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The Role of Transient Crosslinks in the Chromatin Search Response to DNA Damage
Get PDFHomology search is a means through which DNA double-strand breaks (DSBs) explore the genome for sequences that enable error-free repair, known as homologous recombination. A better understanding of this search process is fundamental to the relationship between higher-order chromosome organization and DNA damage. Here, we use an entropic bead-spring polymer chain model to simulate the spatiotemporal dynamics of the yeast genome during interphase. The chromosome is organized by transient and dynamic cross-links representing structural maintenance of chromosome (SMC) complexes. DNA damage is modeled as a break in the bead-spring chain, coupled with a removal of crosslinks from beads proximal to the break site. We show that the removal of cross-links drives the exploration of genomic space by the damaged ends, while rates and densities of intact dynamic crosslinking have only a minor role. Local depletion of SMC cross-links proximal to the break site enables the damaged segment to escape the chromosome territory and enhances its ability to explore the genome. Our study reveals a foundational principle by which DSBs can encounter distant regions of sequence homology
Combining spironolactone to antiretroviral therapy accelerates HIV decay in humanized mice
Get PDFSpironolactone (SP), a clinically used aldosterone antagonist, has been explored as an anti-HIV agent in models of HIV-1 latency for inducing transcriptional silencing of the viral reservoir. SP promotes the degradation of xeroderma pigmentosum group B (XPB) protein, a crucial component of transcription factor II H (TFIIH) required for RNA polymerase II transcriptional initiation. This study evaluated the impact of a long-acting formulation of SP on HIV replication within the context of antiretroviral therapy (ART) in the humanized mice model of HIV infection. The findings demonstrate that adding SP to ART accelerates viral decline and reduces expression of inflammation-related genes in human immune cells - genes often upregulated in chronic viral infections. Although SP treatment did not alter levels of cell-associated viral DNA, it led to a significant 4.4-fold decrease in systemic cell-associated viral RNA. This supports the role of XPB in HIV transcriptional regulation and advocates for incorporating transcriptional inhibitors like SP into primary HIV therapy. Additionally, SP treatment diminished markers of immune activation and inflammation, critical factors contributing to morbidity and mortality in individuals with chronic HIV infection. These results highlight SP's potential to enhance HIV treatment by mitigating key aspects of viral persistence and associated immune challenges
Alcohol Use and HIV Suppression After Release From Prison Among People With HIV in Zambia
Get PDFImportance: Little is known about the factors affecting viral suppression among people living with HIV returning to the community after incarceration (ie, reentrants) in Africa. Objective: To describe changes in viral suppression among reentrants living with HIV in Zambia and estimate the association between postrelease alcohol use and viral suppression. Design, Setting, and Participants: This cohort study enrolled incarcerated people living with HIV from 5 prisons and surrounding communities in Zambia and conducted study visits before and after prison release to assess HIV-associated health behaviors and changes in clinical outcomes between March 2017 and November 2019. Eligible participants were incarcerated people aged at least 18 years, living with HIV, with release planned fewer than 30 days from screening, enrolled in the national HIV program, planning on living in Lusaka postrelease, and providing voluntary informed consent. Data were analyzed from April 20, 2024, to October 2, 2025. Exposure: Postrelease unhealthy alcohol use (UAU), per the World Health Organization Alcohol Use Disorders Identification Test. Main Outcomes and Measures: The primary outcome was HIV-1 viral load (VL) suppression (<1000 copies/mL) before and after release. Mixed-effects Poisson regression was used to estimate the association between postrelease UAU and loss of viral suppression, using a directed acyclic graph to identify confounders. Results: Of 396 individuals screened, a total of 295 incarcerated people living with HIV (74.7%; median [IQR] age, 34 [29-41] years; 237 [80.3%] male) were included, with median (IQR) baseline CD4+ of 378 (244.5-506.5) cells/mL. At release, participants had been incarcerated a median (IQR) of 7.4 (3.5-15.4) months and receiving antiretroviral therapy for 13.2 (4.3-62.5) months. Documented viral suppression decreased from 237 individuals (80.3%) before release to 211 individuals (71.5%) after release. A total of 251 participants (85.1%) completed follow-up at a median (IQR) of 7.8 (5.4-11.6) months after release. UAU (prevalence ratio [PR], 3.35; 95% CI, 1.82-6.15) and unhealthy drug use (PR, 2.82; 95% CI, 1.39-5.71) were associated with postrelease unsuppressed VL. Among 205 participants (69.5%) with prerelease viral suppression, postrelease UAU was significantly associated with loss of viral suppression (adjusted risk ratio, 4.07; 95% CI, 1.97-8.42). Conclusions and Relevance: This cohort study of reentrants living with HIV in Zambia found that postrelease UAU was significantly associated with loss of viral suppression after community reentry. These findings suggest that new care models are needed to support HIV care continuity and address comorbid substance use in this population
APOE4 to APOE2 allelic switching in mice improves Alzheimer's disease-related metabolic signatures, neuropathology and cognition.
Get PDFCompared to individuals carrying two copies of the ε4 allele of apolipoprotein E (APOE), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer's disease (AD) risk. Here we develop a knock-in model that allows for an inducible 'switch' between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes. Finally, when crossed to the 5xFAD background, astrocyte-specific E4 to E2 switching improves cognition, decreases amyloid pathology, lowers gliosis and reduces plaque-associated apolipoprotein E. Together, these data show that a short-term transition from APOE4 to APOE2 can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specific APOE replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies
Comparison of the Nutritional Value of Locally Formulated Food Preparations and Standard Ready‐to‐Use Therapeutic Foods for the Management of Uncomplicated Severe Acute Malnutrition in Children Under Five in the Democratic Republic of the Congo
Get PDFSevere acute malnutrition (SAM) remains a major concern in sub‐Saharan Africa. In the Democratic Republic of the Congo (DRC), health care providers in therapeutic feeding units produce locally formulated food preparations empirically, with unknown macro‐ and micronutrient compositions. This study compares ingredients and nutritional values of locally formulated food preparation with those of standard ready‐to‐use therapeutic foods, as per Codex Alimentarius standards. A descriptive, comparative case study design was employed across outpatient therapeutic nutrition units (OTNUs) in four provinces of the DRC. Food samples were collected. Analysis included theoretical nutritional values calculation using NutVal software and laboratory analyses for selected nutrients (phosphorus, iron, calcium, magnesium, energy, lipids, and proteins) via standard protocols. From theoretical nutritional values, we calculate percentages of WHO/Codex Alimentarius requirements covered by the recipes and recipes in deficit by nutrient group. Laboratory analyses of selected nutrients were compared with the cut‐off of the corresponding nutrient in the Codex Alimentarius. Analyses were conducted using Stata 18. Locally formulated food preparations were mostly milk‐ and peanut‐free, often exceeding protein and lipid recommendations but deficient in vitamins (A, D, E, K, B12, folate), and critical minerals (calcium, iron, iodine, selenium, zinc). Compliance with Codex standards was very low, confirming macronutrient inadequacy but widespread micronutrient gaps. This study highlights critical gaps in locally formulated preparations in the management of SAM compared with WHO/Codex standards, emphasizing the need for fortification, balanced nutrients, and regulatory oversight. Engaging local industries, optimizing ingredient value chains, and rigorous evaluation are essential to ensure sustainable, effective, and context‐appropriate SAM treatment solutions.Locally formulated food preparations were mostly milk‐ and peanut‐free, often exceeding protein and lipid recommendations but deficient in vitamins (A, D, E, K, B12, folate), and critical minerals (calcium, iron, iodine, selenium, zinc). Compliance with Codex standards was very low, confirming macronutrient inadequacy but widespread micronutrient gaps
Economic evaluations of community health worker programs focussed on neglected tropical diseases in low- and middle-income countries (2015–2024): A scoping literature review
Get PDFNeglected tropical diseases (NTDs) are a diverse group of more than twenty diseases caused by parasitic, bacterial, and viral infections, affecting more than one billion individuals worldwide. Economic evidence can help guide the investment in Community Health Workers (CHWs) who can help expand access to preventive and curative NTD services in low- and middle-income countries (LMICs). A scoping review was conducted across ten databases and grey literature, covering studies published between August 2015 and July 2024. Search terms related to “Community Health Workers” and “Economic Evaluations” were used. Studies were screened via Covidence software based on inclusion and exclusion criteria. Data on study methodology, costs, and outcomes were extracted, tabulated in Microsoft Excel, and analysed. Of the 29 included scenarios (n = 10 studies), 7 were about community mass drug administration and 22 focused on other topics - such as disease-specific prevention and treatment (e.g., dengue). Across scenarios, the most commonly reported outcomes were cost per service delivered (ranging from 5.33) and cost per capita (ranging from 21.09). Five scenarios reported on cost-effectiveness, with varied results (40–50% of scenarios were reported as cost effective). One study found that interventions were more likely to be cost-effective when they leveraged integrated care as opposed to vertical approaches. The evidence base for economic evaluations regarding CHW involvement in NTD programs is highly limited. From the 10 studies identified there was no clear conclusion with regards to cost-effectiveness or affordability of CHWs in NTD programs in LMICs. To better understand the critical role CHWs can play in both prevention- and treatment-focused NTD programs, further evidence of the cost-effectiveness and affordability of such interventions is needed
Prospective associations between accelerometer-measured physical activity, sedentary behavior, and healthy longevity: the Women’s Health Accelerometry Collaboration
Get PDFBACKGROUND: The influence of physical activity (PA) and sedentary behavior (SB) on survival to late age with intact mobility is unclear. This study investigated associations between accelerometer-measured daily PA, SB, and survival to age 90 birthyear with and without intact mobility in the Women's Health Accelerometry Collaboration (WHAC). METHODS: Postmenopausal U.S. women aged 78-89 years without mobility disability were followed for an average of 6.1 years. At age 90 birthyear, participants were categorized as: (1) surviving with intact mobility, (2) surviving with mobility disability, or (3) deceased. Participants wore an accelerometer on the hip for up to 7 days at baseline from 2011-2015. Covariate-adjusted multinomial logistic regression models estimated odds ratios (ORs) of PA (light, moderate-to-vigorous [MVPA], total, steps) and SB (sitting time, mean sitting bout duration) with survival outcomes relative to dying. RESULTS: Among 2,656 women (mean baseline age 83.1 years), 62.8% survived with intact mobility, 22.3% with mobility disability, and 15.0% died. Compared to dying before age 90, the OR (95% confidence intervals [CI]) for every 1-SD increment in accelerometer variables and survival with intact mobility were 1.36 (1.20, 1.54) for light PA, 1.69 (1.47, 1.96) for MVPA, 1.51 (1.33, 1.71) for total PA, 1.75 (1.51, 2.03) for steps, 0.70 (0.61, 0.80) for sitting time, and 0.79 (0.70, 0.89) for sitting bouts. Similar, weaker trends were present for mobility disability. CONCLUSIONS: These findings corroborate the potential role of increasing physical activity in preserving physical functioning as an important element of healthy longevity
Systematic Review of Microorganism Removal Performance by Physiochemical Water Treatment Technologies.
Get PDFAccess to safe drinking water is crucial for public health necessitating the use of effective water treatment processes. We conducted a systematic literature review on microorganism removal by physical treatment processes used in drinking water treatment systems with the aim of providing current summary data to update the World Health Organization's Guidelines for Drinking Water Quality (GDWQ) and to reflect on the data available for comparison of treatment technologies. We reviewed peer-reviewed articles reporting original data that were published between 1997 and March 2022 on the following physical treatment technologies: roughing filters, storage reservoirs, bank filtration, conventional and high-rate clarification, dissolved air flotation, lime softening, granular media filtration, slow sand filtration, precoat filtration, membrane filtration, granular activated carbon, ceramic membrane filtration, and soil aquifer treatment. The literature search was conducted in several databases including Web of Science and PubMed. Data from 165 articles were included in the analysis and used to calculate Log Reduction Values (LRVs) for each technology by microbial contaminant type (bacteria, virus, or protozoa). The quantity and quality of data ranged widely for each technology. We found granular media, membranes (microfiltration (MF), ultrafiltration (UF), and reverse osmosis (RO)), and precoat filtration to remove the most protozoa with average LRVs of 3.0 (95% CI 2.8-3.3), 5.7 (95% CI 5.4-6.0), and 4.4 (95% CI 4.1-4.7), respectively. Bacteria was removed most effectively by membrane filtration (MF, UF, RO) with average LRVs of 4.5 (95% CI 3.9-5.1) and moderately by dissolved air flotation, lime softening, and soil aquifer treatment with average LRVs of 2.7, 2.6, and 2.4 respectively. Viruses were removed most effectively by reverse osmosis membrane filtration with an average LRV of 4.9 (95% CI 4.0-5.7). This data provides valuable information on pathogen reduction and areas of needed research. The variation in results underscores the importance of further consideration when selecting technologies to use and the need for standardized reporting in both lab and field studies. It is important to consider variables in water quality and technology operation that may impact treatment effectiveness when selecting treatment options for use. The findings contribute to ongoing efforts to revise the WHO's GDWQ, offering updated insights into LRVs for different water treatment technologies
Ongoing evolution of PE/PPE genes in Mycobacterium tuberculosis associated with drug resistance and host immune response.
Get PDFThe Proline-Glutamate/Proline-Proline-Glutamate (PE/PPE) gene family comprises approximately 10% of the Mycobacterium tuberculosis (Mtb) genome and is characterized by GC-rich, highly repetitive sequences. As a result, these genes are usually excluded from short-read-based whole-genome sequencing analyses, leaving their sequence diversity and evolutionary dynamics poorly characterized. Recently, a genome masking approach demonstrated that roughly 54% of PE/PPE sequences are recoverable from short-read data, providing an opportunity to examine the evolution of this gene family at a population level. Here, we analyzed 51,229 Mtb genomes to characterize sequence diversity and selection pressures across the PE/PPE gene family. Overall, we observed that PE/PPE genes are under relaxed purifying selection compared to other gene categories, as evidenced by higher ratios of nonsynonymous to synonymous polymorphisms (pNpS) and greater mutation burdens. We identified 12 PE/PPE genes with signatures of positive selection and 7 with selective pressure associated with antibiotic resistance. Among these genes, PPE51 exhibited selection favoring loss-of-function mutations, which occurred only in Mtb strains that were already multidrug-resistant (MDR). This pattern suggests either compensatory evolution or adaptation related to resistance against second-line or newly introduced drugs. Additionally, we identified T-cell epitopes in six PE/PPE genes that were subject to diversifying selection, suggesting immune-driven adaptation. Collectively, this work provides a baseline characterization of genetic diversity in PE/PPE genes and highlights specific genes that may be involved in adaptation to host immunity and antibiotic pressure and represent candidates for further investigation.IMPORTANCETuberculosis remains a significant global health challenge, partly due to Mycobacterium tuberculosis (Mtb)'s remarkable evolutionary adaptation to antibiotics and human immune responses. Around 10% of its genome comprises PE/PPE genes, whose functions and evolutionary dynamics are poorly understood due to their repetitive sequences and high GC content. In this study, we analyzed 51,229 global Mtb genomes using an advanced genome-masking method, revealing numerous PE/PPE genes under positive selection, potentially facilitating antibiotic resistance and immune evasion. Notably, PPE51 often loses its function in strains resistant to multiple antibiotics, suggesting a role in bacterial survival during drug treatment. Additionally, we identified mutation-prone regions within six PE/PPE genes, highlighting potential targets for future vaccine development. Collectively, our findings underscore the crucial role of PE/PPE genes in Mtb evolution and drug resistance, providing valuable insights to inform novel therapeutic and vaccine strategies
Evaluating the efficacy of neurokinin-1 (substance P) receptor antagonist CP-99994 on facial grimacing and allodynia in mice postsurgery: a comparative study with known analgesics.
Get PDFNeurokinin-1 (substance P) receptor (NK1R) antagonists failed to effectively treat pain in humans despite having antinociceptive properties in animals. Here, we sought to evaluate the efficacy of NK1R antagonist CP-99994 at reducing facial grimacing in white-coated CD-1 mice after laparotomy surgery when compared to the analgesics carprofen and buprenorphine. To enable this investigation, we developed a machine learning algorithm to automatically score facial grimacing in white-coated mice using the PainFace software platform. This algorithm detects 5 facial action units of the mouse grimace scale (MGS; orbitals, nose, ears, whiskers, cheeks) and assigns a facial grimace score (0-10) for each video frame analyzed. Carprofen and buprenorphine significantly reduced mean MGS scores and percentage of high grimace (MGS scores ≥5) frames for up to 4 hours postsurgery across multiple doses. In contrast, CP-99994 showed limited efficacy, with only the highest 30 mg/kg dose reducing grimacing at 2 hours. Likewise, principal component analysis of grimace data over time indicated that carprofen and buprenorphine were effective at reducing facial grimacing, whereas CP-99994 was not. However, both buprenorphine and CP-99994 reduced mechanical allodynia at the incision site. These findings reveal a dissociation between the effects of CP-99994 on a spontaneous pain measure (grimacing) and an evoked nociceptive response, whereas a known analgesic reduced both measures. Our study suggests that using facial grimacing to assess spontaneous pain alongside traditional nociceptive assays may better predict analgesic potential and possibly reduce risk of translational failures when selecting drug candidates for clinical advancement