RESUMO
INTRODUCTION: Transportation databases have limited data regarding injury severity of pedestrian versus automobile patients. To identify opportunities to reduce injury severity, transportation and trauma databases were integrated to examine the differences in pedestrian injury severity at street crossings that were signalized crossings (SCs) versus nonsignalized crossings (NSCs). It was hypothesized that trauma database integration would enhance safety analysis and pedestrians struck at NSC would have greater injury severity. METHODS: Single-center retrospective review of all pedestrian versus automobile patients treated at a level 1 trauma center from 2014 to 2018 was performed. Patients were matched to the transportation database by name, gender, and crash date. Google Earth Pro satellite imagery was used to identify SC versus NSC. Injury severity of pedestrians struck at SC was compared to NSC. RESULTS: A total of 512 patients were matched (median age = 41 y [Q1 = 26, Q3 = 55], 74% male). Pedestrians struck at SC (n = 206) had a lower injury severity score (ISS) (median = 9 [4, 14] versus 17 [9, 26], P < 0.001), hospital length of stay (median = 3 [0, 7] versus 6 [1, 15] days, P < 0.001), and mortality (21 [10%] versus 52 [17%], P = 0.04), as compared to those struck at NSC (n = 306). The transportation database had a sensitivity of 63.4% (55.8%-70.4%) and specificity of 63.4% (57.7%-68.9%) for classifying severe injuries (ISS >15). CONCLUSIONS: Pedestrians struck at SC were correlated with a lower ISS and mortality compared to those at NSC. Linkage with the trauma database could increase the transportation database's accuracy of injury severity assessment for nonfatal injuries. Database integration can be used for evidence-based action plans to reduce pedestrian morbidity, such as increasing the number of SC.
Assuntos
Pedestres , Ferimentos e Lesões , Humanos , Masculino , Adulto , Feminino , Acidentes de Trânsito/prevenção & controle , Meios de Transporte , Centros de Traumatologia , Bases de Dados Factuais , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/epidemiologiaRESUMO
Intimate partner violence (IPV) has been implicated in HIV acquisition and worse HIV outcomes. Limited research focuses on the experiences of Black gay and bisexual men. Using data from cross-sectional surveys in Baltimore, Maryland, and Jackson, Mississippi, we analyzed the association between IPV victimization and HIV-related outcomes among 629 adult Black gay and bisexual men, among whom 53% self-reported a negative result at last HIV test. 40% of participants reported lifetime physical, sexual, and/or psychological IPV victimization, and 24% past-year victimization. Recent and lifetime IPV were associated with recent clinical diagnosis of STI (adjPrR: 1.44; 95%CI: 1.08-1.92) and ART medication interruptions (adjPrR: 1.59; 95%CI: 1.25-2.01), respectively. Physical IPV was inversely associated with current PrEP use (adjPrR: 0.35; 95%CI: 0.13-0.90). Recent IPV was independently correlated with depression symptomatology (adjPrR: 2.36; 95%CI: 1.61-3.47) and hazardous alcohol use (adjPrR: 1.93; 95%CI: 1.42-2.61), with evidence of interactions. IPV-HIV relationships were intersected by internalized stigma, housing instability, poverty, and lack of insurance. Tailored IPV services are urgently needed for comprehensive HIV services for Black gay and bisexual men in the U.S.
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Infecções por HIV , Violência por Parceiro Íntimo , Minorias Sexuais e de Gênero , Adulto , Estudos Transversais , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/psicologia , Humanos , Masculino , Prevalência , Sindemia , Estados Unidos/epidemiologiaRESUMO
There is a dearth of research on the intersection of incarceration and psychological distress among men who have sex with men including African American (AAMSM) and Latino MSM (LMSM), populations which bear a large burden of HIV in the U.S. Recent incarceration is an important context to examine psychological distress given the critical implications it has on health outcomes. Using baseline data from the Latino and African American Men's Project (LAAMP), a multi-site randomized HIV behavioral intervention trial, this paper examined the association between previous incarceration within the past three months (i.e., recent incarceration) and psychological distress in the past four weeks, assessed by the Kessler Psychological Distress Scale (K10). Among 1482 AAMSM and LMSM (AAMSM: 911, LMSM: 571), we found 768 (52%) were previously incarcerated, but not in past three months and 138 (9.3%) had been recently incarcerated. After adjusting for race, education, access to resources, current living arrangement, HIV status, and substance use, participants who had been recently incarcerated were more likely to have mild psychological distress i.e., K10 score 20-24 (aRRR:1.43, 95% CI 1.20, 1.71) or severe psychological distress, i.e., K10 score > 30 (aRRR: 1.89, 95% CI 1.22, 2.93) in the past four weeks than those never incarcerated and those previously incarcerated, but not in past three months. Our findings have implications for mental health and HIV prevention services for AAMSM and LMSM with previous incarceration within the past three months.
Assuntos
Infecções por HIV , Angústia Psicológica , Minorias Sexuais e de Gênero , Negro ou Afro-Americano/psicologia , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Hispânico ou Latino , Homossexualidade Masculina , Humanos , MasculinoRESUMO
Tumor susceptibility gene 101 (TSG101) is involved in endosomal maturation and has been implicated in the transcriptional regulation of several steroid hormone receptors, although a detailed characterization of such regulation has yet to be conducted. Here we directly measure binding of TSG101 to one steroid hormone receptor, the glucocorticoid receptor (GR). Using biophysical and cellular assays, we show that the coiled-coil domain of TSG101 (1) binds and folds the disordered N-terminal domain of the GR, (2) upon binding improves the DNA binding of the GR in vitro, and (3) enhances the transcriptional activity of the GR in vivo. Our findings suggest that TSG101 is a bona fide transcriptional co-regulator of the GR and reveal how the underlying thermodynamics affect the function of the GR.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/fisiologia , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Proteínas de Ligação a DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Endossomos/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Células HeLa , Humanos , Ligação Proteica , Domínios Proteicos/fisiologia , Elementos Reguladores de Transcrição/fisiologia , Fatores de Transcrição/genética , Transcrição Gênica/genética , Ativação Transcricional/genéticaRESUMO
Cisgender men who have sex with transgender women face elevated risk for HIV, yet are understudied in prevention research. We conducted in-depth interviews with 19 men who have sex with transgender women in Baltimore, Maryland and Atlanta, Georgia to explore perspectives on HIV prevention. Participants used several strategies to reduce HIV risk: condoms, frequent HIV testing, communication about HIV status with partners, and limiting the types of sex acts performed. While condom use was inconsistent, it was preferred over pre-exposure prophylaxis, in part due to medical distrust. HIV self-testing was generally viewed unfavorably. Although most participants were referred to the study by their transgender women partners, they recommended reaching other men who have sex with transgender women in bars, nightclubs, online, and through social media. HIV prevention interventions should be inclusive of the needs and experiences of men who have sex with transgender women.
Assuntos
Infecções por HIV , Pessoas Transgênero , Baltimore/epidemiologia , Feminino , Georgia/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Humanos , MasculinoRESUMO
The N-linked biantennary glycans on the heavy chain of immunoglobulin G (IgG) antibodies (mAbs) are instrumental in the recognition of the Fc region by Fc-gamma receptors (FcγR). In the case of full-length mAb-based imaging tracers targeting immune cell populations, these Fc:FcγR interactions can potentially deplete effector cells responsible for tumor clearance. To bypass this problem, we hypothesize that the enzymatic removal of the Fc glycans will disrupt Fc:FcγR interactions and spare tracer-targeted immune cells from depletion during immunopositron emission tomography (immunoPET) imaging. Herein, we compared the in vitro and in vivo properties of 89Zr-radiolabeled CD8-specific murine mAb (anti-CD8wt, clone 2.43), a well-known depleting mAb, and its deglycosylated counterpart (anti-CD8degly). Deglycosylation was achieved via enzymatic treatment with the peptide: N-glycosidase F (PNGaseF). Both anti-CD8wt and anti-CD8degly mAbs were conjugated to p-SCN-Bn-desferrioxamine (DFO) and labeled with 89Zr. Bindings of both DFO-conjugated mAbs to FcγR and CD8+ splenocytes were compared. In vivo imaging and distribution studies were conducted to examine the specificity and pharmacokinetics of the radioimmunoconjugates in tumor-naive and CT26 colorectal tumor-bearing mice. Ex vivo analysis of CD8+ T cell population in spleens and tumors obtained postimaging were measured via flow cytometry and qRT-PCR. The removal of the Fc glycans from anti-CD8wt was confirmed via SDS-PAGE. A reduction in FcγR interaction was exhibited by DFO-anti-CD8degly, while its binding to CD8 remained unchanged. Tissue distribution showed similar pharmacokinetics of [89Zr]Zr-DFO-anti-CD8degly and the wt radioimmunoconjugate. In vivo blocking studies further demonstrated retained specificity of the deglycosylated radiotracer for CD8. From the imaging studies, no difference in accumulation in both spleens and tumors was observed between both radiotracers. Results from the flow cytometry analysis confirmed depletion of CD8+ T cells in spleens of mice administered with DFO-anti-CD8wt, whereas an increase in CD8+ T cells was shown with DFO-anti-CD8degly. No statistically significant difference in tumor infiltrating CD8+ T cells was observed in cohorts administered with the probes when compared to control unmodulated mice. CD8 mRNA levels from excised tumors showed increased transcripts of the antigen in mice administered with [89Zr]Zr-DFO-anti-CD8degly compared to mice imaged with [89Zr]Zr-DFO-anti-CD8wt. In conclusion, the removal of Fc glycans offers a straightforward approach to develop full length antibody-based imaging probes specifically for detecting CD8+ immune molecules with no consequential depletion of their target cell population in peripheral tissues.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Animais , Linhagem Celular , Citometria de Fluxo , Humanos , Imunoconjugados/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tomografia por Emissão de Pósitrons , RadioquímicaRESUMO
TRA-1-60 (TRA) is a cell-surface antigen implicated in drug resistance, relapse, and recurrence. Its expression has been reported in breast, prostate, pancreatic, ovarian tumors, and follicular lymphoma, which paved the development of the therapeutic antibody, Bstrongomab (Bsg), and its drug conjugates. Because patient selection is critical to achieve clinical benefit, a noninvasive imaging agent to select TRA+ lesions in patients is needed. Herein, we report the development of the immunopositron emission tomography (immunoPET) radiotracer 89Zr-radiolabeled Bsg and its potential to delineate TRA+ tumors. Bsg was conjugated to the bifunctional chelator desferrioxamine (DFO) and radiolabeled with [89Zr]Zr-oxalate. [89Zr]Zr-DFO-Bsg was characterized in vitro and evaluated in vivo for uptake and specificity in high and low TRA-expressing BxPC-3 pancreatic and PC-3 prostate cancer models, respectively. Uptake was compared against [89Zr]Zr-DFO-IgG, a nonspecific control radiotracer. Immunohistochemical (IHC) staining of patient cancer tissues using Bsg was performed to explore its clinical significance. A specific activity of 0.18 ± 0.01 GBq/mg (4.8 ± 0.3 mCi/mg) was obtained for [89Zr]Zr-DFO-Bsg. BxPC-3 xenografts exhibited three-fold higher radiotracer uptake compared to [89Zr]Zr-DFO-IgG. Competitive saturation studies using BxPC-3 xenografts further confirmed tracer specificity. The TRA-specific probe had lower accumulation in PC-3 xenografts. Ex vivo autoradiographs correlated with TRA expression from the histopathology of the resected tumor xenografts. Additionally, patient cancer tissues demonstrated positive staining with Bsg with metastatic lesions exhibiting the highest staining. This study demonstrates the potential of [89Zr]Zr-DFO-Bsg as an imaging agent for noninvasive detection of TRA+ tumors.
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Antígenos de Superfície/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias da Próstata/metabolismo , Proteoglicanas/metabolismo , Radioisótopos/metabolismo , Zircônio/metabolismo , Animais , Linhagem Celular Tumoral , Quelantes/metabolismo , Desferroxamina/metabolismo , Humanos , Imunoconjugados/metabolismo , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Tomografia por Emissão de Pósitrons/métodosRESUMO
Employment status is a key social determinant of health, and many populations in the United States that are impacted by HIV have unequal access to education and employment opportunities which contributes to HIV-related disparities. Black men who have sex with men (BMSM) are one of the groups most heavily burdened by HIV. With improved health outcomes associated with advancements in HIV treatment, research suggests that more people living with HIV want to work. This study describes employment among BMSM living in Baltimore, assesses differences in employment by HIV status and assesses predictors of full-time employment among BMSM. The study found that BMSM have limited access to full-time employment and that this disparity is even more pronounced among BMSM living with HIV. Men living with HIV were less likely to be employed full-time compared to men not living with HIV controlling for education and social contextual factors (OR 0.40 95% CI (0.22-0.73)). HIV will most likely have important implications for employment patterns and trajectories of BMSM over the life course. Additional research is needed among BMSM living with HIV to understand work histories and experiences, facilitating factors, and the impact of various work experiences on the health and wellbeing.
Assuntos
Infecções por HIV , Minorias Sexuais e de Gênero , Baltimore/epidemiologia , Emprego , Homossexualidade Masculina , Humanos , Masculino , Estados UnidosRESUMO
Given the importance of spirituality and religion in the lives of many Black gay, bisexual, and other Black sexual minority men (SMM) and the need for additional resources to improve HIV outcomes within this population, research on how spiritual and religious support can promote HIV prevention and treatment among Black SMM is greatly needed. We conducted nine focus groups with 52 spiritual and religious Black SMM in Baltimore, Maryland, to explore opportunities for HIV-related programming that incorporates spiritual and/or religious supports. Thematic analysis of the focus group transcripts was conducted using an iterative constant comparison coding process. Participants expressed a desire for more spiritual/religious support in non-church-based settings and identified the use of peer supports, inclusion of prayer and gospel music, and messaging related to the ideas that God is love, the Bible says to treat yourself preciously, and taking care of your health can strengthen your relationship with God as ways in which this could be incorporated into HIV-related programming. Participants living with HIV identified the message of "keeping the faith" as important for maintaining their HIV treatment plans. Participants also expressed a need for parental supports to improve HIV-related outcomes for Black SMM and potentially expand opportunities for spiritual and religious support to Black SMM within the church. Spirituality and religion can influence HIV outcomes for Black SMM, and the strategies identified by Black SMM in this study could aid in designing culturally congruent HIV prevention and treatment programs situated in the community.
Assuntos
Negro ou Afro-Americano/psicologia , Infecções por HIV/psicologia , Homossexualidade Masculina/psicologia , Religião , Comportamento Sexual/psicologia , Espiritualidade , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Baltimore/epidemiologia , Infecções por HIV/epidemiologia , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Adulto JovemRESUMO
Black men who have sex with men (BMSM) bear a disproportionate burden of HIV in the USA. BMSM face stigma, discrimination and barriers to health care access, and utilization. Peers (male or female) may assist BMSM in navigating their health issues by engaging in communication to support in their health care needs. Individuals with high self-efficacy of communicating about men's health issues with peers can be trained as community popular opinion leaders (CPOLs) to change peer behaviors by promoting risk reduction communication. We examined the characteristics associated with high self-efficacy of communicating with peers about men's health issues among 256 BMSM from a behavioral HIV intervention conducted in Baltimore, Maryland. In the multivariate logistic model, gay identity (AOR: 2.10, 95% CI: 1.15,3.83), involvement in the house and ballroom community (AOR: 2.50, 95% CI: 1.14,5.49), larger number of network members who are living with HIV (AOR: 6.34, 95% CI: 1.48,27.11), and larger number of network members who would loan them money (AOR: 1.46, 95% CI: 1.05,2.03) were statistically significantly associated with high self-efficacy of communicating with peers about men's health issues. We also found that having depressive symptoms (AOR: 0.43, 95% CI: 0.24, 0.77) was negatively associated with high self-efficacy of communicating with peers about men's health issues. Findings from the current study can inform future studies to identify better CPOLs who are able to communicate effectively with peers about men's health issues for BMSM.
Assuntos
Negro ou Afro-Americano/psicologia , Comunicação , Promoção da Saúde/métodos , Homossexualidade Masculina/psicologia , Grupo Associado , Autoeficácia , Rede Social , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Baltimore , Acessibilidade aos Serviços de Saúde , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
In the USA, Black sexual minority men (BSMM) remain disproportionately impacted upon by HIV and other sexual health issues. Individuals who attend church have lower rates of morbidity and mortality than those that do not; however, church attendance presents a paradox of being protective for some health outcomes and a risk for others among this population. Lesbian, gay, bisexual, and transgender (LGBT) affirming churches may offer support, but little is known about the role of LGBT-affirming churches in the lives of BSMM and how they may impact HIV and other health outcomes. This study explored the role of LGBT-affirming churches in the lives of BSMM. Nine focus groups (N = 52) were conducted in Baltimore City, Maryland between December 2017 and April 2018. Thematic analysis evaluated domains related to how men perceived, experienced, and engaged with LGBT-affirming churches. Three primary themes identified: (1) preferring traditional church environments over LGBT-affirming churches; (2) experiencing the LGBT-affirming church as a space of acceptance, emotional healing, and modelling loving same-sex relationships; and (3) perceiving LGBT-affirming churches as opportunities to engage community members to promote the well-being of BSMM. A secondary theme identified involvement in the house and ballroom community as an LGBT-affirming religious experience.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Promoção da Saúde , Protestantismo , Minorias Sexuais e de Gênero/psicologia , Adulto , Negro ou Afro-Americano/psicologia , Baltimore , Grupos Focais , Humanos , MasculinoRESUMO
AIM: Clerkship-specific interactive reflective writing (IRW)-enhanced reflection may enhance professional identity formation (PIF), a fundamental goal of medical education. PIF process as revealed in students? reflective writing (RW) has been understudied. METHODS: The authors developed an IRW curriculum within a Family Medicine Clerkship (FMC) and analyzed students? reflections about challenging/difficult patient encounters using immersion-crystallization qualitative analysis. RESULTS: The qualitative analysis identified 26 unique emergent themes and five distinct thematic categories (1. Role of emotions, 2. Role of cognition, 3. Behaviorally responding to situational context, 4. Patient factors, and 5. External factors) as well as an emergent PIF model from a directed content analysis. The model describes students? backgrounds, emotions and previous experiences in medicine merging with external factors and processed during student?patient interactions. The RWs also revealed that processing often involves polarities (e.g. empathy/lack of empathy or encouragement/disillusionment) as well as dissonance between idealized visions and lived reality. CONCLUSIONS: IRW facilitates and ideally supports grappling with the lived reality of medicine; uncovering a "positive hidden curriculum" within medical education. The authors propose engaging learners in guided critical reflection about complex experiences for meaning-making within a safe learning climate as a valuable way to cultivate reflective, resilient professionals with "prepared" minds and hearts for inevitable challenges of healthcare practice.
Assuntos
Estágio Clínico , Narração , Identificação Social , Estudantes de Medicina/psicologia , Comportamento , Cognição , Currículo , Emoções , Empatia , Humanos , Relações Médico-PacienteRESUMO
INTRODUCTION: Focus groups are an important learning tool in HIV prevention research among U.S. Black men who have sex with men (BMSM), for whom incidence persists. Focus groups are useful in designing interventions, but many have struggled to engage BMSM in research. To optimize the utility of focus group methodology on HIV prevention among BMSM, this paper offers methodological considerations for conducting and managing focus groups with BMSM. METHODS: Perspectives come from the process of conducting nine focus groups (N = 52) to explore the role of religion and spirituality in the lives of BMSM in Baltimore City and how these concepts could be used to inform local HIV prevention interventions. RESULTS: Themes from field notes captured important concepts to consider regarding the following: recruitment and retention, recruiting from within the social network, screening for HIV status, focus group stratification, and focus group facilitation. DISCUSSION: Considerations and recommendations for mitigating the challenges in focus group research and enriching data collection with BMSM are outlined.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Grupos Focais/métodos , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/estatística & dados numéricos , Serviços Preventivos de Saúde/métodos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Adulto , HIV , Humanos , Masculino , ReligiãoRESUMO
TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Although various TTSPs have been characterized in detail biochemically and functionally, the basic properties of TMPRSS13 remain unclear. Here, we investigate the activation, inhibition, post-translational modification, and localization of TMPRSS13. We show that TMPRSS13 is a glycosylated, active protease and that its own proteolytic activity mediates zymogen cleavage. Full-length, active TMPRSS13 exhibits impaired cell-surface expression in the absence of the cognate Kunitz-type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 or HAI-2. Concomitant presence of TMPRSS13 with either HAI-1 or -2 mediates phosphorylation of residues in the intracellular domain of the protease, and it coincides with efficient transport of the protease to the cell surface and its subsequent shedding. Cell-surface labeling experiments indicate that the dominant form of TMPRSS13 on the cell surface is phosphorylated, whereas intracellular TMPRSS13 is predominantly non-phosphorylated. These data provide novel insight into the cellular properties of TMPRSS13 and highlight phosphorylation of TMPRSS13 as a novel post-translational modification of this TTSP family member and potentially other members of this family of proteases.
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Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/genética , Fosforilação , Serina Endopeptidases/genéticaRESUMO
OBJECTIVES: The effect of shoe-worn insoles on biomechanical variables in people with medial knee osteoarthritis has been studied extensively. The majority of research has focused specifically on the effect of lateral wedge insoles at the knee. The aim of this systematic review and meta-analysis was to summarise the known effects of different shoe-worn insoles on all biomechanical variables during level walking in this patient population to date. METHODS: Four electronic databases were searched to identify studies containing biomechanical data using shoe-worn insole devices in the knee osteoarthritis population. Methodological quality was assessed and a random effects meta-analysis was performed on biomechanical variables reported in three or more studies for each insole. RESULTS: Twenty-seven studies of moderate-to-high methodological quality were included in this review. The primary findings were consistent reductions in the knee adduction moment with lateral wedge insoles, although increases in ankle eversion with these insoles were also found. CONCLUSION: Lateral wedge insoles produce small reductions in knee adduction angles and external moments, and moderate increases in ankle eversion. The addition of an arch support to a lateral wedge minimises ankle eversion change, and also minimises adduction moment reductions. The paucity of available data on other insole types and other biomechanical outcomes presents an opportunity for future research.
Assuntos
Órtoses do Pé , Marcha , Osteoartrite do Joelho/fisiopatologia , Articulação do Tornozelo/fisiopatologia , Fenômenos Biomecânicos , Humanos , SapatosRESUMO
The tumor susceptibility gene-101 coiled coil domain (TSG101cc) is an integral component of the endosomal maturation machinery and cytokinesis, and also interacts with several transcription factors. The TSG101cc has been crystallized as a homotetramer but is known to interact with two of its binding partners as a heterotrimer. To investigate this apparent discrepancy, we examined the solution thermodynamics of the TSG101cc. Here, we use circular dichroism, differential scanning calorimetry, analytical ultracentrifugation, fluorescence, and structural thermodynamic analysis to investigate the structural stability and the unfolding of the TSG101cc. We demonstrate that TSG101cc exists in solution primarily as a tetramer, which unfolds in a two-state manner. Surprisingly, no homodimeric or homotrimeric species were detected. Structural thermodynamic analysis of the homotetrameric structure and comparison with known oligomeric coiled-coils suggests that the TSG101cc homotetramer is comparatively unstable on a per residue basis. Furthermore, the homotrimeric coiled-coil is predicted to be much less stable than the functional heterotrimeric coiled-coil in the endosomal sorting complex required for transport 1 (ESCRT1). These results support a model whereby the tetramer-monomer equilibrium of TSG101 serves as the cellular reservoir of TSG101, which is effectively outcompeted when its binding partners are present and the heteroternary complex can form.
Assuntos
Proteínas de Ligação a DNA/química , Complexos Endossomais de Distribuição Requeridos para Transporte/química , Fatores de Transcrição/química , Escherichia coli , Temperatura Alta , Concentração de Íons de Hidrogênio , Conformação Proteica , Domínios Proteicos , Desdobramento de ProteínaRESUMO
This article is part of a Special Issue "Energy Balance". Natural populations display a variety of reproductive responses to environmental cues, but the underlying physiology that causes these responses is largely unknown. This study tested the hypothesis that heritable variation in reproductive traits can be described by heritable variation in concentrations of hormones critical to both energy balance and reproduction. To test this hypothesis, we used mouse lines derived from a wild population and selectively bred for response to short day photoperiod. Reproductive and metabolic traits of Peromyscus leucopus display heritable variation when held in short photoperiods typical of winter. Our two lines of mice have phenotypes spanning the full range of variation observed in nature in winter. We tested male and female mice for heritable variation in fasted serum concentrations of three hormones involved in energetic regulation: leptin, insulin-like growth factor 1 (IGF-1) and insulin, as well as the effects of exogenous leptin and a high energy diet on reproductive maturation. Exogenous leptin decreased food intake, but protected males from the reduction in testis mass caused by equivalent food restriction in pair-fed, saline-infused controls. A high energy diet resulted in calorie adjustment by the mice, and failed to alter reproductive phenotype. Concentrations of the three hormones did not differ significantly between selection lines but had correlations with measures of food intake, fertility, blood glucose, and/or body mass. There was evidence of interactions between reproductive traits and hormones related to energy balance and reproduction, but this study did not find evidence that variation in these hormones caused variation in reproductive phenotype.
Assuntos
Metabolismo Energético/fisiologia , Insulina/sangue , Leptina/sangue , Peromyscus/fisiologia , Reprodução/fisiologia , Animais , Ingestão de Alimentos/fisiologia , Feminino , Fertilidade/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/farmacologia , Masculino , Fenótipo , FotoperíodoRESUMO
Objective: The northeastern state of Rhode Island (RI) has a Vaccinate Before You Graduate (VBYG) program that supplements the traditional primary care infrastructure by providing vaccines to adolescents while they are in school, with no out-of-pocket expenses. We analyzed data from RI's immunization registry to evaluate whether VBYG also reduces disparities in adolescent immunization rates. Methods: We identified adolescent and catch-up vaccines administered in RI to people who were aged 11-18 at any point during the 5-year study period of 2019-2023, and conducted bivariate and multivariate analyses of vaccine administration data by setting (VBYG clinics, community health centers [CHCs], all other primary care practices [oPCPs], other school-based clinics, and other sites) and adolescent demographics (racial and ethnic identity, insurance status, sex, and age at time of vaccine). Results: Of over 387,000 routine vaccines administered during the study period, 3.3 % were administered by a VBYG clinic despite significant declines during school closures associated with the early COVID-19 pandemic. VBYG-administered doses went to slightly older youth, and a higher proportion were catch-up doses (25.7 % versus 14.1 % for CHC doses and 6.5 % for oPCP). Youths received an average of 2.71 vaccines in VBYG clinics compared to 1.77 from oPCPs and 2.08 from CHCs. A higher proportion of vaccines administered by VBYG went to adolescents of color and those without private insurance than those administered by oPCPs. Conclusions: VBYG provides a model to other jurisdictions of a vaccine safety net for adolescents who may not otherwise receive recommended vaccines before exiting the school system.
RESUMO
BACKGROUND: Using data from the Rhode Island immunization registry from January 2019 through September 2022, we assessed whether adolescent routine vaccination rates are catching up on losses experienced early in the pandemic. METHODS: For Q1 2020-Q3 2022, we calculated the number of adolescents ages 11-18 receiving a routine vaccine as a percentage of the same quarter in 2019 along with the cumulative difference through Q3 2022. Human papillomavirus (HPV) vaccine trends were further stratified by racial/ethnic identity and by sex. RESULTS: Except for Q1 2021, the number of adolescents receiving each vaccine in each calendar quarter since Q1 2020 was below 100% of the same quarter in 2019, resulting in cumulative "losses" or "deficits" relative to pre-pandemic numbers. CONCLUSIONS: We describe ways Rhode Island can expand on its existing partnerships between primary care providers, public health, and schools to address the decline in adolescent routine vaccination.