development remains limited.

Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity.

Earlier studies have revealed a substantial amount of transcriptional activity occurring outside annotated protein-coding genes of the Caenorhabditis elegans genome. One important fraction of this transcriptional activity relates to intermediate-size (70-500 nt) transcripts (is-ncRNAs) of mostly unknown function. Profiling the expression of this segment of the transcriptome on a tiling array through the C. elegans life cycle identified 5866 hitherto unannotated transcripts. The novel loci were distributed across intronic and intergenic space, with some enrichment toward protein-coding gene termini. The majority of the putative is-ncRNAs showed either stage-specific expression, or distinct developmental variation in their expression levels. More than 200 loci showed male-specific expression, and conserved loci were significantly enriched on the X chromosome, both observations strongly suggesting involvement of is-ncRNAs in sex-specific functions. Half of the novel loci were conserved in other nematodes, and numerous loci showed significant conservational correlations to nearby coding genes. Assuming functional roles for most of the novel loci, the data imply a nematode is-ncRNA tool kit of considerable size and variety.

The development of biomaterials with the potential to accelerate wound healing is a great challenge in biomedicine. In this study, four types of samples including pepsin soluble collagen sponge (PCS), acid soluble collagen sponge (ACS), bovine collagen electrospun I (BCE I) and bovine collagen electrospun II (BCE II) were used as wound dressing materials. We showed that the PCS, ACS, BCE I and BCE II treated rats increased the percentage of wound contraction, reduced the inflammatory infiltration, and accelerated the epithelization and healing. PCS, ACS, BCE I, and BCE II significantly enhanced the total protein and hydroxyproline level in rats. ACS could induce more fibroblasts proliferation and differentiation than PCS, however, both PCS and ACS had a lower effect than BCE I and BCE II. PCS, ACS, BCE I, and BCE II could regulate deposition of collagen, which led to excellent alignment in the wound healing process. There were similar effects on inducing the level of cytokines including EGF, FGF, and vascular endothelial marker CD31 among these four groups. Accordingly, this study disclosed that collagens (PCS and ACS) from tilapia skin and bovine collagen electrospun (BCE I and BCE II) have significant bioactivity and could accelerate wound healing rapidly and effectively in rat model.

Antibody affinity maturation, which is an antigen-based selection process for B cells, occurs in germinal centers (GCs). GCB cells must efficiently recognize, acquire, and present antigens from follicular dendritic cells (FDCs) to receive positive selection signals from T helper cells. Previous studies showed that GCB cells undergo adhesive interactions with FDCs, but the regulatory mechanisms underlying the cell adhesions and their functional relevance remain unclear. Here, we identified H3K36me2 methyltransferase Nsd2 as a critical regulator of GCB cell-FDC adhesion. Nsd2 deletion modestly reduced GC responses but strongly impaired B cell affinity maturation. Mechanistically, Nsd2 directly regulated expression of multiple actin polymerization-related genes in GCB cells. Nsd2 loss reduced B cell adhesion to FDC-expressed adhesion molecules, thus affecting both B cell receptor (BCR) signaling and antigen acquisition. Overall, Nsd2 coordinates GCB positive selection by enhancing both BCR signaling and T cell help.

In closed mitotic systems such as Saccharomyces cerevisiae, nuclear pore complexes (NPCs) and the spindle pole body (SPB) must assemble into an intact nuclear envelope (NE). Ndc1 is a highly conserved integral membrane protein involved in insertion of both complexes. In this study, we show that Ndc1 interacts with the SUN domain-containing protein Mps3 on the NE in live yeast cells using fluorescence cross-correlation spectroscopy. Genetic and molecular analysis of a series of new ndc1 alleles allowed us to understand the role of Ndc1-Mps3 binding at the NE. We show that the ndc1-L562S allele is unable to associate specifically with Mps3 and find that this mutant is lethal due to a defect in SPB duplication. Unlike other ndc1 alleles, the growth and Mps3 binding defect of ndc1-L562S is fully suppressed by deletion of POM152, which encodes a NPC component. Based on our data we propose that the Ndc1-Mps3 interaction is important for controlling the distribution of Ndc1 between the NPC and SPB.

In the field of tissue engineering, polymeric materials with high biocompatibility like polylactic acid and polyglycolic acid have been widely used for fabricating living constructs. For hypopharynx tissue engineering, skeletal muscle is one important functional part of the whole organ, which assembles the unidirectionally aligned myotubes. In this study, a polyurethane (PU) scaffold with microchannel patterns was used to provide aligning guidance for the seeded human myoblasts. Due to the low hydrophilicity of PU, the scaffold was grafted with silk fibroin (PU-SF) or gelatin (PU-Gel) to improve its cell adhesion properties. Scaffolds were observed to degrade slowly over time, and their mechanical properties and hydrophilicities were improved through the surface grafting. Also, the myoblasts seeded on PU-SF had the higher proliferative rate and better differentiation compared with those on the control or PU-Gel. Our results demonstrate that polyurethane scaffolds seeded with myoblasts hold promise to guide hypopharynx muscle regeneration.

Soil salinity reduces soybean growth and yield. The recently identified GmSALT3 (Glycine max salt Tolerance-associated gene on chromosome 3) has the potential to improve soybean yields in salinized conditions. Here we evaluate the impact of GmSALT3 on soybean performance under saline or non-saline conditions. Three sets of near isogenic lines (NILs), with genetic similarity of 95.6-99.3% between each pair of NIL-T and NIL-S, were generated from a cross between two varieties 85-140 (salt-sensitive, S) and Tiefeng 8 (salt-tolerant, T) by using marker-assisted selection. Each NIL-T; 782-T, 820-T and 860-T, contained a common ~1000 kb fragment on chromosome 3 where GmSALT3 was located. We show that GmSALT3 does not contribute to an improvement in seedling emergence rate or early vigor under salt stress. However, when 12-day-old seedlings were exposed to NaCl stress, the NIL-T lines accumulated significantly less leaf Na+ compared with their corresponding NIL-S, while no significant difference of K+ concentration was observed between NIL-T and NIL-S; the magnitude of Na+ accumulation within each NIL-T set was influenced by the different genetic backgrounds. In addition, NIL-T lines accumulated less Cl- in the leaf and more in the root prior to any difference in Na+; in the field they accumulated less pod wall Cl- than the corresponding NIL-S lines. Under non-saline field conditions, no significant differences were observed for yield related traits within each pair of NIL-T and NIL-S lines, indicating there was no yield penalty for having the GmSALT3 gene. In contrast, under saline field conditions the NIL-T lines had significantly greater plant seed weight and 100-seed weight than the corresponding NIL-S lines, meaning GmSALT3 conferred a yield advantage to soybean plants in salinized fields. Our results indicated that GmSALT3 mediated regulation of both Na+ and Cl- accumulation in soybean, and contributes to improved soybean yield through maintaining a higher seed weight under saline stress.

The cell source for transplantation therapy is always a prerequisite question to be solved in clinical applications. Neural cells are considered non-regenerable, which highly restrict their application in the treatment for nerve injury. Therefore, neural trans-differentiation based on gene transfection provides a new solution to this issue. Compared to viral strategy, non-viral gene delivery systems are considered as a more promising way to achieve this aim. This study centers on a novel application of Porphyra yezoensis polysaccharide as a non-viral gene carrier for the neural trans-differentiation of mouse fibroblasts.

The purpose of this systematic review and meta-analysis was to explore the literature and collate data comparing the mortality of coronavirus disease 2019 (COVID-19) patients with and without asthma. The databases PubMed, Scopus, Embase, Google Scholar, and medRxiv.org were searched for studies comparing the clinical outcomes of asthmatic patients with those of nonasthmatic patients diagnosed with COVID-19. Mortality data were summarized using the Mantel-Haenszel OR with 95% CI in a random-effects model. Five retrospective studies met the inclusion criteria. A meta-analysis of data from 744 asthmatic patients and 8,151 nonasthmatic patients indicated that the presence of asthma had no significant effect on mortality (OR = 0.96; 95% CI 0.70-1.30; I2 = 0%; p = 0.79). Results were stable in a sensitivity analysis. A descriptive analysis of other clinical outcomes indicated no difference in the duration of hospitalization and the risk of intensive care unit (ICU) transfer between asthmatic and nonasthmatic patients. To conclude, preliminary data indicates that asthma as a comorbidity may not increase the mortality of COVID-19. Data on the influence of asthma on the risk of hospitalization, the duration of hospitalization, the requirement of ICU admission, and disease severity is still too limited to draw any strong conclusions. Further studies with a larger sample size are required to establish strong evidence.

Emerging evidence indicates the role of gut microbiota in the development of cardiovascular diseases. Thus, gut microbiota is increasingly recognized as a potential therapeutic target of cardiovascular disease. However, the effects of gut microbiome-targeted therapies on cardiometabolic outcomes in children and adolescents remain unclear.

The HCMV (human cytomegalovirus) encodes numerous proteins which function to evade the immune response, which allows the virus to replicate. Exploring the mechanisms of HCMV immune escape helps to find the strategy to inhibit HCMV replicate. CD8+ T cells play a critical role in the immune response to viral pathogens. However, the mechanisms of HCMV to evade the attack by CD8+ T cells remain largely unknown. Viral CXCL1 (vCXCL1) is the production of HCMV UL146 gene. Here, we found that vCXCL1 promoted the resistance of hepatic cells to CD8+ T cells. vCXCL1 increased the levels of PD-L1 protein expression and mRNA expression. VCXCL1 enhanced the binding of STAT3 transcription factor to the promoter of PD-L1 and increased the activity of PD-L1 promoter. Furthermore, down-regulation of PD-L1 reduced the effects of vCXCL1 on the resistance of hepatic cells to CD8+ T cells. Taken together, vCXCL1 promotes the resistance of hepatic cells to CD8+ T cells through up-regulation of PD-L1. This finding might provide a new mechanism of HCMV immune escape.

Hepatocellular carcinoma (HCC) is the second leading cause of death among cancers worldwide. In this study, we aimed to identify the molecular target genes and detect the key mechanisms of HCC. Three gene expression profiles (GSE84006, GSE14323, GSE14811) and two miRNA expression profiles (GSE40744, GSE36915) were analyzed to determine the molecular target genes, microRNAs (miRNAs) and the potential molecular mechanisms in HCC.

Entomopathogenic fungi can overcome insecticide resistance and represent promising tools for the control of mosquitoes. Better understanding of fungus-mosquito interactions is critical for improvement of fungal efficacy. Upon insect cuticle induction, pathogenic fungi undergo marked infection-related morphological differentiation. However, regulatory mechanisms of fungal infection-related morphogenesis are poorly understood. Here, we show that a histone lysine methyltransferase KMT2 in Metarhizium robertsii (MrKMT2) is up-regulated upon cuticle induction. MrKMT2 plays crucial roles in regulating infection-related morphogenesis and pathogenicity by up-regulating the transcription factor gene Mrcre1 via H3K4 trimethylation during mosquito cuticle infection. MrCre1 further regulates the cuticle-induced gene Mrhyd4 to modulate infection structure (appressorium) formation and virulence. Overall, the MrKMT2-MrCre1-MrHyd4 regulatory pathway regulates infection-related morphogenesis and pathogenicity in M. robertsii. These findings reveal that the epigenetic regulatory mechanism plays a pivotal role in regulating fungal pathogenesis in insects, and provide new insights into molecular interactions between pathogenic fungi and insect hosts.

Metabolic syndrome is a disorder of energy use and storage, which is characterized by central obesity, dyslipidemia, and raised blood pressure and blood sugar levels. Maternal 25-hydroxyvitamin D deficiency is known to cause metabolic changes, chronic disease, and increased adiposity in adulthood. However, the underlying mechanism of induced metabolic syndrome (MetS) in the offspring in vitamin D deficient pregnant mothers remains unclear. We identified that maternal 25-hydroxyvitamin D deficiency enhances oxidative stress, which leads to the development of MetS in the mother and her offspring. Further, immunohistochemical, Western blotting, and qRT-PCR analyses revealed that maternal 25-hydroxyvitamin D deficiency inhibited the activation of the Nrf2/carbonyl reductase 1 (CBR1) pathway in maternal placenta, liver, and pancreas, as well as the offspring's liver and pancreas. Further analyses uncovered that application of 25-hydroxyvitamin D activated the Nrf2/CBR1 pathway, relieving the oxidative stress in BRL cells, suggesting that 25-hydroxyvitamin D regulates oxidative stress in offspring and induces the activation of the Nrf2/CBR1 pathway. Taken together, our study finds that maternal 25-hydroxyvitamin D deficiency is likely to result in offspring's MetS probably via abnormal nutrition transformation across placenta. Depression of the Nrf2/CBR1 pathway in both mothers and their offspring is one of the causes of oxidative stress leading to MetS. This study suggests that 25-hydroxyvitamin D treatment may relieve the offspring's MetS.

Activation-induced cytidine deaminase (AID) initiates both antibody class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. DNA double-strand break response (DSBR) factors promote rearrangement in CSR, while translesion synthesis (TLS) polymerases generate mutations in SHM. REV7, a component of TLS polymerase zeta, is also a downstream effector of 53BP1-RIF1 DSBR pathway. Here, we study the multi-functions of REV7 and find that REV7 is required for the B cell survival upon AID-deamination, which is independent of its roles in DSBR, G2/M transition or REV1-mediated TLS. The cell death in REV7-deficient activated B cells can be fully rescued by AID-deficiency in vivo. We further identify that REV7-depedent TLS across UNG-processed apurinic/apyrimidinic sites is required for cell survival upon AID/APOBEC deamination. This study dissects the multiple roles of Rev7 in antibody diversification, and discovers that TLS is not only required for sequence diversification but also B cell survival upon AID-initiated lesions.

Novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor with the BRD4 protein. The potent degraders on MV-4-11 cells were discovered through structure-activity relationship study. Modification of warhead on pyrrolopyridone BET degraders significantly regulates BRD4 isoform (long and short) protein degradation, which induces differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that the fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN.

Ploidy is the number of whole sets of chromosomes in a species. Ploidy is typically a stable cellular feature that is critical for survival. Polyploidization is a route recognized to increase gene dosage, improve fitness under stressful conditions and promote evolutionary diversity. However, the mechanism of regulation and maintenance of ploidy is not well characterized. Here, we examine the spontaneous diploidization associated with mutations in components of the Saccharomyces cerevisiae centrosome, known as the spindle pole body (SPB). Although SPB mutants are associated with defects in spindle formation, we show that two copies of the mutant in a haploid yeast favors diploidization in some cases, leading us to speculate that the increased gene dosage in diploids 'rescues' SPB duplication defects, allowing cells to successfully propagate with a stable diploid karyotype. This copy number-based rescue is linked to SPB scaling: certain SPB subcomplexes do not scale or only minimally scale with ploidy. We hypothesize that lesions in structures with incompatible allometries such as the centrosome may drive changes such as whole genome duplication, which have shaped the evolutionary landscape of many eukaryotes.

The embryos of Nelumbo nucifera Gaertn seeds, lianzixin, are used in China as food and traditional herbal medicine. Principal therapeutic indications are insomnia, anxiety and pyrexia. Caffeine is a psychostimulant and excessive use predisposes to cell damage and neurotoxicity. We aimed to investigate the potential protect effect of Neferine and lianzixin extracts on undifferentiated caffeine-damaged phaeochromocytoma cells (PC12 cells).