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PloS One 2024Recent research in economics and sociology demonstrates the existence of significant occupational segregation by sexual orientation and gender identity and differences...
Recent research in economics and sociology demonstrates the existence of significant occupational segregation by sexual orientation and gender identity and differences in a range of labor market outcomes, such as hiring chances, earnings, and leadership positions. In this paper, we examine one possible cause of these differences that is associated with the disadvantaged position of sexual and gender minorities in the labor market: LGBTQ* individuals' choices aimed at avoiding possible discrimination. This paper examines LGBTQ* people's relative importance of income, time, promotion prospects, an LGBTQ*-friendly work environment, and diversity management in the decision for or against a job. Based on a discrete choice experiment conducted in a large online sample recruited through social media in Germany (N = 4,507), an LGBTQ*-friendly work climate accounted, on average, for 33.8 percent of respondents' decisions which is comparable with the relative importance of income. Overtime, a diversity management on company level and promotion prospects are less important in the job decision process of LGBTQ* people. While the results show only small differences by sexual orientation, they show group-specific preferences by gender identity. An LGBTQ*-friendly work climate is more important for cisgender women of the LGBTQ* community and gender minorities than for cisgender men of the LGBTQ* community. In contrast, income is less important for gender minorities and cisgender women of the LGBTQ* community than for cisgender men of the LGBTQ* community.
Topics: Humans; Male; Female; Sexual and Gender Minorities; Adult; Workplace; Germany; Career Choice; Middle Aged; Employment; Choice Behavior; Gender Identity; Young Adult; Working Conditions
PubMed: 38913684
DOI: 10.1371/journal.pone.0296419 -
OncoTargets and Therapy 2024rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, fusions also serve as a...
rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, fusions also serve as a rare acquired resistance mechanism in -mutant NSCLC. Only a few NSCLC cases have been reported with co-occurrence of mutations and fusions as an acquired resistance mechanism induced by EGFR-tyrosine kinase inhibitors (TKIs). A 68-year-old man diagnosed with lung adenocarcinoma harboring L858R mutation initially responded well to dacomitinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI). Afterward, he developed acquired resistance accompanied by a rearrangement. Next-generation sequencing (NGS) analysis revealed that the tumor possessed both the new fusion and the L858R mutation. Subsequently, he was treated with a combination of cisplatin, pemetrexed, and bevacizumab resulting in a partial response. Nevertheless, his condition deteriorated as the disease progressed, manifesting as hydrocephalus, accompanied by altered consciousness and lower limb weakness. The subsequent combined treatment with dacomitinib and selpercatinib resulted in a significant improvement in neurological symptoms. Here, we first identified acquired fusion with a coexisting L858R mutation following dacomitinib treatment. Our findings highlight the importance of NGS for identifying fusions and suggest the potential combination of dacomitinib and selpercatinib to overcome this resistance. For NSCLC patients with rearrangements and no access to RET inhibitors, pemetrexed-based chemotherapy provides a feasible alternative.
PubMed: 38911906
DOI: 10.2147/OTT.S470946 -
Frontiers in Immunology 2024Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a...
Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a strong inflammatory response. Involvement of the lectin complement pathway, a major actor of the innate immune anti-viral defense, has been reported previously. It is initiated by recognition of the viral surface Spike glycoprotein by mannose-binding lectin (MBL), which induces activation of the MBL-associated protease MASP-2 and triggers the proteolytic complement cascade. A role for the viral nucleoprotein (N) has also been reported, through binding to MASP-2, leading to protease overactivation and potentiation of the lectin pathway. In the present study, we reinvestigated the interactions of the SARS-CoV-2 N protein, produced either in bacteria or secreted by mammalian cells, with full-length MASP-2 or its catalytic domain, in either active or proenzyme form. We could not confirm the interaction of the N protein with the catalytic domain of MASP-2 but observed N protein binding to proenzyme MASP-2. We did not find a role of the N protein in MBL-mediated activation of the lectin pathway. Finally, we showed that incubation of the N protein with MASP-2 results in proteolysis of the viral protein, an observation that requires further investigation to understand a potential functional significance in infected patients.
Topics: Mannose-Binding Protein-Associated Serine Proteases; Humans; SARS-CoV-2; Complement Pathway, Mannose-Binding Lectin; COVID-19; Protein Binding; Coronavirus Nucleocapsid Proteins; Complement Activation; Mannose-Binding Lectin; Phosphoproteins
PubMed: 38911852
DOI: 10.3389/fimmu.2024.1419165 -
Differential gene expression and gut microbiota composition in low-altitude and high-altitude goats.Genomics Jun 2024Previous studies have presented evidence suggesting that altitude exerts detrimental effects on reproductive processes, yet the underlying mechanism remains elusive. Our...
Previous studies have presented evidence suggesting that altitude exerts detrimental effects on reproductive processes, yet the underlying mechanism remains elusive. Our study employed two distinct goat breeds inhabiting low and high altitudes, and conducted a comparative analysis of mRNA profiles in testis tissues and the composition of gut microbiota. The results revealed a reduced testis size in high-altitude goats. RNA-seq analysis identified the presence of 214 differentially expressed genes (DEGs) in the testis. These DEGs resulted in a weakened immunosuppressive effect, ultimately impairing spermatogenesis in high-altitude goats. Additionally, 16S rDNA amplicon sequencing recognized statistically significant variations in the abundance of the genera Treponema, unidentified_Oscillospiraceae, Desulfovibrio, Butyricicoccus, Dorea, Parabacteroides between the two groups. The collective evidence demonstrated the gut and testis played a synergistic role in causing decreased fertility at high altitudes. Our research provides a theoretical basis for future investigations into the reproductive fitness of male goats.
PubMed: 38909906
DOI: 10.1016/j.ygeno.2024.110890 -
Scientific Reports Jun 2024Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for...
Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for regulating the alternative splicing of its own mRNA and ensuring that its expression is balanced to maintain homeostasis. Moreover, the exon skipping of SRSF3 leads to the production of a truncated protein instead of a frameshift mutation that generates a premature termination codon (PTC). However, the precise regulatory mechanism involved in the splicing of SRSF3 remains unclear. In this study, we first established a platform for coexpressing full-length SRSF3 (SRSF3-FL) and SRSF3-PTC and further identified a specific antibody against the SRSF3-FL and truncated SRSF3 (SRSF3-TR) proteins. Next, we found that exogenously overexpressing SRSF3-FL or SRSF3-PTC failed to reverse the effects of digoxin, caffeine, or both in combination on this molecule and its targets. Endoplasmic reticulum-related pathways, transcription factors, and chemicals such as palmitic acid and phosphate were found to be involved in the regulation of SRSF3 expression. The downregulation of SRSF3-FL by palmitic acid and phosphate was mediated via different regulatory mechanisms in HeLa cells. In summary, we provide new insights into the altered expression of the SRSF3-FL and SRSF3-TR proteins for the identification of the functions of SRSF3 in cells.
Topics: Serine-Arginine Splicing Factors; Humans; HeLa Cells; Alternative Splicing; Protein Stability; Gene Expression Regulation, Neoplastic; Neoplasms; RNA, Messenger
PubMed: 38909100
DOI: 10.1038/s41598-024-64640-1 -
Microbiome Jun 2024Although the microbiota has been extensively associated with HIV pathogenesis, the majority of studies, particularly those using omics techniques, are largely... (Review)
Review
BACKGROUND
Although the microbiota has been extensively associated with HIV pathogenesis, the majority of studies, particularly those using omics techniques, are largely correlative and serve primarily as a basis for hypothesis generation. Furthermore, most have focused on characterizing the taxonomic composition of the bacterial component, often overlooking other levels of the microbiome. The intricate mechanisms by which the microbiota influences immune responses to HIV are still poorly understood. Interventional studies on gut microbiota provide a powerful tool to test the hypothesis of whether we can harness the microbiota to improve health outcomes in people with HIV.
RESULTS
Here, we review the multifaceted role of the gut microbiome in HIV/SIV disease progression and its potential as a therapeutic target. We explore the complex interplay between gut microbial dysbiosis and systemic inflammation, highlighting the potential for microbiome-based therapeutics to open new avenues in HIV management. These include exploring the efficacy of probiotics, prebiotics, fecal microbiota transplantation, and targeted dietary modifications. We also address the challenges inherent in this research area, such as the difficulty in inducing long-lasting microbiome alterations and the complexities of study designs, including variations in probiotic strains, donor selection for FMT, antibiotic conditioning regimens, and the hurdles in translating findings into clinical practice. Finally, we speculate on future directions for this rapidly evolving field, emphasizing the need for a more granular understanding of microbiome-immune interactions, the development of personalized microbiome-based therapies, and the application of novel technologies to identify potential therapeutic agents.
CONCLUSIONS
Our review underscores the importance of the gut microbiome in HIV/SIV disease and its potential as a target for innovative therapeutic strategies.
Topics: Gastrointestinal Microbiome; Dysbiosis; Humans; HIV Infections; Simian Acquired Immunodeficiency Syndrome; Probiotics; Fecal Microbiota Transplantation; Animals; Simian Immunodeficiency Virus; Prebiotics; HIV
PubMed: 38907315
DOI: 10.1186/s40168-024-01825-w -
PLoS Pathogens Jun 2024Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that...
Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that JMJD2D can protect intestine from dextran sulfate sodium (DSS)-induced colitis by activating Hedgehog signaling; however, its involvement in host defense against enteric attaching and effacing bacterial infection remains unclear. The present study was aimed to investigate the role of JMJD2D in host defense against enteric bacteria and its underlying mechanisms. The enteric pathogen Citrobacter rodentium (C. rodentium) model was used to mimic clinical colonic infection. The responses of wild-type and JMJD2D-/- mice to oral infection of C. rodentium were investigated. Bone marrow chimeric mice were infected with C. rodentium. JMJD2D expression was knocked down in CMT93 cells by using small hairpin RNAs, and Western blot and real-time PCR assays were performed in these cells. The relationship between JMJD2D and STAT3 was studied by co-immunoprecipitation and chromatin immunoprecipitation. JMJD2D was significantly up-regulated in colonic epithelial cells of mice in response to Citrobacter rodentium infection. JMJD2D-/- mice displayed an impaired clearance of C. rodentium, more body weight loss, and more severe colonic tissue pathology compared with wild-type mice. JMJD2D-/- mice exhibited an impaired expression of IL-17F in the colonic epithelial cells, which restricts C. rodentium infection by inducing the expression of antimicrobial peptides. Accordingly, JMJD2D-/- mice showed a decreased expression of β-defensin-1, β-defensin-3, and β-defensin-4 in the colonic epithelial cells. Mechanistically, JMJD2D activated STAT3 signaling by inducing STAT3 phosphorylation and cooperated with STAT3 to induce IL-17F expression by interacting with STAT3 and been recruited to the IL-17F promoter to demethylate H3K9me3. Our study demonstrates that JMJD2D contributes to host defense against enteric bacteria through up-regulating IL-17F to induce β-defensin expression.
PubMed: 38905308
DOI: 10.1371/journal.ppat.1012316 -
Frontiers in Toxicology 2024Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and...
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (, , , -) and downregulation of lipid transport genes (, , ). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis () and bile acid synthesis () were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis () showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
PubMed: 38903859
DOI: 10.3389/ftox.2024.1390196 -
Frontiers in Plant Science 2024Clubroot disease, which is caused by the obligate biotrophic protist , leads to the formation of galls, commonly known as pathogen-induced tumors, on the roots of...
Clubroot disease, which is caused by the obligate biotrophic protist , leads to the formation of galls, commonly known as pathogen-induced tumors, on the roots of infected plants. The identification of crucial regulators of host tumor formation is essential to unravel the mechanisms underlying the proliferation and differentiation of within plant cells. To gain insight into this process, transcriptomic analysis was conducted to identify key genes associated with both primary and secondary infection of in Chinese cabbage. Our results demonstrate that the k-means clustering of subclass 1, which exhibited specific trends, was closely linked to the infection process of . Of the 1610 differentially expressed genes (DEGs) annotated in subclass 1, 782 were identified as transcription factors belonging to 49 transcription factor families, including bHLH, B3, NAC, MYB_related, WRKY, bZIP, C2H2, and ERF. In the primary infection, several genes, including the predicted probable pectate lyase, RPM1-interacting protein 4-like, L-type lectin-domain-containing receptor kinase, G-type lectin S-receptor-like serine, photosystem II 22 kDa protein, and MLP-like protein, showed significant upregulation. In the secondary infection stage, 45 of 50 overlapping DEGs were upregulated. These upregulated DEGs included the predicted endoglucanase, long-chain acyl-CoA synthetase, WRKY transcription factor, NAC domain-containing protein, cell division control protein, auxin-induced protein, and protein variation in compound-triggered root growth response-like and xyloglucan glycosyltransferases. In both the primary and secondary infection stages, the DEGs were predicted to be putative disease resistance proteins, L-type lectin domain-containing receptor kinases, ferredoxin-NADP reductases, 1-aminocyclopropane-1-carboxylate synthases, histone deacetylases, UDP-glycosyltransferases, putative glycerol-3-phosphate transporters, and chlorophyll a-binding proteins, which are closely associated with plant defense responses, biosynthetic processes, carbohydrate transport, and photosynthesis. This study revealed the pivotal role of transcription factors in the initiation of infection and establishment of intracellular parasitic relationships during the primary infection stage, as well as the proliferation and differentiation of the pathogen within the host cell during the secondary infection stage.
PubMed: 38903421
DOI: 10.3389/fpls.2024.1391173 -
Frontiers in Plant Science 2024Sugarcane aphid has emerged as a major pest of sorghum recently, and a few sorghum accessions were identified for resistance to this aphid so far. However, the molecular...
Sugarcane aphid has emerged as a major pest of sorghum recently, and a few sorghum accessions were identified for resistance to this aphid so far. However, the molecular and genetic mechanisms underlying this resistance are still unclear. To understand these mechanisms, transcriptomics was conducted in resistant Tx2783 and susceptible BTx623 sorghum genotypes infested with sugarcane aphids. A principal component analysis revealed differences in the transcriptomic profiles of the two genotypes. The pathway analysis of the differentially expressed genes (DEGs) indicated the upregulation of a set of genes related to signal perception (nucleotide-binding, leucine-rich repeat proteins), signal transduction [mitogen-activated protein kinases signaling, salicylic acid (SA), and jasmonic acid (JA)], and plant defense (transcription factors, flavonoids, and terpenoids). The upregulation of the selected DEGs was verified by real-time quantitative PCR data analysis, performed on the resistant and susceptible genotypes. A phytohormone bioassay experiment showed a decrease in aphid population, plant mortality, and damage in the susceptible genotype when treated with JA and SA. Together, the results indicate that the set of genes, pathways, and defense compounds is involved in host plant resistance to aphids. These findings shed light on the specific role of each DEG, thus advancing our understanding of the genetic and molecular mechanisms of host plant resistance to aphids.
PubMed: 38903420
DOI: 10.3389/fpls.2024.1324085