Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation.

Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.

Effects of stress management interventions on heart rate variability in adults with cardiovascular disease: a systematic review and meta-analysis.

Meta-analysis was used to investigate the potential benefits of stress management interventions (SMIs) on vagally-mediated heart rate variability (HRV) in adults with cardiovascular disease. Electronic bibliographic databases were searched through August 2022. Randomized controlled trials and quasi-experimental studies assessing effects of SMIs on HRV were included. Methodological quality was assessed with a standardized checklist. A pooled effect size was calculated for vagally-mediated HRV indices (standard deviation of normal-to-normal intervals, root mean square of the successive differences, and high frequency power) using random effects models. Fourteen studies (1202 participants, Mage: 59 ± 6.25 years; 25% ± 16% women; 61% ± 22% White) were included. Ten studies (11 effects) reported short-term HRV assessment; a small between-group difference emerged for vagally-mediated HRV (d+ = .27, 95% confidence interval [CI] 0.01-0.52, k = 11). Most interventions examined biofeedback; these studies yielded a small between-group difference on vagally-mediated HRV (d+ = 0.31, 95% CI 0.09-0.53, k = 7, Q [6] = 3.82, p = .70, I2 = 11%). This is the first systematic examination of the effect of SMIs on HRV in adults with CVD. Findings suggest a small effect of SMIs on vagally-mediated HRV, with biofeedback likely driving the effect. More research is required to fully understand whether this benefit on vagally-mediated HRV applies to other SMIs.

The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling.

Inducible nucleosome remodeling at hundreds of latent enhancers and several promoters shapes the transcriptional response to Toll-like receptor 4 (TLR4) signaling in macrophages. We aimed to define the identities of the transcription factors that promote TLR-induced remodeling. An analysis strategy based on ATAC-seq and single-cell ATAC-seq that enriched for genomic regions most likely to undergo remodeling revealed that the transcription factor nuclear factor κB (NF-κB) bound to all high-confidence peaks marking remodeling during the primary response to the TLR4 ligand, lipid A. Deletion of NF-κB subunits RelA and c-Rel resulted in the loss of remodeling at high-confidence ATAC-seq peaks, and CRISPR-Cas9 mutagenesis of NF-κB-binding motifs impaired remodeling. Remodeling selectivity at defined regions was conferred by collaboration with other inducible factors, including IRF3- and MAP-kinase-induced factors. Thus, NF-κB is unique among TLR4-activated transcription factors in its broad contribution to inducible nucleosome remodeling, alongside its ability to activate poised enhancers and promoters assembled into open chromatin.

Street trees provide an opportunity to mitigate urban heat and reduce risk of high heat exposure.

Climate change is exacerbating the need for urban greening and the associated environmental and human well-being benefits. Trees can help mitigate urban heat, but more detailed understanding of cooling effects of green infrastructure are needed to guide management decisions and deploy trees as effective and equitable climate adaptation infrastructure. We investigated how urban trees affect summer air temperature along sidewalks within a neighborhood of Tacoma, Washington, USA, and to what extent urban trees reduce risks of high summer temperatures (i.e., the levels regulated by state outdoor heat exposure rules intended to reduce heat-related illnesses). Air temperature varied by 2.57 °C, on average, across our study area, and the probability of daytime temperatures exceeding regulated high temperature thresholds was up to five times greater in locations with no canopy cover within 10 m compared to those with 100% cover. Air temperatures decreased linearly with increasing cover within 10 m, suggesting that every unit of added tree cover can help cool the air. Our findings highlight the value of trees in mitigating urban heat, especially given expected warming with climate change. Protecting existing urban trees and increasing tree cover (e.g., by planting street trees), are important actions to enhance climate change resilience of urban areas.

Transcriptional and epigenetic dysregulation impairs generation of proliferative neural stem and progenitor cells during brain aging.

The decline in stem cell function during aging may affect the regenerative capacity of mammalian organisms; however, the gene regulatory mechanism underlying this decline remains unclear. Here we show that the aging of neural stem and progenitor cells (NSPCs) in the male mouse brain is characterized by a decrease in the generation efficacy of proliferative NSPCs rather than the changes in lineage specificity of NSPCs. We reveal that the downregulation of age-dependent genes in NSPCs drives cell aging by decreasing the population of actively proliferating NSPCs while increasing the expression of quiescence markers. We found that epigenetic deregulation of the MLL complex at promoters leads to transcriptional inactivation of age-dependent genes, highlighting the importance of the dynamic interaction between histone modifiers and gene regulatory elements in regulating transcriptional program of aging cells. Our study sheds light on the key intrinsic mechanisms driving stem cell aging through epigenetic regulators and identifies potential rejuvenation targets that could restore the function of aging stem cells.

Multilevel Resilience and HIV Virologic Suppression Among African American/Black Adults in the Southeastern United States.

OBJECTIVE: To assess overall and by neighborhood risk environments whether multilevel resilience resources were associated with HIV virologic suppression among African American/Black adults in the Southeastern United States. SETTING AND METHODS: This clinical cohort sub-study included 436 African American/Black participants enrolled in two parent HIV clinical cohorts. Resilience was assessed using the Multilevel Resilience Resource Measure (MRM) for African American/Black adults living with HIV, where endorsement of a MRM statement indicated agreement that a resilience resource helped a participant continue HIV care despite challenges or was present in a participant's neighborhood. Modified Poisson regression models estimated adjusted prevalence ratios (aPRs) for virologic suppression as a function of categorical MRM scores, controlling for demographic, clinical, and behavioral characteristics at or prior to sub-study enrollment. We assessed for effect measure modification (EMM) by neighborhood risk environments. RESULTS: Compared to participants with lesser endorsement of multilevel resilience resources, aPRs for virologic suppression among those with greater or moderate endorsement were 1.03 (95% confidence interval: 0.96-1.11) and 1.03 (0.96-1.11), respectively. Regarding multilevel resilience resource endorsement, there was no strong evidence for EMM by levels of neighborhood risk environments. CONCLUSIONS: Modest positive associations between higher multilevel resilience resource endorsement and virologic suppression were at times most compatible with the data. However, null findings were also compatible. There was no strong evidence for EMM concerning multilevel resilience resource endorsement, which could have been due to random error. Prospective studies assessing EMM by levels of the neighborhood risk environment with larger sample sizes are needed.

Differential heat shock protein responses in two species of Pacific salmon and their utility in identifying heat stress.

Rapid and accelerating warming of salmon habitat has the potential to lower productivity of Pacific salmon (Oncorhynchus species) populations. Heat stress biomarkers can indicate where warming is most likely affecting fish populations; however, we often lack clear classifications that separate individuals with and without heat stress needed to make these tools operational. We conducted a heat exposure experiment with trials lasting 12 or 36 h using juvenile Chinook salmon (Oncorhynchus tshawytscha) and coho salmon (Oncorhynchus kisutch) to validate heat stress biomarkers in white muscle. Following habituation to 13°C, individuals were exposed to water temperatures that increased to 15°C, 17°C, 19°C, 21°C or 23°C. Heat shock protein 70 abundance (HSP70 measured by ELISA) and transcription of 13 genes (mRNA measured by qPCR) including three heat shock protein genes (hsp70, hsp90, hsp27) were measured. A distinct heat stress response was apparent by 21°C in juvenile Chinook salmon and 23°C in juvenile coho salmon using HSP70. A threshold for heat stress classification in Chinook salmon of > 2 ng HSP70 mg.1 total protein identified heat stress in 100% of 21 and 23°C treated individuals compared to 4% in cooler treatments. For coho salmon, > 3 ng HSP70 mg.1 total protein identified heat stress in 100% of 23°C treated individuals compared to 4% in cooler treatments. Transcription from a panel of genes separated individuals between cooler and stressful temperature experiences (≥21°C for Chinook salmon and ≥23°C for coho salmon) with ~ 85% correct classification. Our findings indicate that juvenile Chinook salmon were more temperature-sensitive than juvenile coho salmon and support the use of a HSP70 threshold sampled from muscle for assessing heat stress in individual wild Pacific salmon with an option for non-lethal biopsies for spawning adults.

Patients' attitudes to bedside teaching after the COVID-19 pandemic.

BACKGROUND: Bedside teaching (BST) is a method of structured clinical teaching where the patient is central in education. We had previously explored the patients' perceptions of BST using both a qualitative research study and validation of a questionnaire, both showing strong support by patients for BST once basic rules of respect and confidentiality are followed. With the COVID-19 pandemic, clinical education transitioned to online/virtual learning. AIM: The aim of this study was to explore patients' attitudes towards reintroduction of BST as the pandemic restrictions have lifted. METHODS: Patients were invited to complete a validated questionnaire exploring their attitudes towards BST. A descriptive analysis was performed. Results were compared to a previous study performed before the COVID-19 pandemic. RESULTS: Four hundred patients consented to complete the questionnaires. Participants included women attending for antenatal (40%), postnatal (33%) and gynaecology issues (28%). Most patients (> 94%) reported that they were happy to be involved in BST. Patients believed that they should not be asked to participate in BST should they feel stressed or unwell (69%). These findings were the same as our previous study, performed prior to the pandemic. CONCLUSION: This study shows extensive and persisting patient support for BST. BST is unique in that it allows students to gain a deeper understanding of the disease which are hard to elicit through online/virtual methods.

Temporal regulation of head-on transcription at replication initiation sites.

Head-on (HO) collisions between the DNA replication machinery and RNA polymerase over R-loop forming sequences (RLFS) are genotoxic, leading to replication fork blockage and DNA breaks. Current models suggest that HO collisions are avoided through replication initiation site (RIS) positioning upstream of active genes, ensuring co-orientation of replication fork movement and genic transcription. However, this model does not account for pervasive transcription, or intragenic RIS. Moreover, pervasive transcription initiation and CG-rich DNA is a feature of RIS, suggesting that HO transcription units (HO TUs) capable of forming R-loops might occur. Through mining phased GRO-seq data, and developing an informatics strategy to stringently identify RIS, we demonstrate that HO TUs containing RLFS occur at RIS in MCF-7 cells, and are downregulated at the G1/S phase boundary. Our analysis reveals a novel spatiotemporal relationship between transcription and replication, and supports the idea that HO collisions are avoided through transcriptional regulatory mechanisms.

Investigating effects of climate-induced changes in water temperature and diet on mercury concentrations in an Arctic freshwater forage fish.

The amount of mercury (Hg) in Arctic lake food webs is, and will continue to be, affected by rapid, ongoing climate change. At warmer temperatures, fish require more energy to sustain growth; changes in their metabolic rates and consuming prey with potentially higher Hg concentrations could result in increased Hg accumulation. To examine the potential implications of climate warming on forage fish Hg accumulation in Arctic lakes, we quantified growth and Hg accumulation in Ninespine Stickleback Pungitius pungitius under different temperature and diet scenarios using bioenergetics models. Four scenarios were considered that examined the role of climate, diet, climate × diet, and climate × diet × elevated prey Hg. As expected, annual fish growth increased with warmer temperatures, but growth rates and Hg accumulation were largely diet dependent. Compared to current growth rates of 0.3 g⋅y-1, fish growth increased at least 200% for fish consuming energy-dense benthic prey and decreased at least 40% for fish consuming pelagic prey. Compared to baseline levels, the Hg burden per kilocalorie of Ninespine Stickleback declined up to 43% with benthic consumption - indicating strong somatic growth dilution - but no more than 4% with pelagic consumption; elevated prey Hg concentrations led to moderate Hg declines in benthic-foraging fish and Hg increases in pelagic-foraging fish. Bioenergetics models demonstrated the complex interaction of water temperature, growth, prey proportions, and prey Hg concentrations that respond to climate change. Further work is needed to resolve mechanisms and rates linking climate change to Hg availability and uptake in Arctic freshwater systems.

Delayed onset phlegmasia cerulea dolens post-SARS-CoV-2 infection treated with minimally invasive clot retrieval technology.

Coronavirus disease 2019 is associated with a significant venous thromboembolic risk. Phlegmasia cerulean dolens is a severe form of deep vein thrombosis that can lead to acute limb ischemia. In this report, we present a 58-year-old woman who developed a delayed-onset left lower extremity phlegmasia cerulean dolens 8 weeks after coronavirus disease 2019 onset that led to compartment syndrome and acute limb ischemia from external compression of the arterial vasculature from edematous muscle. The patient received an emergent minimally invasive percutaneous mechanical thrombectomy and four-compartment fasciotomy, resulting in adequate perfusion and ultimately made a full recovery.

Scalable and sustainable production of Ti3C2T z MXene and fluorine recovery from wastewater through cryolite precipitation.

Treatment of HF or HCl/LiF etched Ti3C2T z with 0.05 M NaHCO3 before water washing reduces the wastewater generated by 75%. When etched with HF, cryolite (Na3AlF6) precipitation from spent etching waste effectively removes fluorine from this waste stream, offers insight into the etching chemistry of MAX to MXene, and provides an effective analytical tool for optimization of MXene production. Additionally, washing HF etched multilayered Ti3C2T z with 0.05 M NaHCO3 allows for the production of delaminated Ti3C2T z colloidal suspensions, which typically requires the use of TBAOH or DMSO for intercalation and subsequent delamination. Ti3C2T z made with HCl/LiF and washed with 0.05 M NaHCO3 yields a colloidal suspension with a concentration of 18 mg mL-1 and a film conductivity of 1150 S cm-1.

Sexual assault predicts unhealthy weight management among college women: A longitudinal, prospective study.

Objective: To examine whether sexual assault prospectively predicts unhealthy weight management behaviors in college women. Method: Participants were female college students (N = 483) with monthly assessments across the first year, including the frequency and severity of sexual assault and unhealthy weight management behaviors. Results: Frequency of sexual assault prior to college predicted dieting, purging, and diet pill use, over the first year. Severity of those experiences predicted dieting and diet pill use. Frequency of sexual assault during the first semester predicted purging and diet pill use during the second semester. Severity predicted all three unhealthy weight management behaviors. Findings held consistently when controlling for socioeconomic status (SES), race/ethnicity, body mass index (BMI), and pre-college mood, anxiety, and eating disorders, as well as unhealthy weight management behaviors during the first semester in longitudinal analyses. Reverse models were non-significant. Conclusions: This research documents the detrimental effects of sexual assault on unhealthy weight management behaviors in college women, and highlights the importance of prevention and intervention.

Risk stratification through allergy history: single-centre experience of specialized COVID-19 vaccine clinic.

Anaphylaxis is a rare side-effect of COVID-19 vaccines. To (a) provide direct advice and reassurance to certain persons with a history of anaphylaxis/complex allergy, in addition to that available in national guidelines, and (b) to provide a medically supervised vaccination, a specialist regional vaccine allergy clinic was established. The main objective was to determine if risk stratification through history can lead to safe COVID-19 vaccination for maximum population coverage. A focused history was taken to establish contraindications to giving COVID-19 vaccines. People who reported a high-risk allergy history were given a vaccine not containing the excipient thought to have directly caused previous anaphylaxis. All vaccines were monitored for 30 min after administration. A total of 206 people were vaccinated between 6 July 2021 and 31 August 2021; Comirnaty (Pfizer-BioNTech) (n = 34), and Janssen (n = 172). In total, 78% were women. Ninety-two people (45%) reported a high-risk allergy history. There were no cases of anaphylaxis. Three people developed urticaria and one of these also developed transient tachycardia. One vaccinee developed a pseudoseizure. Two of 208 people (<1%) referred during this time declined vaccination based on personal preference, despite the assessment of low clinical risk. In our experience, all vaccines with high-risk allergy histories were administered Pfizer BioNTech or Janssen Covid-19 vaccines uneventfully following screening based on allergy-focussed history. Our data support that drug allergy is not associated with a higher risk of vaccine-related anaphylaxis but may act to guide the administration of alternate vaccines to people with polyethylene glycol/polysorbate 80/trometamol allergies or anaphylaxis after the first dose.

Resistance training for Black men with depressive symptoms: a pilot randomized controlled trial to assess acceptability, feasibility, and preliminary efficacy.

BACKGROUND: Depression is under-recognized in Black men, who are less likely to seek or have access to psychiatric treatment. Resistance training (RT; i.e., weight lifting) can improve depressive symptoms and may be more acceptable to Black men, but its effects have not been examined for Black men with depressive symptoms. METHODS: Fifty Black men with depressive symptoms were randomized to either (a) 12 weeks of RT (coupled with Behavioral Activation techniques to promote adherence) or (b) an attention-control group (Health, Wellness, and Education; HWE). Both groups met twice/week for 12 weeks, and follow-up assessments were done at end-of-treatment (EOT) and 6 months after enrollment. Changes in physical activity and muscular strength were collected as a manipulation check. The primary outcome was interviewer assessed symptoms of depression using the Quick Inventory of Depression Symptomology (QIDS). Secondary outcomes included self-reported depressive symptoms, anxiety, and stress. The association between change in QIDS from baseline to EOT and concurrent changes in physical activity and muscular strength in the RT group were explored as an initial assessment of mechanism. Longitudinal mixed effects regression models with subject-specific intercepts were used to examine intervention effects. RESULTS: A sample with high rates of medical comorbidities (e.g., 44% HIV positive), substance use (e.g., 34% smoking), and negative social determinates of health (e.g., 50% unemployed) was enrolled. Recruitment, engagement, and retention data indicate that the intervention and design were feasible. The RT group showed greater gains in self-reported exercise (b = 270.94, SE = 105.69, p = .01) and muscular strength (b = 11.71, SE = 4.23, p = .01 for upper body and b = 4.24, SE = 2.02, p = .04 for lower body) than the HWE group. The RT group had greater reductions in QIDS scores at both EOT (b = -3.00, SE = 1.34, p = .01) and 6 months (b = -2.63, SE = 1.81, p = .04). The RT group showed a greater reduction in anxiety at EOT (b = -2.67, SE = 1.06, p = .02). Findings regarding self-reported depressive symptoms and stress were non-significant, but in the expected direction with effect sizes in the small to medium range. In the RT group, improvement on the QIDS between baseline and EOT was associated with concurrent improvements in physical activity (b = 21.03, SE = 11.16, p = .02) and muscular strength (b = 1.27, SE = .44, p = .03 for upper body and b = .75, SE = .14, p = .03 for lower body). CONCLUSIONS: Results suggest that RT is feasible and may be efficacious for reducing depressive symptoms among underserved urban Black men. TRIAL REGISTRATION: ClinicalTrial.gov #: NCT03107039 (Registered 11/04/2017).

Disclosure of male attraction to primary care clinicians by adolescent sexual minority males.

Introduction: Adolescent sexual minority males (ASMM) experience higher rates of HIV and other sexually transmitted infections (STIs) relative to their heterosexual peers. Primary care clinicians (PCCs) are well positioned to discuss sexual health and STI prevention with adolescent males; however, ASMM report they are rarely asked about their sexual health, especially with respect to attraction and identity. This study sought to determine variables associated with disclosure of male attraction ("being out") to a PCC. Methods: ASMM (N=206; 14 to 17 years in the United States) completed an online sexual health survey in 2017. We assessed socio-demographics, sexuality, being out to a guardian, and being out to a PCC, and calculated proportions and associations among the variables using univariable (Fisher exact) and multivariable (Firth logistic regression) analyses. Results: Only 20% (n=41) of ASMM were out to their PCC even though 53% (n=109) were out to a parent or guardian. ASMM who were out to a parent or guardian were seven times more likely to be out to their PCC (adjusted odds ratio = 6.69, 95% confidential interval 2.69 to 16.60). No other variables were associated with being out to a PCC. Conclusions: Among ASMM, the only predictor of outness to a PCC in this study was outness to a parent or guardian, yet only half were out to a parent or guardian. Policy Implications: PCCs should proactively and routinely inquire about sexual health and screen adolescent males for same sex attraction and sexual minority identity in order to provide optimal health care.

Subscribing to big data at scale.

Today, data is being actively generated by a variety of devices, services, and applications. Such data is important not only for the information that it contains, but also for its relationships to other data and to interested users. Most existing Big Data systems focus on passively answering queries from users, rather than actively collecting data, processing it, and serving it to users. To satisfy both passive and active requests at scale, application developers need either to heavily customize an existing passive Big Data system or to glue one together with systems like Streaming Engines and Pub-sub services. Either choice requires significant effort and incurs additional overhead. In this paper, we present the BAD (Big Active Data) system as an end-to-end, out-of-the-box solution for this challenge. It is designed to preserve the merits of passive Big Data systems and introduces new features for actively serving Big Data to users at scale. We show the design and implementation of the BAD system, demonstrate how BAD facilitates providing both passive and active data services, investigate the BAD system's performance at scale, and illustrate the complexities that would result from instead providing BAD-like services with a "glued" system.

Development of Long and Short Forms of the Multilevel Resilience Resource Measure for African American/Black Adults Living with HIV.

Understanding resilience in relation to HIV-related outcomes may help address racial/ethnic disparities, however, significant gaps in its measurement preclude in-depth study. Thus, this research aims to develop and evaluate the psychometric properties of long and short forms of the Multilevel Resilience Resource Measure for African American/Black Adults Living with HIV. To develop the items, we conducted a mixed methods study (N = 48) and reviewed published resilience measures. We completed content validity index analyses to ensure the items reflected the resilience construct. Next, we conducted 20 cognitive interviews and a field survey (N = 400). The long and short forms demonstrated acceptable to excellent psychometric properties based on factorial validity, internal consistency and convergent validity and on measurement invariance (conducted for the short form only). These measures provide a comprehensive framework to examine resilience and HIV-related outcomes and can inform resilience-building interventions to reduce racial and ethnic health disparities.

Validated HIV Knowledge Scales for Use with Adults and Adolescents: A Systematic Review.

HIV knowledge - the information a person possesses about HIV - is essential for the prevention and management of HIV. Therefore, the accurate measurement of HIV knowledge is important for both science and practice. This systematic review identifies extant HIV knowledge scales that have been validated with adolescent and adult populations and summarizes the state of this research. We searched seven electronic databases, which resulted in 6,525 articles. After title/abstract and full-text review, 27 studies remained and underwent qualitative review of reported scale psychometric properties. Many studies were conducted in the last decade (n = 12), reflecting advances in scientific knowledge of HIV. Five were exclusively adolescent-based studies (sample age ≤ 18). Most studies reported reliability (n = 25) or at least one form of validity (n = 21). Future studies should develop or refine HIV knowledge scales so that they reflect recent scientific developments, use rigorous psychometric testing, and target samples that include those persons at highest risk for HIV.