Search

Genome stability is significantly influenced by the precise coordination of chromatin complexes that facilitate the loading and eviction of histones from chromatin during replication, transcription, and DNA repair processes. In this study, we investigate the role of the Arabidopsis H3 histone chaperones ANTI-SILENCING FUNCTION 1 (ASF1) and HISTONE REGULATOR A (HIRA) in the maintenance of telomeres and 45S rDNA loci, genomic sites that are particularly susceptible to changes in the chromatin structure. We find that both ASF1 and HIRA are essential for telomere length regulation, as telomeres are significantly shorter in asf1a1b and hira mutants. However, these shorter telomeres remain localized around the nucleolus and exhibit a comparable relative H3 occupancy to the wild type. In addition to regulating telomere length, ASF1 and HIRA contribute to silencing 45S rRNA genes and affect their copy number. Besides, ASF1 supports global heterochromatin maintenance. Our findings also indicate that ASF1 transiently binds to the TELOMERE REPEAT BINDING 1 protein and the N terminus of telomerase in vivo, suggesting a physical link between the ASF1 histone chaperone and the telomere maintenance machinery., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Abstract: Substance use stigma is a barrier to care among people with HIV (PWH), which is exacerbated in the Deep U.S. South. Nurses and nonclinical staff serve a central role in strengthening and expanding care coordination in clinics that serve PWH. We sought to implement and evaluate a pilot training intervention that aimed to reduce substance use stigma among clinical and nonclinical staff who provide care for PWH in the Deep South. In total, 32 clinical and nonclinical staff from five clinics participated in the training, of whom 22% were nurses and 38% were linkage coordinators. We evaluated the association between the intervention and stigma by asking respondents about their agreement with varying levels of stigmatized statements both before and after the training. Overall, we observed a slight reduction in stigma scores. This training has promise as one low-burden approach to substance use stigma reduction in HIV care settings., (Copyright © 2024 Association of Nurses in AIDS Care.)

Stemness and pluripotency are mediated by transcriptional master regulators that promote self-renewal and repress cell differentiation, among which is the high-mobility group (HMG) box transcription factor SOX2. Dysregulated SOX2 expression, by contrast, leads to transcriptional aberrations relevant to oncogenic transformation, cancer progression, metastasis, therapy resistance, and relapse. Here, we report a post-transcriptional mechanism by which the cytosolic pool of SOX2 contributes to these events in an unsuspected manner. Specifically, a low-complexity region within SOX2's C-terminal segment connects to the ribosome to modulate the expression of cognate downstream factors. Independent of nuclear structures or DNA, this C-terminal functionality alone changes metabolic properties and induces non-adhesive growth when expressed in the cytosol of SOX2 knockout cells. We thus propose a revised model of SOX2 action where nuclear and cytosolic fractions cooperate to impose cell fate decisions via both transcriptional and translational mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The current study sought to determine if the release of COVID-19 vaccines influenced Alabama mothers' attitudes and behaviors regarding HPV vaccination of their adolescent children., Methods: A social media survey was conducted August - September 2022 among mothers of adolescents ages 9-18, who self-identified as Alabama residents and their child(ren)'s primary medical decision maker. The survey assessed demographics, vaccine knowledge and opinions, vaccination history, influences on vaccination decisions, and how COVID-19 vaccine release affected vaccine opinions. Univariable and multivariable analyses were conducted., Results: Of 241 responses, most participants were white (82.0 %, n = 196), non-Hispanic (96.6 %, n = 230), and privately insured (64.5 %, n = 151), with annual household incomes ≥$61,000 (45.4 %, n = 103). The majority (60.8 %) reported that their child either had or planned to receive the HPV vaccine. The release of COVID-19 vaccines did not change the majority of parental opinions towards HPV, with 78.5 % (n = 161) reporting no change. Among those who experienced a change, 25 % (n = 5) reported an increased likelihood of having their child vaccinated for HPV and 75 % (n = 15) reported a decrease in likelihood. Moderate and high HPV knowledge scores were associated in multivariable analysis with increased likelihood of having their child vaccinated for HPV ("moderate" knowledge AOR: 12.4, 95 % CI: 1.98-78.1; "high" knowledge AOR: 12.8, 95 % CI: 2.00-82.1). Positive HPV opinion scores in the univariable analysis similarly showed increased odds (AOR = 1.5)., Conclusions: These findings indicate that, in this population, COVID-19 vaccine release did not significantly impact subsequent HPV vaccination decision making. Parental perceptions regarding vaccination are critical to informing future interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: We developed the Healthy Families-PrEP intervention to support HIV-prevention during periconception and pregnancy. We evaluated preexposure prophylaxis (PrEP) use with three objective measures., Design: This single-arm intervention study enrolled women in KwaZulu-Natal, South Africa, who were HIV-uninfected, not pregnant, in a relationship with a partner with HIV or unknown-serostatus, and with pregnancy plans. PrEP was offered as part of a comprehensive HIV prevention intervention. Participants were followed for 12 months., Methods: We evaluated periconception PrEP uptake and adherence using quarterly plasma tenofovir concentrations. We modeled factors associated with PrEP uptake and high plasma tenofovir (past day dosing). Patterns of use were analyzed using electronic pillcap data. Dried blood spots to measure intracellular tenofovir product (past 2 months dosing) were analyzed for a subset of women., Results: Three hundred thirty women with median age 24 (IQR: 22-27) years enrolled. Partner HIV-serostatus was unknown by 96% ( N  = 316); 60% (195) initiated PrEP. High plasma tenofovir concentrations were seen in 35, 25, 22, and 20% of samples at 3, 6, 9, and 12 months, respectively. Similar adherence was measured by pillcap and dried blood spots. In adjusted models, lower income, alcohol use, and higher HIV stigma were associated with high plasma tenofovir. Eleven HIV-seroconversions were observed (incidence rate: 4.04/100 person-years [95% confidence interval: 2.24-7.30]). None had detectable plasma tenofovir., Conclusion: The Healthy Families-PrEP intervention supported women in PrEP use. We observed high interest in periconception PrEP and over one-third adhered to PrEP in the first quarter; one-fifth were adherent over a year. High HIV incidence highlights the importance of strategies to reduce HIV incidence among periconception women., Clinical Trial Number: NCT03194308., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Injection-related infections continue to rise, particularly in the South. People who inject drugs are increasingly utilizing hospital services for serious injection-related infections but may be discharged to areas without harm reduction services. We explored the availability and travel time to services for HIV and substance use in Alabama., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The DEAD-box helicase Dbp4 plays an essential role during the early assembly of the 40S ribosome, which is only poorly understood to date. By applying the yeast two-hybrid method and biochemical approaches, we discovered that Dbp4 interacts with the Efg1-Bud22 dimer. Both factors associate with early pre-90S particles and smaller complexes, each characterized by a high presence of the U14 snoRNA. A crosslink analysis of Bud22 revealed its contact to the U14 snoRNA and the 5' domain of the nascent 18S rRNA, close to its U14 snoRNA hybridization site. Moreover, depletion of Bud22 or Efg1 specifically affects U14 snoRNA association with pre-ribosomal complexes. Accordingly, we concluded that the role of the Efg1-Bud22 dimer is linked to the U14 snoRNA function on early 90S ribosome intermediates chaperoning the 5' domain of the nascent 18S rRNA. The successful rRNA folding of the 5' domain and the release of Efg1, Bud22, Dpb4, U14 snoRNA and associated snoRNP factors allows the subsequent recruitment of the Kre33-Bfr2-Enp2-Lcp5 module towards the 90S pre-ribosome., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Assessing the neuromechanical coupling of inspiratory muscles during mechanical ventilation (MV) could reveal the physiological mechanism of MV failure. This study examined the respiratory neuromechanical characteristics between MV liberation success and failure., Methods: This is an observational prospective study that included patients during their ventilator liberation process. Assessment of surface electromyography (sEMG) of inspiratory muscles, including the diaphragm and extra-diaphragmatic (scalene, sternocleidomastoid, and parasternal) muscles, was performed 15 minutes after the initiation of spontaneous breathing trials. Neuromechanical efficiency of the diaphragm (NME Dia ) and extra-diaphragmatic muscles (NME Extra ) were compared in patients who were successfully liberated from MV with those who failed MV liberation within 72 hours after extubation., Results: A total of 45 patients were enrolled and 28 were female (67%). The sample median age was 63 (IQR 47, 69) years old. One-third of patients failed MV liberation within 72 hours of their spontaneous breathing trials (SBTs). NME Dia was significantly lower in patients who failed MV liberation with a root mean square of (M 0.27), (IQR 0.21, 0.37) compared with (M 0.371), (IQR 0.3, 0.631) for the success group (p=0.0222). The area under the curve for NME Dia was lower in the failure group (M 0.270), (IQR 0.160, 0.370) and (M 0.485), (IQR 0.280, 0.683) for the success group (p=0.024). However, NME Extra was not statistically different between the two groups., Conclusion: Reduced NME Dia is a predictor of MV liberation failure. NME Extra was not a major contributor to MV liberation outcomes. Further studies should assess the performance of inspiratory muscles NME indices to predict MV liberation outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Aljohani et al.)

We integrated safer conception care into a Ugandan HIV clinic. People with HIV (PWH), or partnered with a PWH, and desiring children were eligible for the Healthy Families Clinic Program. Clients completed quarterly safer conception counselling visits and questionnaires to provide information around method preferences and outcomes (partner pregnancy, partner seroconversion). We used clinic level data to evaluate longitudinal viral suppression among PWH. Between November 2016 and January 2020, 361 clients (53% men) accessed services. 75% were PWH (51% women, 96% men): 99% were on antiretroviral therapy (ART) and most reported HIV-sero-different partnerships (97%). Frequently selected safer conception methods included ART (86%), timed condomless sex (74%), and PrEP (40%) with important differences by HIV-serostatus and gender. 22.5% reported pregnancy. Most (97%) PWH were virally suppressed at enrolment and 81% of non-virally suppressed PWH were virally suppressed at 15 months. Two HIV-negative clients (2%) had HIV seroconversion. There is demand for safer conception care in a public sector HIV-clinic in Uganda. Men and women have unique safer conception care preferences. The majority of clients engaged in safer conception care had viral suppression at follow up.

The 5S ribonucleoprotein (RNP) is assembled from its three components (5S rRNA, Rpl5/uL18 and Rpl11/uL5) before being incorporated into the pre-60S subunit. However, when ribosome synthesis is disturbed, a free 5S RNP can enter the MDM2-p53 pathway to regulate cell cycle and apoptotic signaling. Here we reconstitute and determine the cryo-electron microscopy structure of the conserved hexameric 5S RNP with fungal or human factors. This reveals how the nascent 5S rRNA associates with the initial nuclear import complex Syo1-uL18-uL5 and, upon further recruitment of the nucleolar factors Rpf2 and Rrs1, develops into the 5S RNP precursor that can assemble into the pre-ribosome. In addition, we elucidate the structure of another 5S RNP intermediate, carrying the human ubiquitin ligase Mdm2, which unravels how this enzyme can be sequestered from its target substrate p53. Our data provide molecular insight into how the 5S RNP can mediate between ribosome biogenesis and cell proliferation., (© 2023. The Author(s).)

The thermophilic fungus Chaetomium thermophilum has been used extensively for biochemical and high-resolution structural studies of protein complexes. However, subsequent functional analyses of these assemblies have been hindered owing to the lack of genetic tools compatible with this thermophile, which are typically suited to other mesophilic eukaryotic model organisms, in particular the yeast Saccharomyces cerevisiae. Hence, we aimed to find genes from C. thermophilum that are expressed under the control of different sugars and examine their associated 5' untranslated regions as promoters responsible for sugar-regulated gene expression. To identify sugar-regulated promoters in C. thermophilum, we performed comparative xylose- versus glucose-dependent gene expression studies, which uncovered a number of enzymes with induced expression in the presence of xylose but repressed expression in glucose-supplemented media. Subsequently, we cloned the promoters of the two most stringently regulated genes, the xylosidase-like gene (XYL) and xylitol dehydrogenase (XDH), obtained from this genome-wide analysis in front of a thermostable yellow fluorescent protein (YFP) reporter. With this, we demonstrated xylose-dependent YFP expression by both Western blotting and live-cell imaging fluorescence microscopy. Prompted by these results, we expressed the C. thermophilum orthologue of a well-characterized dominant-negative ribosome assembly factor mutant, under the control of the XDH promoter, which allowed us to induce a nuclear export defect on the pre-60S subunit when C. thermophilum cells were grown in xylose- but not glucose-containing medium. Altogether, our study identified xylose-regulatable promoters in C. thermophilum, which might facilitate functional studies of genes of interest in this thermophilic eukaryotic model organism., (© 2023. The Author(s).)

Background: In the United States (US), 44% of people with human immunodeficiency virus (PWH) live in the Southeastern census region; many PWH remain undiagnosed. Novel strategies to inform testing outreach in rural states with dispersed HIV epidemics are needed., Methods: Alabama state public health HIV testing surveillance data from 2013 to 2017 were used to estimate time from infection to HIV diagnosis using CD4 T-cell depletion modeling, mapped to county. Diagnostic HIV tests performed during 2013-2021 by commercial testing entities were used to estimate HIV tests per 100 000 adults (aged 15-65 years), mapped to client ZIP Code Tabulation Area (ZCTA). We then defined testing "cold spots": those with <10% adults tested plus either (1) within or bordering 1 of the 13 counties with HIV prevalence >400 cases per 100 000 population or (2) within a county with average time to diagnosis greater than the state average to inform testing outreach., Results: Time to HIV diagnosis was a median of 3.7 (interquartile range [IQR], 0-9.2) years across Alabama, with a range of 0.06-12.25 years. Approximately 63% of counties (n = 42) had a longer time to diagnosis compared to national US estimates. Six hundred forty-three ZCTAs tested 17.3% (IQR, 10.3%-25.0%) of the adult population from 2013 to 2017. To prioritize areas for testing outreach, we generated maps to describe 47 areas of HIV-testing cold spots at the ZCTA level., Conclusions: Combining public health surveillance with commercial testing data provides a more nuanced understanding of HIV testing gaps in a state with a rural HIV epidemic and identifies areas to prioritize for testing outreach., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Increasingly, injection opioid use and opioid use disorder (OUD) are complicated by methamphetamine use, but the impact of stimulant use on the care of people who inject drugs (PWID) with serious injection-related infections (SIRIs) is unknown. The objective of this study was to explore hospital outcomes and postdischarge trends for a cohort of hospitalized PWID to identify opportunities for intervention., Methods: We queried the electronic medical record for patients hospitalized at the University of Alabama at Birmingham with injection drug use-related infections between 1/11/2016 and 4/24/2021. Patients were categorized as having OUD only (OUD), OUD plus methamphetamine use (OUD/meth), or injection of other substance(s) (other). We utilized statistical analyses to assess group differences across hospital outcomes and postdischarge trends. We determined the OUD continuum of care for those with OUD, with and without methamphetamine use., Results: A total of 370 patients met inclusion criteria-many with readmissions (98%) and high mortality (8%). The majority were White, male, and uninsured, with a median age of 38. One in 4 resided outside of a metropolitan area. There were significant differences according to substance use in terms of sociodemographics and hospital outcomes: patients with OUD/meth were more likely to leave via patient-directed discharge, but those with OUD only had the greatest mortality. Comorbid methamphetamine use did not significantly impact the OUD care continuum., Conclusions: The current drug crisis in AL will require targeted interventions to engage a young, uninsured population with SIRI in evidence-based addiction and infection services., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis)., Objective: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis., Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341)., Setting: Academic and community-based rheumatology, gastroenterology, and dermatology practices., Patients: Adults aged 50 years or older receiving TNFis for any indication., Intervention: Random assignment to ZVL versus placebo., Measurements: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid., Results: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL ( n = 310) or placebo ( n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively., Limitation: Potentially limited generalizability to patients receiving other types of immunomodulators., Conclusion: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics., Primary Funding Source: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

APR-246 (Eprenetapopt/PRIMA-1 Met ) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples ( n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.

The ribosome assembly factor Nsa2 is part of the Rea1-Rsa4-Nsa2 interconnected relay on nuclear pre-60S particles that is essential for 60S ribosome biogenesis. Cryo-EM structures depict Nsa2 docked via its C-terminal β-barrel domain to nuclear pre-60S particles, whereas the extended N-terminus, consisting of three α-helical segments, meanders between various 25S rRNA helices with the extreme N-terminus in close vicinity to the Nog1 GTPase center. Here, we tested whether this unappreciated proximity between Nsa2 and Nog1 is of functional importance. Our findings demonstrate that a conservative mutation, Nsa2 Q3N, abolished cell growth and impaired 60S biogenesis. Subsequent genetic and biochemical analyses verified that the Nsa2 N-terminus is required to target Nsa2 to early pre-60S particles. However, overexpression of the Nsa2 N-terminus abolished cytoplasmic recycling of the Nog1 GTPase, and both Nog1 and the Nsa2-N (1-58) construct, but not the respective Nsa2-N (1-58) Q3N mutant, were found arrested on late cytoplasmic pre-60S particles. These findings point to specific roles of the different Nsa2 domains for 60S ribosome biogenesis.

Very dense artifacts confound bone density measurement. Hologic and GE densitometers exclude artifact density and GE also excludes associated area. Consequently, BMD is decreased with Hologic software. Despite different manufacturers' approaches, when dense artifacts overlay the spine, the affected vertebral body should be excluded from the reported BMD., Purpose: Very dense objects, such as lead bullets are described as "black hole" artifacts on Hologic densitometers. Whether similar results occur on GE scanners is not reported. We hypothesized that dense artifacts confound both brands of densitometers., Methods: Three lead bullets of varying size were placed overlying or adjacent to L3 on anthropomorphic and encapsulated aluminum spine phantoms. Three scans were acquired with and without projectiles on a Hologic Discovery W, GE iDXA, and Prodigy densitometer., Results: Lead bullets are measured as having high bone mineral content (BMC); they appear black in dual-energy mode on Hologic scanners and are colored blue on GE scanners. On Hologic scanners, BMC of a dense artifact over bone is excluded, but the bone area is not altered. Consequently, bone mineral density (BMD) of the affected vertebra, and of L1-4, is decreased. For example, a .45 caliber bullet over L3 decreased BMD (p < 0.05) by 48.3% and L1-4 by 9.1%. GE scanners excluded associated BMC and area covered by the artifact, thereby minimizing impact on BMD. Dense artifacts over soft tissue on a phantom do not substantially affect BMD on either manufacturer's densitometer when scanned., Conclusion: Densitometer manufacturers handle very dense artifacts differently. GE software removes artifact BMC and area with resultant minimal impact on BMD, Hologic removes only BMC, not area, thereby decreasing BMD. Regardless of this difference, when dense artifacts overlay the spine, it is best to exclude the affected vertebral body. Finally, the BMD stability observed with artifacts over soft tissue may not be replicated in humans.

Background: Public health experts recommend school-based policies as a population based approach to increase youth physical activity. The purpose of this case study is to describe one, largely rural, state's efforts to translate this recommendation into practice. Details about the genesis, implementation and evolution of two state level policies (physical education and physical activity), as well as in-house efforts of a State Department of Education to monitor policy compliance and challenges encountered are described. Two specific years are highlighted, due to policy and monitoring enhancements made during those particular time periods., Methods: Data for this paper come from the West Virginia Department of Education for two time periods: 2013-2014 and 2014-2015 (n=369 elementary schools). Descriptive statistics for quantitative data and content analysis for qualitative data were used to document school level compliance and provide context for implementation challenges., Results: Greater than 70% of school principals reported achievement of physical education and physical activity policy expectations for each year. Limited staff was the predominant explanation for nonfulfillment of physical education expectations, followed by lack of time and facilities. Recess and classroom-based physical activity were the primary strategies used to comply with the physical activity expectations. PE and PA policy compliance varied significantly by certain school characteristics in each school year studied., Conclusions: Further investigation is warranted on how states translate public health policy recommendations into practice, including how physical education and physical activity policies are developed and monitored at the state level and how to support states and schools with monitoring and implementation challenges., Competing Interests: Conflict of Interest The authors have no conflicts of interest to disclose. Further, the results of this study do not constitute endorsement from the ACSM.

There has been limited study of the syndemic link between HIV and intimate partner violence (IPV) among rural populations in the United States. We utilized the Revised Conflict Tactics Scale-2 to examine the past year prevalence, type (psychological aggression, physical assault, and sexual assault), and the impact of IPV on HIV clinical outcomes among men living with HIV in rural Appalachia. Approximately 39% of participants experienced some type of IPV in the preceding year, with 67% of those individuals experiencing more than 1 type of IPV. Approximately 77% of participants endorsing IPV exposure experienced psychological aggression. Most participants exposed to psychological aggression (70%) and/or physical assault (57%) were both victims and perpetrators, and those experiencing sexual assault reported being exclusively victims (65%). There were no significant differences in clinical outcomes including viral load and CD4 count, which may be secondary to small sample size derived from a clinic population with a high rate of virologic suppression (94%). This study demonstrates the need to assess IPV exposure in men living with HIV and further highlights the intricacies of relationship violence in these individuals.

Eukaryotic ribosome biogenesis involves RNA folding and processing that depend on assembly factors and small nucleolar RNAs (snoRNAs). The 90S (SSU-processome) is the earliest pre-ribosome structurally analyzed, which was suggested to assemble stepwise along the growing pre-rRNA from 5' > 3', but this directionality may not be accurate. Here, by analyzing the structure of a series of 90S assembly intermediates from Chaetomium thermophilum, we discover a reverse order of 18S rRNA subdomain incorporation. Large parts of the 18S rRNA 3' and central domains assemble first into the 90S before the 5' domain is integrated. This final incorporation depends on a contact between a heterotrimer Enp2-Bfr2-Lcp5 recruited to the flexible 5' domain and Kre33, which reconstitutes the Kre33-Enp-Brf2-Lcp5 module on the compacted 90S. Keeping the 5' domain temporarily segregated from the 90S scaffold could provide extra time to complete the multifaceted 5' domain folding, which depends on a distinct set of snoRNAs and processing factors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cell envelope of bacteria shows great diversity in architecture and composition, to a large extent due to its proteome. Proteins localized to the cell envelope, whether integrally embedded in the membrane, membrane-anchored, or peripherally associated as part of a macromolecular complex, often form elongated fibers, in which coiled coils represent a prominent structural element. These coiled-coil segments show a surprising degree of structural variability, despite being shaped by a small number of simple biophysical rules, foremost being their geometry of interaction referred to as 'knobs-into-holes'. Here we will review this diversity, particularly as it has emerged over the last decade., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The nucleotide cyclase CyaC of Sinorhizobium meliloti is a member of class III adenylate cyclases (AC), a diverse group present in all forms of life. CyaC is membrane-integral by a hexahelical membrane domain (6TM) with the basic topology of mammalian ACs. The 6TM domain of CyaC contains a tetra-histidine signature that is universally present in the membrane anchors of bacterial diheme-B succinate-quinone oxidoreductases. Heterologous expression of cyaC imparted activity for cAMP formation from ATP to Escherichia coli, whereas guanylate cyclase activity was not detectable. Detergent solubilized and purified CyaC was a diheme-B protein and carried a binuclear iron-sulfur cluster. Single point mutations in the signature histidine residues caused loss of heme-B in the membrane and loss of AC activity. Heme-B of purified CyaC could be oxidized or reduced by ubiquinone analogs (Q 0 or Q 0 H 2 ). The activity of CyaC in bacterial membranes responded to oxidation or reduction by Q 0 and O 2 , or NADH and Q 0 H 2 respectively. We conclude that CyaC-like membrane anchors of bacterial ACs can serve as the input site for chemical stimuli which are translated by the AC into an intracellular second messenger response., (© 2019 John Wiley & Sons Ltd.)

Ribosomes, which synthesize the proteins of a cell, comprise ribosomal RNA and ribosomal proteins, which coassemble hierarchically during a process termed ribosome biogenesis. Historically, biochemical and molecular biology approaches have revealed how preribosomal particles form and mature in consecutive steps, starting in the nucleolus and terminating after nuclear export into the cytoplasm. However, only recently, due to the revolution in cryo-electron microscopy, could pseudoatomic structures of different preribosomal particles be obtained. Together with in vitro maturation assays, these findings shed light on how nascent ribosomes progress stepwise along a dynamic biogenesis pathway. Preribosomes assemble gradually, chaperoned by a myriad of assembly factors and small nucleolar RNAs, before they reach maturity and enter translation. This information will lead to a better understanding of how ribosome synthesis is linked to other cellular pathways in humans and how it can cause diseases, including cancer, if disturbed.

Cancer-relevant signalling pathways rely on bidirectional nucleocytoplasmic transport events through the nuclear pore complex (NPC). However, mechanisms by which individual NPC components (Nups) participate in the regulation of these pathways remain poorly understood. We discover by integrating large scale proteomics, polysome fractionation and a focused RNAi approach that Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response. The underlying mechanism involves transcriptional regulation of the putative tRNA and rRNA methyltransferase FTSJ1 by Nup155. Furthermore, we observe that Nup155 and FTSJ1 are p53 repression targets and accordingly find a correlation between the p53 status, Nup155 and FTSJ1 expression in murine and human hepatocellular carcinoma. Our data suggest an unanticipated regulatory network linking translational control by and repression of a structural NPC component modulating the p53 pathway through its effectors.

Context: Emerging adults (aged 18-25 years) are increasingly seeking evaluation in acute-care clinics for sexual health-related concerns to receive treatment and education., Objective: To assess the sexual health knowledge of emerging adult patients by gender at acute-care health centers., Methods: A prospective, self-administered survey was distributed from August 2014 through May 2016 to patients aged 18 to 24 years who presented to 1 of 4 acute-care locations in a university town in a mid-Atlantic state. Analyses included descriptive statistics, as well as χ2 and Fisher exact test crosstabulations to determine differences between genders., Results: A total of 388 patients aged 18 to 24 years responded to the survey, with 81% of the sample identifying themselves as students and 64% identifying as female. Women were more likely than men to state that they sought sexual health advice at an urgent-care or walk-in clinic (70.3% vs 52.1%; P<.05). Human papillomavirus knowledge among women was significantly greater than among men (P<.0001). Open-ended responses were widespread and often incorrect, specifically with regard to the human papillomavirus vaccine and routine testing for sexually transmitted infections., Conclusion: Women were more knowledgeable about sexual health than men. However, both genders were not as knowledgeable overall on sexual health topics as hypothesized. A stronger emphasis on gender-specific programming for sexual health education via community- and school-based programs throughout adolescence, supplemented with greater emphasis on routine preventive health care during adolescence and emerging adulthood, is encouraged.

Exposures to perfluoroalkyl substances (PFAS) including perfluoroalkyl acids (PFAAs) are associated with increased liver enzymes in cohort studies including the C8 Health Study. In animal models, PFAAs disrupt hepatic lipid metabolism and induce apoptosis to cause nonalcoholic fatty liver disease (NAFLD). PFAAs are immunotoxic and inhibit pro-inflammatory cytokine release from stimulated leukocytes in vitro. This cross-sectional study tests the hypothesis that environmental PFAAs are associated with increased hepatocyte apoptosis and decreased pro-inflammatory cytokines in serum. Biomarkers previously associated with PFAS exposures and/or NAFLD were evaluated as secondary endpoints. Two hundred adult C8 Health Study participants were included. Measured serum biomarkers included: perfluorohexane sulfonate (PFHxS); perfluorooctanoic acid (PFOA); perfluorooctane sulfonate (PFOS); perfluorononanoic acid (PFNA); cytokeratin 18 M30 (CK18 M30, hepatocyte apoptosis); adipocytokines; insulin; and cleaved complement 3 (C3a). Confounder-adjusted linear regression models determined associations between PFAS and disease biomarkers with cut-offs determined by classification and regression tree analysis. CK18 M30 was positively associated with PFHxS (β = 0.889, p = 0.042); PFOA (β = 2.1, p = 0.005); and PFNA (β = 0.567, p = 0.03). Tumor necrosis factor α (TNFα) was inversely associated with PFHxS (β = -0.799, p = 0.001); PFOA (β = - 1.242, p = 0.001); and PFOS (β = -0.704, p < 0.001). Interleukin 8 was inversely associated with PFOS and PFNA. PFAAs were also associated with sexually dimorphic adipocytokine and C3a responses. Overall, PFAA exposures were associated with the novel combination of increased biomarkers of hepatocyte apoptosis and decreased serum TNFα. These data support previous findings from cohorts and experimental systems that PFAAs may cause liver injury while downregulated some aspects of the immune response. Further studies of PFAAs in NAFLD are warranted and should evaluate sex differences., (Published by Elsevier Ltd.)

Objectives: Sonography is a clinical tool being incorporated in multiple medical specialties with evidence of improved patient care and cost. Some schools have begun implementing ultrasound curricula. We hope to build upon that foundation and provide another potential framework of incorporation. There are several barriers, including curricular space, equipment and physical space, adequate faculty, and performing assessment., Methods: At West Virginia University, we began a longitudinal ultrasound curriculum in 2012 with incorporation of didactic and practical sessions into gross anatomy, our systems-based second-year curriculum, physical diagnosis course, and clinical rotations. We included both written and practical assessment from the onset. After the initial 4 years, the first graduates were surveyed on their perceptions of the curriculum. Responses were correlated with specialty choice and clinical campus site., Results: Based on our survey (90% response rate), students felt sonography was useful for anatomical understanding and patient care. Overall, 93% of our respondents reviewed the curriculum favorably. Qualitative feedback was very positive, with students desiring more ultrasound education and more required components, specifically in clinical rotations., Conclusions: Based on these results, some changes have already been implemented, including decreased student-to-instructor ratios, more open scan time, and more required components. The breadth of formal assessment has increased. Multiple pilot programs for clinical rotations are being developed. There is an ongoing need for faculty development and continued assessment of ultrasound competency., (© 2018 by the American Institute of Ultrasound in Medicine.)