Daxx mediated histone H3.3 deposition on HSV-1 DNA restricts genome decompaction and the progression of immediate-early transcription.

Herpesviruses are ubiquitous pathogens that cause a wide range of disease. Upon nuclear entry, their genomes associate with histones and chromatin modifying enzymes that regulate the progression of viral transcription and outcome of infection. While the composition and modification of viral chromatin has been extensively studied on bulk populations of infected cells by chromatin immunoprecipitation, this key regulatory process remains poorly defined at single-genome resolution. Here we use high-resolution quantitative imaging to investigate the spatial proximity of canonical and variant histones at individual Herpes Simplex Virus 1 (HSV-1) genomes within the first 90 minutes of infection. We identify significant population heterogeneity in the stable enrichment and spatial proximity of canonical histones (H2A, H2B, H3.1) at viral DNA (vDNA) relative to established promyelocytic leukaemia nuclear body (PML-NB) host factors that are actively recruited to viral genomes upon nuclear entry. We show the replication-independent histone H3.3/H4 chaperone Daxx to cooperate with PML to mediate the enrichment and spatial localization of variant histone H3.3 at vDNA that limits the rate of HSV-1 genome decompaction to restrict the progress of immediate-early (IE) transcription. This host response is counteracted by the viral ubiquitin ligase ICP0, which degrades PML to disperse Daxx and variant histone H3.3 from vDNA to stimulate the progression of viral genome expansion, IE transcription, and onset of HSV-1 replication. Our data support a model of intermediate and sequential histone assembly initiated by Daxx that limits the rate of HSV-1 genome decompaction independently of the stable enrichment of histones H2A and H2B at vDNA required to facilitate canonical nucleosome assembly. We identify HSV-1 genome decompaction upon nuclear infection to play a key role in the initiation and functional outcome of HSV-1 lytic infection, findings pertinent to the transcriptional regulation of many nuclear replicating herpesvirus pathogens.

Mitochondrial Probe for Glutathione Depletion Reveals NME3 Essentiality for Mitochondrial Redox Response.

Maintenance of the mitochondrial thiol redox state is essential for cell survival. However, we lack a comprehensive understanding of the redox response to mitochondrial glutathione depletion. We developed a mitochondria-penetrating peptide, mtCDNB, to specifically deplete mitochondrial glutathione. A genome-wide CRISPR/Cas9 screen in tandem with mtCDNB treatment was employed to uncover regulators of the redox response to mitochondrial glutathione depletion. We identified nucleoside diphosphate kinase 3 (NME3) as a regulator of mitochondrial dynamics. We show that NME3 is recruited to the mitochondrial outer membrane when under redox stress. In the absence of NME3, there is impaired mitophagy, which leads to the accumulation of dysfunctional mitochondria. NME3 knockouts depleted of mitochondrial glutathione have increased mitochondrial ROS production, accumulate mtDNA lesions, and present a senescence-associated secretory phenotype. Our findings suggest a novel role for NME3 in selecting mitochondria for degradation through mitophagy under conditions of mitochondrial redox stress.

Revealing the Structural Intricacies of Biomembrane-Interfaced Emulsions with Small- and Ultra-Small-Angle Neutron Scattering.

Utilizing cell membranes from diverse cell types for biointerfacing has demonstrated significant advantages in enhancing colloidal stability and incorporating biological properties, tailored specifically for various biomedical applications. However, the structures of these materials, particularly emulsions interfaced with red blood cell (RBC) or platelet (PLT) membranes, remain an underexplored area. This study systematically employs small- and ultra-small-angle neutron scattering (SANS and USANS) with contrast variation to investigate the structure of emulsions containing perfluorohexane within RBC (RBC/PFH) and PLT membranes (PLT/PFH). The findings reveal that the scattering length density of RBC and PLT membranes is 1.5 × 10-6 Å-2, similar to 30% (w/w) deuterium oxide. Using this solvent as a cell membrane-matching medium, estimated droplet diameters are 770 nm (RBC/PFH) and 1.5 µm (PLT/PFH), based on polydispersed sphere model fitting. Intriguingly, calculated patterns and invariant analysis reveal native droplet architectures featuring entirely liquid PFH cores, differing significantly from the observed bubble-droplet core system in electron microscopy. This highlights the advantage of SANS and USANS in differentiating genuine colloidal structures in complex dispersions. In summary, this work underscores the pivotal role of SANS and USANS in characterizing biointerfaced colloids and in uncovering novel colloidal structures with significant potential for biomedical applications and clinical translation.

Direct Exfoliation of Nanoribbons from Bulk van der Waals Crystals.

Confinement of monolayers into quasi-1D atomically thin nanoribbons could lead to novel quantum phenomena beyond those achieved in their bulk and monolayer counterparts. However, current experimental availability of nanoribbon species beyond graphene is limited to bottom-up synthesis or lithographic patterning. In this study, a versatile and direct approach is introduced to exfoliate bulk van der Waals crystals as nanoribbons. Akin to the Scotch tape exfoliation method for producing monolayers, this technique provides convenient access to a wide range of nanoribbons derived from their corresponding bulk crystals, including MoS2, WS2, MoSe2, WSe2, MoTe2, WTe2, ReS2, and hBN. The nanoribbons are predominantly monolayer, single-crystalline, parallel-aligned, flat, and exhibit high aspect ratios. The role of confinement, strain, and edge configuration of these nanoribbons is observed in their electrical, magnetic, and optical properties. This versatile exfoliation technique provides a universal route for producing a variety of nanoribbon materials and supports the study of their fundamental properties and potential applications.

Mortality follow-up of Fernald Feed Materials Production Center workers exposed to uranium from 1951 to 1985.

OBJECTIVE: This follow-up study of uranium processing workers at the Fernald Feed Materials Production Center examines the relationship between radiation exposure and cancer and non-cancer mortality among 6403 workers employed for at least 30 days between 1951 and 1985. METHODS: We estimated cumulative, individual, annualised doses to 15 organs/tissues from external, internal and radon exposures. Vital status and cause of death were ascertained in 2017. The analysis employed standardised mortality ratios, Cox proportional hazards and Poisson regression models. Competing risk analysis was conducted for cardiovascular disease (CVD) mortality risk given several assumptions about risk independent of competing outcomes. Emphysema was examined to assess the potential for confounding by smoking. RESULTS: Vital status was confirmed for 98.1% of workers, with 65.1% deceased. All-cause mortality was less than expected in salaried but not hourly workers when compared with the US population. A statistically significant dose response was observed between external (but not total or internal) lung dose and lung cancer mortality (HR at 100 mGy adjusted for internal dose=1.45; 95% CI=1.05 to 2.01). Significantly increased HRs at 100 mGy dose to heart were observed for CVD (1.27; 95% CI=1.07 to 1.50) and ischaemic heart disease (1.30; 95% CI=1.07 to 1.58). CVD risk remained elevated regardless of competing risk assumptions. Both external and internal radiation were associated with emphysema. CONCLUSIONS: Lung cancer was associated with external dose, though positive dose responses for emphysema imply residual confounding by smoking. Novel use of competing risk analysis for CVD demonstrates leveraging retrospective data for future risk prediction.

The Role of Emergency Medicine in Intimate Partner Violence: A Scoping Review of Screening, Survivor Resources, and Barriers.

At the front line of our medical system and population health, emergency medicine (EM) settings serve as a commonly perceived place for safety. Survivors of intimate partner violence (IPV) may present to the emergency department (ED) with injuries, illness, or specifically to seek help for IPV. In 2018, the U.S. Preventive Services Task Force (USPSTF) recommended screening women of reproductive age for IPV across all healthcare settings. Our objective was to examine the application of IPV interventions, resource allocation, and persistent barriers for screening within the EM setting following the USPSTF recommendation. This scoping review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Our initial search of two major databases, PubMed and CINAHL, found 259 articles. After screening for inclusion and exclusion criteria, 15 articles met the full study criteria. Inconsistencies in screening women for IPV in EM are still prevalent. No study used the same validated IPV screening tool and four did not specify the tool. Significant barriers to screening included time constraints, patient acuity, language barriers, staff education, and inability to connect patients to resources. There is a need for more consistent IPV screening in the EM setting, which may include the development of a standardized, inclusive screening tool, as well as additional research and sharing of best practices. Advancement of IPV identification must go beyond a recommendation with greater awareness and education changes at all levels: personal, institutional, and policy.

Economic Impact of Whole Genome Sequencing and Whole Transcriptome Sequencing Versus Routine Diagnostic Molecular Testing to Stratify Patients with B-Cell Acute Lymphoblastic Leukemia.

Whole genome and whole transcriptome sequencing (WGTS) can accurately distinguish B-cell acute lymphoblastic leukemia (B-ALL) genomic subtypes. However, whether this is economically viable remains unclear. This study compared the direct costs and molecular subtype classification yield using different testing strategies for WGTS in adolescent and young adult/adult patients with B-ALL. These approaches were: (1) combined BCR::ABL1 by fluorescence in situ hybridization (FISH) + WGTS for all patients; and (2) sequential BCR::ABL1 FISH + WGTS contingent on initial BCR::ABL1 FISH test outcome. The cost of routine diagnostic testing was estimated using Medicare or hospital fees, and the additional cost of WGTS was evaluated from the health care provider perspective using time-driven activity-based costing with resource identification elicited from experts. Molecular subtype classification yield data were derived from literature sources. Parameter uncertainty was assessed through deterministic sensitivity analysis; additional scenario analyses were performed. The total per patient cost of WGTS was $4319 (all costs reported in US dollars); consumables accounted for 74% of the overall cost, primarily driven by sequencing-related consumables. The incremental cost per additional patient categorized into molecular subtype was $8498 for combined BCR::ABL1 FISH + WGTS for all patients and $5656 for initial BCR::ABL1 FISH + WGTS for select patients compared with routine diagnostic testing. A reduction in the consumable costs of WGTS or an increase in the yield of molecular subtype classification is favorable.

HAP-FAST: a feasibility study incorporating qualitative, mechanistic and costing sub-studies alongside a randomised pilot trial comparing chest x-ray to low-dose CT scan and empirical antibiotics to antibiotics guided by the BIOFIRE® FILM ARRAY® pneumonia plus panel in adults with suspected non-ventilator-associated hospital-cquired pneumonia.

INTRODUCTION: Non-ventilator-associated hospital-acquired pneumonia (nv-HAP) is the most common healthcare-associated infection (HCAI), is associated with high mortality and morbidity and places a major burden on healthcare systems. Diagnosis currently relies on chest x-rays to confirm pneumonia and sputum cultures to determine the microbiological cause. This approach leads to over-diagnosis of pneumonia, rarely identifies a causative pathogen and perpetuates unnecessary and imprecise antibiotic use. The HAP-FAST study aims to evaluate the feasibility of a randomised trial to evaluate the clinical impact of low-dose, non-contrast-enhanced thoracic CT scans and rapid molecular sputum analysis using the BIOFIRE® FILMARRAY® pneumonia plus panel (FAPP) for patients suspected with nv-HAP. METHODS AND ANALYSIS: The HAP-FAST feasibility study consists of a pilot randomised trial, a qualitative study, a costing analysis and exploratory analyses of clinical samples to investigate the immune-pathophysiology of HAP. Participants are identified and recruited from four acute hospitals in the Northwest of the UK. Using a Research Without Prior Consent model, the pilot trial will recruit 220 adult participants, with or without mental capacity, and with suspected HAP. HAP-FAST is a non-blinded, sequential, multiple assignment, randomised trial with two possible stages of randomisation: first, chest x-ray (CXR) or CT; second, if treated as nv-HAP, FAPP or standard microbiological processing alone (no FAPP). Pathogen-specific antibiotic guidance will be provided for FAPP results. Randomisation uses a web-based platform and followed up for 90 days. The feasibility of a future trial will be determined by assessing trial processes, outcome measures and patient and staff experiences. ETHICS AND DISSEMINATION: This study has undergone combined review by the UK NHS Research Ethics Committee and Health Research Authority. Results will be disseminated via peer-reviewed journals, via the funders' website and through a range of media to engage the public. TRIAL REGISTRATION NUMBER: NCT05483309.

Promoting Polysulfide Redox Reactions through Electronic Spin Manipulation.

Catalytic additives able to accelerate the lithium-sulfur redox reaction are a key component of sulfur cathodes in lithium-sulfur batteries (LSBs). Their design focuses on optimizing the charge distribution within the energy spectra, which involves refinement of the distribution and occupancy of the electronic density of states. Herein, beyond charge distribution, we explore the role of the electronic spin configuration on the polysulfide adsorption properties and catalytic activity of the additive. We showcase the importance of this electronic parameter by generating spin polarization through a defect engineering approach based on the introduction of Co vacancies on the surface of CoSe nanosheets. We show vacancies change the electron spin state distribution, increasing the number of unpaired electrons with aligned spins. This local electronic rearrangement enhances the polysulfide adsorption, reducing the activation energy of the Li-S redox reactions. As a result, more uniform nucleation and growth of Li2S and an accelerated liquid-solid conversion in LSB cathodes are obtained. These translate into LSB cathodes exhibiting capacities up to 1089 mA h g-1 at 1 C with 0.017% average capacity loss after 1500 cycles, and up to 5.2 mA h cm-2, with 0.16% decay per cycle after 200 cycles in high sulfur loading cells.

Revisiting the Historic Strontium-90 Ingestion Beagle Study Conducted at the University of California Davis: Opportunity in Archival Materials.

Strontium-90 is a radionuclide found in high concentrations in nuclear reactor waste and nuclear fallout from reactor accidents and atomic bomb explosions. In the 1950s, little was known regarding the health consequences of strontium-90 internalization. To assess the health effects of strontium-90 ingestion in infancy through adolescence, the Atomic Energy Commission and Department of Energy funded large-scale beagle studies at the University of California Davis. Conducted from 1956 to 1989, the strontium-90 ingestion study followed roughly 460 beagles throughout their lifespans after they were exposed to strontium-90 in utero (through feeding of the mother) and fed strontium-90 feed at varying doses from weaning to age 540 days. The extensive medical data and formalin-fixed paraffin-embedded tissues were transferred from UC Davis to the National Radiobiology Archive in 1992 and subsequently to the Northwestern University Radiobiology Archive in 2010. Here, we summarize the design of the strontium-90 ingestion study and give an overview of its most frequent recorded findings. As shown before, radiation-associated neoplasias (osteosarcoma, myeloproliferative syndrome and select squamous cell carcinomas) were almost exclusively observed in the highest dose groups, while the incidence of neoplasias most frequent in controls decreased as dose increased. The occurrence of congestive heart failure in each dose group, not previously assessed by UC Davis researchers, showed a non-significant increase between the controls and lower dose groups that may have been significant had sample sizes been larger. Detailed secondary analyses of these data and samples may uncover health endpoints that were not evaluated by the team that conducted the study.

Beam Effects in Synchrotron Radiation Operando Characterization of Battery Materials: X-Ray Diffraction and Absorption Study of LiNi0.33Mn0.33Co0.33O2 and LiFePO4 Electrodes.

Operando synchrotron radiation-based techniques are a precious tool in battery research, as they enable the detection of metastable intermediates and ensure characterization under realistic cycling conditions. However, they do not come exempt of risks. The interaction between synchrotron radiation and samples, particularly within an active electrochemical cell, can induce relevant effects at the irradiated spot, potentially jeopardizing the experiment's reliability and biasing data interpretation. With the aim of contributing to this ongoing debate, a systematic investigation into these phenomena was carried out by conducting a root cause analysis of beam-induced effects during the operando characterization of two of the most commonly employed positive electrode materials in commercial Li-ion batteries: LiNi0.33Mn0.33Co0.33O2 and LiFePO4. The study spans across diverse experimental conditions involving different cell types and absorption and scattering techniques and seeks to correlate beam effects with factors such as radiation energy, photon flux, exposure time, and other parameters associated with radiation dosage. Finally, it provides a comprehensive set of guidelines and recommendations for assessing and mitigating beam-induced effects that may affect the outcome of battery operando experiments.

Salt-Induced Linker Dehydration Modulates Micellar Structure in Ether-Linked Sulfate Surfactants.

Ether-linked surfactants are widely used in formulations such as liquid soaps, but despite their ubiquity, it is unclear how n-ethylene glycol linkers in surfactants, such as sodium lauryl n-(ethylene glycol) sulfate (SLEnS), influence micellar packing in the presence of NaCl. In the present work, we probe the structure and hydration of ether linkers in micelles comprising monodisperse SLEnS surfactants using contrast-variation small-angle neutron scattering (CV-SANS) and small-angle X-ray scattering (SAXS). Using SAXS, changes in micellar structure were observed for SLEnS (n = 1, 2, or 3) arising from the extent of ethoxylation. Scattering profiles indicated a clear transition from elongated cylindrical micelles to shorter ellipsoidal micelles with increasing ethoxylation. With CV-SANS, micellar structure and linker geometries of SLE3S were able to be resolved, indicating that a change in micellar architecture is modulated by dehydration of the tri(ethylene glycol) linker, offering new insights into the role of water and ions in the self-assembly of this key class of surfactants.

Exploring the contribution of inter-individual factors to the development of physiological heat strain in older adults exposed to simulated indoor overheating.

Older adults are at elevated risk of heat-related mortality due to age-associated declines in thermoregulatory and cardiovascular function. However, the inter-individual factors that exacerbate physiological heat strain during heat exposure remain unclear, making it challenging to identify more heat-vulnerable subgroups. We therefore explored factors contributing to inter-individual variability in physiological responses of older adults exposed to simulated hot weather. Thirty-seven older adults (61-80 years, 16 females) rested for 8 h in 31 and 36 °C (45% relative humidity). Core (rectal) temperature, heart rate (HR), HR variability, mean arterial pressure (MAP), and cardiac autonomic responses to standing were measured at baseline and end-exposure. Bootstrapped least absolute shrinkage and selection operator regression was used to evaluate whether variation in these responses was related to type 2 diabetes (T2D, n = 10), hypertension (n = 18), age, sex, body morphology, habitual physical activity levels, and/or heat-acclimatization. T2D was identified as a predictor of end-exposure HR (with vs. without: 13 beats/min (bootstrap 95% confidence interval: 6, 23)), seated MAP (-7 mmHg (-18, 1)), and the systolic pressure response to standing (20 mmHg (4, 36)). HR was also influenced by sex (female vs. male: 8 beats/min (1, 16)). No other predictors were identified. The inter-individual factors explored did not meaningfully contribute to the variation in body temperature responses in older adults exposed to simulated indoor overheating. By contrast, cardiovascular responses were exacerbated in females and individuals with T2D. These findings improve understanding of how inter-individual differences contribute to heat-induced physiological strain in older persons.

Evaluating functions of praise for children diagnosed with autism spectrum disorder.

We assessed whether novel praise statements could be used to (a) maintain and increase responses with existing reinforcement histories and (b) teach a previously untaught response among children diagnosed with autism spectrum disorder across two experiments. During response-stimulus pairing, two responses resulted in preferred edibles but only one also produced a praise statement. In the absence of edibles, the response continuing to produce praise tended to persist more. Next, reversing the praise contingency tended to increase the other response. However, in no case did contingent delivery of those same praise statements result in the acquisition of untaught responses. These findings suggest that conditioning praise statements could serve different functions (antecedent or consequence) depending on the reinforcement history for particular responses.

Small-angle scattering of complex fluids in flow.

Complex fluids encompass a significant proportion of the materials that we use today from feedstocks such as cellulose fibre dispersions, materials undergoing processing or formulation, through to consumer end products such as shampoo. Such systems exhibit intricate behaviour due to their composition and microstructure, particularly when analysing their texture and response to flow (rheology). In particular, these fluids when flowing may undergo transitions in their nano- to microstructure, potentially aligning with flow fields, breaking and reassembling or reforming, or entirely changing phase. This manifests as macroscopic changes in material properties, such as core-annular flow of concentrated emulsions in pipelines or the favourable texture of liquid soaps. Small-angle scattering provides a unique method for probing underlying changes in fluid nano- to microstructure, from a few angströms to several microns, of complex fluids under flow. In particular, the alignment of rigid components or shape changes of soft components can be explored, along with local inter-particle ordering and global alignment with macroscopic flow fields. This review highlights recent important developments in the study of such complex fluid systems that couple flow or shear conditions with small-angle scattering measurements, and highlights the physical insight obtained by these experiments. Recent results from neutron scattering measurements made using a simple flow cell are presented, offering a facile method to explore alignment of complex fluids in an easily accessible geometry, and contextualised within existing and potential future research questions.

Emerging Variants of Canine Enteric Coronavirus Associated with Outbreaks of Gastroenteric Disease.

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus-like viruses associated with human disease but represent a model for coronavirus population adaptation.