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1.
JMIR Res Protoc ; 13: e55210, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38502156

RESUMO

BACKGROUND: Sexual and gender minority youths (lesbian, gay, bisexual, transgender, nonbinary, and queer individuals) face elevated risks of substance use (eg, alcohol and tobacco) and mental health issues (eg, depressive symptoms and suicidality) compared to their cisgender heterosexual peers. These inequities are hypothesized to be reduced by building supportive high school environments via the training of school staff. An intervention that trains school staff to better understand and support sexual and gender minority youths and engage in positive bystander behaviors that protect them from bullying exposure may reduce disparities in drug and alcohol use among them. Experts, school staff, and sexual and gender minority youths developed Providing LGBTQ+ Adolescents with Nurturance, Trustworthiness, and Safety (PLANTS), a web-based intervention to train school staff on how to support, affirm, and protect sexual and gender minority youths. OBJECTIVE: This paper describes the design of the PLANTS pilot trial primarily aimed at assessing its acceptability, usability, appropriateness, and feasibility. We hypothesize PLANTS will have high acceptability, usability, appropriateness, and feasibility as rated by the school staff. Secondary objectives focus on implementation, safety, and pre-post changes in high school staff outcomes, including self-efficacy and skills (eg, active-empathic listening and bullying intervention). Exploratory objectives focus on the impact of PLANTS on student health outcomes. METHODS: In a 2-arm cluster randomized controlled trial, high schools in Massachusetts are allocated to PLANTS or an active comparator group (publicly available sexual and gender minority youths resources or training). High school staff complete pretest and posttest surveys containing validated scales. Primary outcomes are validated measures of acceptability, usability, appropriateness, and feasibility of the intervention completed by staff during posttest surveys. To test our primary hypotheses for each outcome, we will calculate means and 95% CIs and P values using 1-sample 2-sided t tests against a priori thresholds or benchmarks of success. Secondary outcomes include staff's active-empathetic listening skills, self-efficacy for working with sexual and gender minority youths, bystander intervention behaviors for bullying and cyberbullying, and self-efficacy for PLANTS' change objectives completed during pretest and posttest staff surveys. Staff can also complete a posttest interview guided by the Information-Motivation-Behavior model and Consolidated Framework for Implementation Research. Exploratory outcomes include student-level data collected via the 2021 and 2023 MetroWest Adolescent Health Surveys, a health behavior surveillance system in 30 Massachusetts schools. RESULTS: School enrollment began in May 2023 and participant enrollment began in June 2023. Data collection is expected to be completed by February 2024. CONCLUSIONS: This pilot trial will yield important information about the PLANTS intervention and provide necessary information to conduct a fully powered trial of the efficacy of PLANTS for reducing the deleterious health inequities experienced by sexual and gender minority youths. TRIAL REGISTRATION: ClinicalTrials.gov NCT05897827; https://clinicaltrials.gov/study/NCT05897827. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55210.

3.
Res Sq ; 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38464196

RESUMO

Background: Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with poor survival rates, especially for cancers arising in the oral cavity or larynx. Cisplatin is a key chemotherapeutic for HNSCC; however poor survival rates may be partially due to cisplatin resistance observed in some HNSCCs. Here, we examined the utility of genome-wide CRISPR knockout profiling for nominating pivotal mechanisms of cisplatin resistance in HNSCC models. Methods: We characterized the cisplatin sensitivity of 18 HNSCC cell lines. Next, we used a genome-wide CRISPR/Cas9 library to identify genes involved in cisplatin resistance. We next performed validation assays in the UM-SCC-49 cell line model. Results: Our data prioritized 207 genes as pivotal for cisplatin resistance in HNSCC, including novel genes VGLL3, CIRHA1, NCOR1, SPANXA1, MAP2K7, ULK1, and CDK16. Gene set enrichment analysis identified several NOTCH family genes comprising the top pathway driving cisplatin resistance, which we then validated using a targeted NOTCH1 knockout model. Interestingly, we noted that HNSCC models with natural NOTCH pathway alterations including single allele mutations and/or frameshift alterations had diverse responses to cisplatin treatment suggesting that complex and multi-faceted mechanisms contribute to cisplatin resistance in HNSCC. Conclusions: Collectively, our study validates a genome-wide CRISPR/Cas9 approach for the discovery of resistance mechanisms in HNSCC, adds to the growing evidence that NOTCH1 status should be evaluated as a biomarker of cisplatin response and provides a framework for future work aimed at overcoming cisplatin resistance.

4.
J Cell Biol ; 223(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38478018

RESUMO

The essential Golgi protein Sly1 is a member of the Sec1/mammalian Unc-18 (SM) family of SNARE chaperones. Sly1 was originally identified through remarkable gain-of-function alleles that bypass requirements for diverse vesicle tethering factors. Employing genetic analyses and chemically defined reconstitutions of ER-Golgi fusion, we discovered that a loop conserved among Sly1 family members is not only autoinhibitory but also acts as a positive effector. An amphipathic lipid packing sensor (ALPS)-like helix within the loop directly binds high-curvature membranes. Membrane binding is required for relief of Sly1 autoinhibition and also allows Sly1 to directly tether incoming vesicles to the Qa-SNARE on the target organelle. The SLY1-20 mutation bypasses requirements for diverse tethering factors but loses this ability if the tethering activity is impaired. We propose that long-range tethers, including Golgins and multisubunit tethering complexes, hand off vesicles to Sly1, which then tethers at close range to initiate trans-SNARE complex assembly and fusion in the early secretory pathway.


Assuntos
Vesículas Citoplasmáticas , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Animais , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Mamíferos/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Munc18/análise , Proteínas Munc18/genética , Proteínas Munc18/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Vesículas Citoplasmáticas/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo
5.
Open Forum Infect Dis ; 11(3): ofad694, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38449916

RESUMO

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

6.
J Adolesc Health ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38493394

RESUMO

PURPOSE: The purpose of this study was to identify factors affecting contraceptive intention and behavior among adolescent females in the pediatric Emergency Department. METHODS: We conducted a qualitative interview study nested within a larger prospective cohort study examining adolescent contraceptive counseling for females ages 15-18 years at-risk of unintended pregnancy presenting to the pediatric Emergency Department. Interviews were conducted in a subset of participants. The ecologically expanded Theory of Planned Behavior, expert opinion, and literature review informed the interview guide. Interviews were recorded, transcribed, coded and monitored for thematic saturation. RESULTS: Twenty-eight interviews were analyzed. Mean age was 17.1 years. Themes were mapped to ecologically expanded Theory of Planned Behavior constructs. Within health system influences, prior contraceptive experiences and patient-clinician interactions were described. Within community influences, contraceptive education, knowledge and misinformation, teen pregnancy norms, and social media impacts were described. Within attitudes influences, side-effect and safety concerns, contraceptive motivations and teen pregnancy beliefs were described. Within subjective norm influences, peer and family impacts were described. Within perceived behavioral control, Emergency Department (ED) counseling intervention impacts were described. DISCUSSION: We identified factors affecting contraceptive initiation/behavior among an ED adolescent population that otherwise may not have received contraceptive education in similar detail as provided by study clinicians. Adolescents' prior contraceptive and clinician interactions, limited access to contraceptive education, knowledge and misinformation, and side-effect and safety concerns affected initiation. Peer/family sharing and social media were leading contraceptive information sources. Future studies should incorporate insights into adolescent ED intervention design to make optimal use of resources while maximizing potential benefit.

7.
J Med Primatol ; 53(2): e12694, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38454198

RESUMO

BACKGROUND: Animal models of respiratory viral infections are essential for investigating disease pathogenesis and the efficacy of antivirals and vaccine candidates. A major limitation in the research of respiratory diseases in animal models is correlating clinically relevant changes in pulmonary physiology with cellular and molecular mechanistic studies. Few animal models have captured and correlated physiologic changes in lung function and immune response within same experiment, which is critical given the heterogeneous nature of lung disease due to viral infections. In ventilated human patients, pulmonary physiology testing can be used to not only capture oxygenation, ventilation, but also pulmonary mechanics to yield quantitative measures of lung function and scalar tracings of flow-volume and pressure-volume loops. Application of this protocol during mechanical ventilation in non-human (NHP) models would represent a major advance in respiratory viral disease research. METHODS: We have applied and optimized a human pulmonary physiology testing protocol to ventilated pigtail macaques (Macaca nemestrina) at baseline and 5 days after influenza A (IAV) viral inoculation. RESULTS: The NHPs manifested clinical disease with hypothermia and loss of body weight. Declines in lung function were striking with a 66%-81% decline in P/F ratio, a measure of oxygenation reflecting the ratio of partial pressure of oxygen in arterial blood (PaO2 ) to the fraction of inspiratory oxygen concentration (FiO2 ). There was also a 16%-45% decline in lung compliance. CONCLUSION: We describe a new approach to performing pulmonary physiology testing protocol in non-human primates to better capture quantitative correlates of respiratory disease and demonstrate protection by therapeutics and vaccines.


Assuntos
Pulmão , Viroses , Humanos , Animais , Respiração Artificial/métodos , Oxigênio , Primatas
9.
J Interpers Violence ; : 8862605241233267, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38379210

RESUMO

Firearms are the leading cause of pediatric deaths. Few studies have identified protective factors that reduce the risk of firearm violence. Interpersonal factors, including school connectedness and social support, protect against multiple health-affecting risk behaviors. Therefore, this study examines associations of school connectedness and social support with firearm and weapon violence involvement. Data were gathered through an anonymous survey conducted across 13 high schools within an urban school district in 2018 (n = 2,604) modeled on the Centers for Disease Control and Prevention Youth Risk Behavior Surveillance Survey. Separate hierarchical logistic regression models examined associations between school connectedness and social support, and the outcomes of firearm carrying and engaging in violence with a weapon on school property in the past 12 months. Models were adjusted for age, race, and covariates representing basic needs, education, and mental health. The mean age was 15.7 years, and 57.5% of youth were female. 5.8% of youth had carried firearms and 5.5% engaged in violence with a weapon on school property in the past 12 months. School connectedness was significantly inversely associated with engaging in violence with a weapon on school property (odds ratio [OR] 0.225, 95% confidence interval [CI] [0.080, 0.632] and high levels of social support were significantly inversely associated with firearm carrying (OR 0.522, 95% CI [0.313, 0.870]). School connectedness and social support may be important in protecting youth from firearm and weapon-related violence. Interventions that strengthen safe and supportive interpersonal relationships within school environments and broader support systems across contexts may help reduce firearm and weapon violence involvement.

10.
Vaccines (Basel) ; 12(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38400097

RESUMO

BACKGROUND: We investigated whether COVID-19 vaccination reduced SARS-CoV-2 infection risk among adult household contacts of COVID-19 index cases during the Alpha, Delta, and Omicron waves in England. METHODS: Between February 2021 and February 2022, SARS-CoV-2 RT-PCR nasal swabs were collected from COVID-19-confirmed index cases aged ≥20 years and their household contacts at enrolment and three and seven days thereafter. Generalized Estimating Equations models were fitted with SARS-CoV-2 positivity as the outcome and household contacts' vaccination status as the main exposure while adjusting for confounders. RESULTS: SARS-CoV-2 infection was confirmed in 238/472 household contacts (50.4%) aged ≥20 years. The adjusted relative risk (95% confidence interval) of infection in vaccinated versus unvaccinated household contacts was 0.50 (0.35-0.72) and 0.69 (0.53-0.90) for receipt of two doses 8-90 and >90 days ago, respectively, and 0.34 (0.23-0.50) for vaccination with three doses 8-151 days ago. Primary vaccination protected household contacts against infection during the Alpha and Delta waves, but only three doses protected during the Omicron wave. Vaccination with three doses in the index case independently reduced contacts' infection risk: 0.45 (0.23-0.89). CONCLUSIONS: Vaccination of household contacts reduces their risk of infection under conditions of household exposure though, for Omicron, only after a booster dose.

11.
BMC Med Res Methodol ; 24(1): 53, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418949

RESUMO

BACKGROUND: Public health initiatives, including human biomonitoring, have been impacted by unique challenges since the onset of the COVID-19 pandemic, compounding a decades-long trend of declining public participation. To combat low public participation rates, public health professionals often employ extensive engagement approaches including in-person interactions related to enrollment and sampling, success of which is an essential component of a statistically defensible study. The onset of the COVID-19 pandemic challenged public health programs to diversify engagement and sampling approaches, limiting direct interactions for the health and safety of the population. This study explores biomonitoring recruitment strategies through non-contact mechanisms and evaluate the application feasibility for population-based studies. METHODS: The Iowa Biomonitoring Program at the State Hygienic Laboratory developed a human biomonitoring study that utilized a multifaceted, distance-based approach. Traditional techniques, such as mailed recruitment invitations and phone-based discussions, were coupled with internet-based surveys and self-collected, shipped urine and water samples. Participation rates were evaluated by employing different mailing methods, and the demographics of enrolled participants were examined. RESULTS: This non-human contact approach achieved a nearly 14% participation rate among a rural population, well above our target rates. Our improved mailing strategy for targeting initially unresponsive participants yielded a significantly increase in the participation rates. The respondents were predominantly individuals with educational attainment of at least high school level. Among all the eligible participants, 83% submitted self-collected samples, a rate comparable to the National Health and Nutrition Examination Survey which involved in-person interviews. CONCLUSIONS: The practice of engaging a rural population during the COVID-19 pandemic by transitioning from face-to-face interactions to a combination of mailing and internet-based approaches resulted in higher-than-expected participant recruitment and sample collection rates. Given the declining trend in the response rates for population-based survey studies, our results suggest conducting human biomonitoring without direct human interaction is feasible, which provides further opportunity to improve response rates and the relevance and reach of public health initiatives.


Assuntos
Monitoramento Biológico , COVID-19 , Humanos , Saúde Pública , Inquéritos Nutricionais , Pandemias , COVID-19/epidemiologia
12.
J Org Chem ; 89(5): 3058-3064, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38354334

RESUMO

When electron-rich arylpyrrolinium salts are irradiated with ultraviolet light in the presence of Michael acceptors, the pyrrolinyl and aryl fragments add to the activated and polarized double bond in a regioselective manner, forming two C-C bonds and fragmenting the substrate. In this paper, we present a model for this intriguing reaction, supported by spectroscopy and computational analyses, and provide evidence for rectifying previously misassigned structures. We postulate that the photochemical reaction is inefficient because the reaction between the twisted intramolecular charge-transfer state and the olefin competes with fluorescence from this state upon photon absorption. We also discuss the practical advantages of performing this photochemical reaction in a continuous flow setup. Additionally, we explore several subsequent reactions that allow us to further modify the products of the photochemical step, ultimately leading to the creation of new chemical structures.

13.
Alzheimers Dement (N Y) ; 10(1): e12453, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38356470

RESUMO

INTRODUCTION: Hearing loss is highly prevalent among older adults and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a multicenter randomized control trial (partially nested within the infrastructure of an observational cohort study, the Atherosclerosis Risk in Communities [ARIC] study) to determine the efficacy of best-practice hearing treatment to reduce cognitive decline over 3 years. The goal of this paper is to describe the recruitment process and baseline results. METHODS: Multiple strategies were used to recruit community-dwelling 70-84-year-old participants with adult-onset hearing loss who were free of substantial cognitive impairment from the parent ARIC study and de novo from the surrounding communities into the trial. Participants completed telephone screening, an in-person hearing, vision, and cognitive screening, and a comprehensive hearing assessment to determine eligibility. RESULTS: Over a 24-month period, 3004 telephone screenings resulted in 2344 in-person hearing, vision, and cognition screenings and 1294 comprehensive hearing screenings. Among 1102 eligible, 977 were randomized into the trial (median age = 76.4 years; 53.5% female; 87.8% White; 53.3% held a Bachelor's degree or higher). Participants recruited through the ARIC study were recruited much earlier and were less likely to report hearing loss interfered with their quality of life relative to participants recruited de novo from the community. Minor differences in baseline hearing or health characteristics were found by recruitment route (i.e., ARIC study or de novo) and by study site. DISCUSSION: The ACHIEVE study successfully completed enrollment over 2 years that met originally projected rates of recruitment. Substantial operational and scientific efficiencies during study startup were achieved through embedding this trial within the infrastructure of a longstanding and well-established observational study. Highlights: The ACHIEVE study tests the effect of hearing intervention on cognitive decline.The study is partially nested within an existing cohort study.Over 2 years, 977 participants recruited and enrolled.Eligibility assessed by telephone and in-person for hearing, vision, and cognitive screening.The ACHIEVE study findings will have significant public health implications.

14.
Pediatr Cardiol ; 45(4): 821-828, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38416202

RESUMO

Differences in surveillance methods have resulted in significant variability in referral volumes and referral completion rates across cardiac neurodevelopmental programs, with frequent barriers to referral completion including high no-show rates, lack of education, and inaccessibility for underrepresented populations. The purpose of this study was to describe implementation of a standardized surveillance program and investigate impact on referral volume and completion over a two-year period. Between fiscal years 2021 and 2022, a surveillance program was implemented which standardized assessment of neurodevelopmental risk via a checklist as well as family education and referral procedures. All patients referred to the cardiac neurodevelopmental program during these two fiscal years were included in the analysis, and patient referrals were categorized as complete or incomplete (due to physician-related or patient-related factors). Referral completion rates between fiscal years were compared using two sample Z test of proportions, while associations between referral completion and demographic/anatomical variables were completed using chi-square tests of independence. Implementation of the formal surveillance program resulted in a 66.7% increase in referral volume. Proportions of both incomplete referrals (z = 2.00, p < 0.05) and incomplete referrals due to physician-related factors (z = 4.34, p < 0.01) were significantly lower after implementation. A significant association was found after implementation between referral completion and race/ethnicity (x2 = 14.08, p < 0.01) due to a significantly high proportion of completed referrals for patients identifying as Hispanic/Latino within the overall distribution of patients. This study describes the successful implementation of a standardized surveillance program, including improvements to referral volume and completion rate. Findings also support implementation of methods that emphasize physician surveillance methods and improve accessibility for historically marginalized groups at greatest risk for disparities in access and quality of care.


Assuntos
Encaminhamento e Consulta , Humanos
15.
Biologicals ; 85: 101750, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38360428

RESUMO

The COVID-19 pandemic underscored the need for rapid evidence generation to inform public health decisions beyond the limitations of conventional clinical trials. This report summarises presentations and discussions from a conference on the role of Real-World Evidence (RWE) in expediting vaccine deployment. Attended by regulatory bodies, public health entities, and industry experts, the gathering was a collaborative exchange of experiences and recommendations for leveraging RWE for vaccine deployment. RWE proved instrumental in refining decision-making processes to optimise dosing regimens, enhance guidance on target populations, and steer vaccination strategies against emerging variants. Participants felt that RWE was successfully integrated into lifecycle management, encompassing boosters and safety considerations. However, challenges emerged, prompting a call for improvements in data quality, standardisation, and availability, acknowledging the variability and potential inaccuracies in data across diverse healthcare systems. Regulatory transparency should also be prioritised to foster public trust, and improved collaborations with governments are needed to streamline data collection and navigate data privacy regulations. Moreover, building and sustaining resources, expertise, and infrastructure in LMICs emerged as imperative for RWE-generating capabilities. Continued stakeholder collaboration and securing adequate funding emerged as vital pillars for advancing the use of RWE in shaping responsive and effective public health strategies.


Assuntos
Pandemias , Vacinas , Humanos , Pandemias/prevenção & controle , Saúde Pública
16.
ISME Commun ; 4(1): ycae002, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38390521

RESUMO

Pneumococcal carriage studies have suggested that pneumococcal colonization in adults is largely limited to the oral cavity and oropharynx. In this study, we used total abundance-based ß-diversity (dissimilarity) and ß-diversity components to characterize age-related differences in pneumococcal serotype composition of respiratory samples. quantitative PCR (qPCR) was applied to detect pneumococcal serotypes in nasopharyngeal samples collected from 946 toddlers and 602 adults, saliva samples collected from a subset of 653 toddlers, and saliva and oropharyngeal samples collected from a subset of 318 adults. Bacterial culture rates from nasopharyngeal samples were used to characterize age-related differences in rates of colonizing bacteria. Dissimilarity in pneumococcal serotype composition was low among saliva and nasopharyngeal samples from children. In contrast, respiratory samples from adults exhibited high serotype dissimilarity, which predominantly consisted of abundance gradients and was associated with reduced nasopharyngeal colonization. Age-related serotype dissimilarity was high among nasopharyngeal samples and relatively low for saliva samples. Reduced nasopharyngeal colonization by pneumococcal serotypes coincided with significantly reduced Moraxella catarrhalis and Haemophilus influenzae and increased Staphylococcus aureus nasopharyngeal colonization rates among adults. Findings from this study suggest that within-host environmental conditions, utilized in the upper airways by pneumococcus and other bacteria, undergo age-related changes. It may result in a host-driven ecological succession of bacterial species colonizing the nasopharynx and lead to competitive exclusion of pneumococcus from the nasopharynx but not from the oral habitat. This explains the poor performance of nasopharyngeal samples for pneumococcal carriage among adults and indicates that in adults saliva more accurately represents the epidemiology of pneumococcal carriage than nasopharyngeal samples.

18.
PNAS Nexus ; 3(1): pgae006, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38269070

RESUMO

A number of intrinsically disordered proteins (IDPs) encoded in stress-tolerant organisms, such as tardigrade, can confer fitness advantage and abiotic stress tolerance when heterologously expressed. Tardigrade-specific disordered proteins including the cytosolic-abundant heat-soluble proteins are proposed to confer stress tolerance through vitrification or gelation, whereas evolutionarily conserved IDPs in tardigrades may contribute to stress tolerance through other biophysical mechanisms. In this study, we characterized the mechanism of action of an evolutionarily conserved, tardigrade IDP, HeLEA1, which belongs to the group-3 late embryogenesis abundant (LEA) protein family. HeLEA1 homologs are found across different kingdoms of life. HeLEA1 is intrinsically disordered in solution but shows a propensity for helical structure across its entire sequence. HeLEA1 interacts with negatively charged membranes via dynamic disorder-to-helical transition, mainly driven by electrostatic interactions. Membrane interaction of HeLEA1 is shown to ameliorate excess surface tension and lipid packing defects. HeLEA1 localizes to the mitochondrial matrix when expressed in yeast and interacts with model membranes mimicking inner mitochondrial membrane. Yeast expressing HeLEA1 shows enhanced tolerance to hyperosmotic stress under nonfermentative growth and increased mitochondrial membrane potential. Evolutionary analysis suggests that although HeLEA1 homologs have diverged their sequences to localize to different subcellular organelles, all homologs maintain a weak hydrophobic moment that is characteristic of weak and reversible membrane interaction. We suggest that such dynamic and weak protein-membrane interaction buffering alterations in lipid packing could be a conserved strategy for regulating membrane properties and represent a general biophysical solution for stress tolerance across the domains of life.

19.
Prev Sci ; 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38214789

RESUMO

Sexual violence (SV) on college campuses disproportionately affects cisgender (nontransgender) women, sexual minorities (e.g., gays/lesbians, bisexuals), and gender minority (e.g., transgender/nonbinary) people. This study investigates gender and sexual behavior differences in common SV intervention targets-SV-related knowledge, prevention behaviors, and care-seeking. We analyzed cross-sectional survey data, collected in 9/2015-3/2017, from 2202 students aged 18-24 years attending college health and counseling centers at 28 Pennsylvania and West Virginia campuses. Multivariable multilevel models tested gender and sexual behavior differences in SV history; recognition of SV; prevention behaviors (self-efficacy to obtain sexual consent, intentions to intervene, positive bystander behaviors); and care-seeking behaviors (knowledge of, self-efficacy to use, and actual use of SV services). Adjusting for lifetime exposure to SV, compared with cisgender men, cisgender women had higher recognition of SV and reproductive coercion, prevention behaviors, and care-seeking self-efficacy (beta range 0.19-1.36) and gender minority people had higher recognition of SV and intentions to intervene (beta range 0.33-0.61). Cisgender men with any same-gender sexual partners had higher SV knowledge (beta = 0.23) and self-efficacy to use SV services (beta = 0.52) than cisgender men with only opposite-gender partners. SV history did not explain these differences. Populations most vulnerable to SV generally have higher SV knowledge, prevention behaviors, and care-seeking behaviors than cisgender men with only opposite-gender sexual partners. Innovative SV intervention approaches are necessary to increase SV-related knowledge among heterosexual cisgender men and may need to target alternative mechanisms to effectively reduce inequities for sexual and gender minority people.

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