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JAMA Network Open Jun 2024Transgender and gender-diverse (TGD) communities experience disproportionate levels of violence, yet due to limitations in measuring TGD identity, few...
IMPORTANCE
Transgender and gender-diverse (TGD) communities experience disproportionate levels of violence, yet due to limitations in measuring TGD identity, few state-representative estimates are available.
OBJECTIVE
To assess gender identity differences in experiences of violence among adults.
DESIGN, SETTING, AND PARTICIPANTS
Cross-sectional data from the 2023 California Violence Experiences (CalVEX) survey, weighted to provide state-representative estimates, was used to assess associations between gender identity and past-year experiences of violence among adults 18 years and older. Data were analyzed from June to December 2023.
EXPOSURE
Gender identity (cisgender women, cisgender men, transgender women, transgender men, and nonbinary individuals).
MAIN OUTCOMES AND MEASURES
Experience of physical violence (including physical abuse and threat or use of a weapon), sexual violence (verbal sexual harassment, homophobic or transphobic slurs, cyber and physically aggressive sexual harassment, and forced sex), and intimate partner violence (IPV; emotional, physical, or sexual violence) using age-adjusted logistic regression.
RESULTS
In total 3560 individuals (weighted cumulative response rate, 5%) completed the 2023 CalVEX survey, with 1978 cisgender women, 1431 cisgender men, 35 transgender women, 52 transgender men, and 64 nonbinary respondents (mean [SD] age, 47.1 [17.5] years; 635 [17%] were Asian, 839 [37%] were Hispanic, and 1159 [37%] were White). Past-year physical violence was reported by 22 transgender men (43%), 9 transgender women (24%), and 9 nonbinary respondents (14%). Past-year sexual violence was reported by 23 transgender men (42%), 11 transgender women (14%), and 31 nonbinary respondents (56%). Compared with cisgender women, transgender women and transgender men had greater risk of past-year physical violence (any form) (transgender women adjusted incidence rate ratio [AIRR], 6.7; 95% CI, 2.5-18.2; transgender men AIRR, 9.7; 95% CI, 5.3-17.7), as well as past-year IPV (any form) (transgender women AIRR, 3.2; 95% CI, 1.3-8.0; transgender men AIRR, 6.7; 95% CI, 4.0-11.3). Relative to cisgender women, transgender men (AIRR, 3.0; 95% CI, 1.7-5.1) and nonbinary respondents (AIRR, 3.3; 95% CI, 2.1-5.2) had greater risk of past-year sexual violence (any form).
CONCLUSIONS AND RELEVANCE
In this survey study of adults in California, results showed that TGD individuals, especially transgender men, are at higher risk of experiencing all forms of violence relative to cisgender women. Results highlight the need for gender-affirming violence prevention and intervention services as well as policies that protect TGD individuals from discriminatory violence.
Topics: Humans; Male; Female; Intimate Partner Violence; Adult; Transgender Persons; Cross-Sectional Studies; Middle Aged; California; Sex Offenses; Young Adult; Physical Abuse; Adolescent; Surveys and Questionnaires; Gender Identity
PubMed: 38916887
DOI: 10.1001/jamanetworkopen.2024.19137 -
Microbiology Spectrum Jun 2024() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug...
UNLABELLED
() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug resistance. The loss of antibiotic efficacy has raised interest in the identification of host-directed therapeutics (HDT) to develop novel treatment strategies for mycobacterial infections. In this study, we identified amiodarone as a potential HDT candidate that inhibited both intracellular and in primary human macrophages without directly impairing bacterial growth, thereby confirming that amiodarone acts in a host-mediated manner. Moreover, amiodarone induced the formation of (auto)phagosomes and enhanced autophagic targeting of mycobacteria in macrophages. The induction of autophagy by amiodarone is likely due to enhanced transcriptional regulation, as the nuclear intensity of the transcription factor EB, the master regulator of autophagy and lysosomal biogenesis, was strongly increased. Furthermore, blocking lysosomal degradation with bafilomycin impaired the host-beneficial effect of amiodarone. Finally, amiodarone induced autophagy and reduced bacterial burden in a zebrafish embryo model of tuberculosis, thereby confirming the HDT activity of amiodarone . In conclusion, we have identified amiodarone as an autophagy-inducing antimycobacterial HDT that improves host control of mycobacterial infections.
IMPORTANCE
Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including () and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of and in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an tuberculosis model based on infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
PubMed: 38916320
DOI: 10.1128/spectrum.00167-24 -
MBio Jun 2024causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs...
UNLABELLED
causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against . BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system by analyzing libraries of mutants grown in the presence of BRI. In , BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. experiments show BRI significantly reduces survival inside macrophages and partially clears lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against . BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis.
IMPORTANCE
Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, and . There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against . BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of , acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against . We propose BRI as a new antifungal agent against cryptococcosis.
PubMed: 38916308
DOI: 10.1128/mbio.01031-24 -
Frontiers in Plant Science 2024Rapid industrialization and urbanization have caused severe soil contamination with cadmium (Cd) necessitating effective remediation strategies. Phytoremediation is a...
Rapid industrialization and urbanization have caused severe soil contamination with cadmium (Cd) necessitating effective remediation strategies. Phytoremediation is a widely adopted technology for remediating Cd-contaminated soil. Previous studies have shown that has a high Cd accumulation capacity and tolerance indicating its potential for Cd soil remediation. However, the mechanisms underlying its response to Cd stress remain unclear. In this study, physiological, transcriptomic, and metabolomic analyses were conducted to explore the response of roots to Cd stress at different time points. The results revealed that Cd stress significantly increased malondialdehyde (MDA) levels in , which simultaneously activated its antioxidant defense system, enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) by 19.73%-50%, 22.87%-38.89%, and 32.31%-45.40% at 12 h, 36 h, 72 h, and 7 days, respectively, compared with those in the control (CK). Moreover, transcriptomic and metabolomic analyses revealed 245, 5,708, 9,834, and 2,323 differentially expressed genes (DEGs), along with 66, 62, 156, and 90 differentially expressed metabolites (DEMs) at 12 h, 36 h, 72 h, and 7 days, respectively. Through weighted gene coexpression network analysis (WGCNA) of physiological indicators and transcript expression, eight hub genes involved in phenylpropanoid biosynthesis, signal transduction, and metal transport were identified. In addition, integrative analyses of metabolomic and transcriptomic data highlighted the activation of lipid metabolism and phenylpropanoid biosynthesis pathways under Cd stress suggesting that these pathways play crucial roles in the detoxification process and in enhancing Cd tolerance in . This comprehensive study provides detailed insights into the response mechanisms of to Cd toxicity.
PubMed: 38916029
DOI: 10.3389/fpls.2024.1389207 -
Frontiers in Molecular Biosciences 2024Newcastle disease is a highly infectious disease caused by the Newcastle Disease Virus (NDV) and has a devastating financial impact on the global chicken industry. It...
Newcastle disease is a highly infectious disease caused by the Newcastle Disease Virus (NDV) and has a devastating financial impact on the global chicken industry. It was previously established that Leghorn and Fayoumi breeds of chicken exhibit variable resistance against NDV infection. The harderian gland is the less studied tissue of the chicken, known to play an essential role in the immune response. Our previous study, we reported differential gene expression and long noncoding RNAs (lncRNAs) between challenged and non-challenged chickens in the Harderian gland transcriptomic data. Now, we report the analysis of the same data studying the differential expression patterns between Leghorn and Fayoumi and between different timepoints during disease. First, the pipeline FHSpipe was used for identification of lncRNAs, followed by differential expression analysis by edgeR (GLM), functional annotation by OmicsBox, co-expression analysis using WGCNA and finally validation of selected lncRNAs and co-expressing genes using qRT-PCR. Here, we observed that Leghorn showed a higher number of upregulated immune-related genes than Fayoumi in timepoint-based analysis, especially during the initial stages. Surprisingly, Fayoumi, being comparatively resistant, showed little difference between challenged and non-challenged conditions and different time points of the challenge. The breed-based analysis, which compared Leghorn with Fayoumi in both challenged and non-challenged conditions separately, identified several immune-related genes and positive co-expressing cis lncRNAs to be upregulated in Fayoumi when compared to Leghorn in both challenged and non-challenged conditions. The current study shows that Leghorn, being comparatively more susceptible to NDV than Fayoumi, showed several immune-related genes and positive co-expressing cis lncRNAs upregulated in challenged Leghorn when compared to non-challenged Leghorn and also in different timepoints during challenge. While, breed-based analysis showed that there were more upregulated immune genes and positive cis-lncRNAs in Fayoumi than Leghorn. This result clearly shows that the differences in the expression of genes annotated with immune-related GO terms and pathways, i.e., immune-related genes and the co-expressing cis-lncRNAs between Leghorn and Fayoumi, and their role in the presence of differences in the resistance of Leghorn and Fayoumi chicken against NDV. These immune-genes and cis-lncRNAs could play a role in Fayoumi being comparatively more resistant to NDV than Leghorn. Our study elucidated the importance of lncRNAs during the host defense against NDV infection, paving the way for future research on the mechanisms governing the genetic improvement of chicken breeds.
PubMed: 38915939
DOI: 10.3389/fmolb.2024.1365888 -
Molecular Neurodegeneration Jun 2024Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury...
BACKGROUND
Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models.
METHODS
We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects.
RESULTS
Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice.
CONCLUSIONS
The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.
Topics: Animals; Tauopathies; tau Proteins; Mice; Acetylation; Humans; Immunotherapy; Disease Models, Animal; Mice, Transgenic; Brain Injuries, Traumatic; Brain Injuries; Brain; Neuroprotective Agents
PubMed: 38915105
DOI: 10.1186/s13024-024-00733-9 -
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 -
Veterinary World May 2024Modern scientific research focuses on a detailed study of the immune system, the mechanisms of immunosuppression, and the search for an effective means to restore...
BACKGROUND AND AIM
Modern scientific research focuses on a detailed study of the immune system, the mechanisms of immunosuppression, and the search for an effective means to restore disturbed immune homeostasis in farm animals. The present study examined the cytokine and immunoglobulin (Ig) profiles of healthy broiler chickens during physiological development.
MATERIALS AND METHODS
Arbor Acres broilers (n = 28) were used in the study to achieve this objective. The immune status of broiler chickens was assessed on 7, 14, 28, and 42 days of age, including serum levels of cytokines, Igs, and lysozyme by enzyme immunoassay.
RESULTS
We observed a decrease in the efficiency of immune system functioning of birds with increasing age. The most pronounced immunological deficiency in the body of broiler chickens is noted at the age of 7-14 days, which is associated with immaturity of the immune system and is characterized by the fact that non-specific humoral and specific cellular defense factors are at a rather low level. The levels of lysozyme, interleukin (IL)-2, IL-10, and IgA in blood serum at this age were minimal; starting from 28 days of age, there is a specific humoral immune deficiency, which is compensated by strengthening of cellular defense factors. The serum level of IgY intensively decreases against the background of an increase of lysozyme, IL-2, IL-4, and IL-10.
CONCLUSION
During postnatal ontogenesis, the immune system of broiler chickens undergoes dynamic changes that have an age direction and phase character. Changes in the immune system may affect immunocompetence, disease susceptibility, and, consequently, productivity.
PubMed: 38911092
DOI: 10.14202/vetworld.2024.988-993