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Efficient repair of DNA double-strand breaks (DSBs) requires a coordinated DNA Damage Response (DDR), which includes phosphorylation of histone H2Ax, forming γH2Ax. This histone modification spreads beyond the DSB into neighboring chromatin, generating a DDR platform that protects against end disassociation and degradation, minimizing chromosomal rearrangements. However, mechanisms that determine the breadth and intensity of γH2Ax domains remain unclear. Here, we show that chromosomal contacts of a DSB site are the primary determinants for γH2Ax landscapes. DSBs that disrupt a topological border permit extension of γH2Ax domains into both adjacent compartments. In contrast, DSBs near a border produce highly asymmetric DDR platforms, with γH2Ax nearly absent from one broken end. Collectively, our findings lend insights into a basic DNA repair mechanism and how the precise location of a DSB may influence genome integrity. Formation of γH2Ax serves as a checkpoint for double-strand break (DSB) repair pathways. Here the authors reveal via integrated chromatin analysis that γH2Ax domains are established by chromosomal contacts with the DSB site.

Although the interferon (IFN) signaling pathway is a key host mechanism to restrict infection of a diverse range of viral pathogens, its unrestrained activity either at baseline or in the context of an immune response can result in host cell damage and injury. Here, we used a genome-wide CRISPR-Cas9 screen and identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1) as a modulator of basal cell-intrinsic immunity. A loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline, which triggered IFN-stimulated gene expression via a cGAS-STING-IRF3 axis that did not require type I IFN or STAT1 signaling. Our experiments define a regulatory network in which Banf1 limits basal inflammation by preventing self DNA accumulation in the cytosol. Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, including Oas2 , Rsad2 (viperin), Ifit1 , and ISG15 . The phenotype in Banf1-deficient cells occurred through a cGAS-, STING-, and IRF3-dependent signaling axis, was associated with reduced infection of RNA and DNA viruses, and was reversed in Banf1 complemented cells. Confocal microscopy and biochemical studies revealed that a loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline. Our study identifies an undescribed role for Banf1 in regulating the levels of cytoplasmic DNA and cGAS-dependent ISG homeostasis and suggests possible therapeutic directions for promoting or inhibiting cell-intrinsic innate immune responses. IMPORTANCE Although the interferon (IFN) signaling pathway is a key host mechanism to restrict infection of a diverse range of viral pathogens, its unrestrained activity either at baseline or in the context of an immune response can result in host cell damage and injury. Here, we used a genome-wide CRISPR-Cas9 screen and identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1) as a modulator of basal cell-intrinsic immunity. A loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline, which triggered IFN-stimulated gene expression via a cGAS-STING-IRF3 axis that did not require type I IFN or STAT1 signaling. Our experiments define a regulatory network in which Banf1 limits basal inflammation by preventing self DNA accumulation in the cytosol.

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describe Toxoplasma gondii infection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes− Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

The Centers for Disease Control and Prevention’s Partnering for Vaccine Equity program was developed during the COVID-19 public health emergency to fund more than 500 community-based organizations working to improve vaccine equity. Organizations were supported by a virtual learning community where members received tailored learning content, peer-to-peer learning opportunities, and resources that facilitated deployment of vaccine-related programming during a dynamic pandemic. Process evaluation metrics indicate successful implementation of the learning community. The virtual learning community model can be duplicated to address other public health issues. ( Am J Public Health. 2025;115(4):469–472. https://doi.org/10.2105/AJPH.2024.307965 )

Biofilm formation by Bacillus subtilis is a communal process that culminates in the formation of architecturally complex multicellular communities. Here we reveal that the transition of the biofilm into a nonexpanding phase constitutes a distinct step in the process of biofilm development. Using genetic analysis we show that B. subtilis strains lacking the ability to synthesize pulcherriminic acid form biofilms that sustain the expansion phase, thereby linking pulcherriminic acid to growth arrest. However, production of pulcherriminic acid is not sufficient to block expansion of the biofilm. It needs to be secreted into the extracellular environment where it chelates Fe3+ from the growth medium in a nonenzymatic reaction. Utilizing mathematical modeling and a series of experimental methodologies we show that when the level of freely available iron in the environment drops below a critical threshold, expansion of the biofilm stops. Bioinformatics analysis allows us to identify the genes required for pulcherriminic acid synthesis in other Firmicutes but the patchwork presence both within and across closely related species suggests loss of these genes through multiple independent recombination events. The seemingly counterintuitive self-restriction of growth led us to explore if there were any benefits associated with pulcherriminic acid production. We identified that pulcherriminic acid producers can prevent invasion by neighboring communities through the generation of an “iron-free” zone, thereby addressing the paradox of pulcherriminic acid production by B. subtilis.

Older adults are at a greater risk for food insecurity compared to the general population. This study aimed to describe changes in diet quality and food insecurity following a free meal program at low-income, older adult housing complexes. Study participants were recruited from two low-income older adult public housing complexes in Kentucky. Fifty participants were enrolled and received 1–4 free weekly meals across 3 months as part of the Meals on Wings pilot program. Surveys and a 24 h dietary recall were completed at baseline and 3 months. Participants were predominately female, 69 years of age, and Black or African American race. Food security status (FSS) and dietary quality through the Healthy Eating Index (HEI) were assessed as primary measures. Participants were placed in “at-risk” categories of the (1a) lower quartile of the HEI and (1b) lower than 51% HEI, or (2) “low” or “very low” food security status based on the USDA Household Food Security Screener (FSS). Multiple linear regression (MLR) models were conducted for HEI and FSS scores to include time, group, time*group interaction, and control of meal utilization percentage (i.e., dose). The MLR for the HEI quartile had a significant time by quartile interaction that was present for an increase in the HEI in Q1 (n = 12; 32.42 ± 5.95% to n = 6; 46.10 ± 10.62%; p < 0.0001) and a decrease in the HEI for Q4 (n = 12; 70.68 ± 7.13% to n = 9; 52.36 ± 11.57%; p < 0.0001). For those low food security participants (n = 24; 48.0%), the average food insecurity score from the 6-item USDA screener improved from 4.09 ± 1.62 at baseline to 2.63 ± 2.41 at 3 months (p = 0.0064). The MLR for the FSS had a significant group*time interaction (p = 0.0071). In our population, particularly those vulnerable with lowest dietary quality and food insecurity status, we did see improvements across the free meal pilot program. However, a small sample, limited generalizability, and limited data collection measures urge caution when using these results to extrapolate for the general population. However, the current results are promising and should encourage further investigation of the effects of meal assistance programs on the health and well-being of older adults.

Respiratory syncytial virus (RSV) represents a high burden of disease in children and the primary cause of hospitalization, especially in children under 1 year old. In the Valencian Community (Spain), nirsevimab, a long-acting monoclonal antibody, was introduced for the RSV 2023–2024 season as a universal pre-exposure prophylaxis for high-risk children and those under 6 months old. This study examines its impact, coverage, and effectiveness. The campaign achieved 88.5 % coverage and 73.7 % of effectiveness. Analysis of over 27,000 susceptible children (over 24,000 immunized), showed that those immunized exhibited a threefold reduction in RSV incidence compared to non-immunized ones. To prevent one case, the number needed to immunize (NNI) was 63. Hospitalizations due to acute respiratory infections were almost two times lower in immunized children compared to non-immunized ones (0.9 % vs 1.6 %, respectively). These first results showcase the preliminary positive impact of this public health intervention.

In ecology, prey switching refers to a predator's adaptive change of habitat or diet in response to prey abundance. In this paper, we study piecewise-smooth models of predator-prey interactions with a linear trade-off in a predator's prey preference. We consider optimally foraging predators and derive a model for a 1 predator-2 prey interaction with a tilted switching manifold between the two sides of discontinuous vector fields. We show that the 1 predator-2 prey system undergoes a novel adding-sliding-like (center to two-part periodic orbit; \"C2PO'') bifurcation in which the prey ratio transitions from constant to time-dependent. Farther away from the bifurcation point, the period of the oscillating prey ratio doubles, which suggests a possible cascade to chaos. We compare our model predictions with data on freshwater plankton, and we successfully capture the periodicity in the ratio between the predator's preferred and alternative prey types. Our study suggests that it is useful to investigate prey ratio as a possible indicator of how population dynamics can be influenced by ecosystem diversity. [PUBLICATION ABSTRACT]

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

Background The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. Methods Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n = 7) or cardiac transplantation (n = 4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1 = 1/T1 and R2 = 1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. Results From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (±SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p < 0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R 2 0.566, p < 0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R 2 0.790, p < 0.001). The relation was [Fe] = 5081•(T2) -2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R 2 0.517, p < 0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R 2 0.657, p < 0.001). Conclusion Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies.