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Abstract Feline hyperthyroidism (FHT) is a debilitating disease affecting > 10% of elderly cats. It is generally characterised by chronic elevation of thyroid hormone in the absence of circulating TSH. Understanding of the molecular pathogenesis of FHT is currently limited. However, FHT shares clinical and histopathological similarities with human toxic multinodular goitre, which has been associated with activating mutations in TSH receptor (TSHR) and Gsα encoding genes. Using RNA-seq transcriptomic analysis of thyroid tissue from hyperthyroid and euthyroid cats, we identified differentially expressed genes and dysregulated pathways in FHT, many of which are downstream of TSHR. In addition, we detected missense variants in thyroid RNA-seq reads that alter the structure of both TSHR and Gsα. All FHT-associated mutations were absent in germline sequence from paired blood samples. Only a small number of hyperthyroid cats demonstrated TSHR variation, however all thyroids from advanced cases of FHT carried at least one missense variant affecting Gsα. The activating nature of the acquired Gsα mutations was demonstrated by increased cAMP production in vitro. These data indicate that constitutive activation of signalling downstream of TSHR is central to the TSH-independent production of thyroid hormone in FHT, offering a novel therapeutic target pathway in this common disease.

Abstract ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.

Abstract Six Schiff bases with general name 5-(diethylamino)-2-(((halophenyl)imino)methyl)phenol (where halo = 4-fluoro (H1), 2-fluoro (H2), 2-bromo (H3), 4-bromo (H4), 4-chloro (H5) and 3-chloro-4-fluoro (H6)) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and suitable halogenated aromatic amines. The six halogenated Schiff bases were elucidated using different spectroscopic techniques and the structure of H3 and H6 were confirmed using single-crystal X-ray crystallography. The bond lengths of C7–N1, C7–C8 and C8–C9 obtained from structural analysis for both compounds depicted their enol-tautomeric characteristic form. The Hirshfeld analysis revealed that H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). Quantum chemical calculation studies showed that H1 and H2 have the highest and lowest energy band gap (∆E = 3.80 eV for H1 and ∆E = 3.73 eV for H2), depicting H2 and H1 as the most and least chemically reactive respectively among all the compounds. α-Amylase and α-glucosidase assay were used to evaluate the antidiabetes prowess of the synthesized compounds. All the compounds exhibited lower IC50 values than acarbose (reference drug) in α-amylase assay experiments and H5 with lowest IC50 value of 63.54 μM could be suggested to have the highest α-amylase inhibitory potential among the test samples. For α-glucosidase assay, H1–H6 displayed good antidiabetic potential. However, none of the compounds outshined acarbose with H6 having highest α-glucosidase inhibitory potential when compared to others i.e., IC50 of H6 = 60.89 μM and IC50 of acarbose = 51.42 μM. We measured the antioxidant potential of H1–H6 exploring 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric reducing ability power (FRAP) assays. The DPPH as well as NO radical scavenging assay showed that all the compounds exhibited excellent antioxidant results with some of the compounds surpassing catechin (reference drug). Compound H5 with IC50 values of 30.32 mM and 31.73 mM outshined catechin with IC50 values of 31.17 mM and 140.62 mM for DPPH and NO assays respectively. All the compounds fell within the threshold of Lipinski’s Ro5 projecting them as orally bioavailable and less toxic future therapeutics.

Abstract Drug resistance remains a challenge for targeted therapy of cancers driven by EML4-ALK and related fusion oncogenes. EML4-ALK forms cytoplasmic protein condensates, which result from networks of interactions between oncogene and adapter protein multimers. While these assemblies are associated with oncogenic signaling, their role in drug response is unclear. Here, we use optogenetics and live-cell imaging to find that EML4-ALK assemblies suppress transmembrane receptor tyrosine kinase (RTK) signaling by sequestering RTK adapter proteins including GRB2 and SOS1. Furthermore, ALK inhibition, while suppressing oncogenic signaling, simultaneously releases the sequestered adapters and thereby resensitizes RTK signaling. Resensitized RTKs promote rapid and pulsatile ERK reactivation that originates from paracrine ligands shed by dying cells. Reactivated ERK signaling promotes cell survival, which can be counteracted by combination therapies that block paracrine signaling. Our results identify a regulatory role for RTK fusion assemblies and uncover a mechanism of tolerance to targeted therapies.

Abstract Hawking’s black hole area theorem provides a geometric realization of the second law of thermodynamics and constrains gravitational processes. In this work we explore a one-parameter extension of this constraint formulated in terms of the monotonicity properties of Rényi entropies. We focus on black hole mergers in asymptotically AdS space and determine new restrictions which these Rényi second laws impose on the final state. We evaluate the entropic inequalities starting from the thermodynamic ensembles description of black hole geometries, and find that for many situations they set more stringent bounds than those imposed by the area increase theorem.

Abstract The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Abstract In the AdS/CFT correspondence, the causal structure of the bulk AdS spacetime is tied to entanglement in the dual CFT. This relationship is captured by the connected wedge theorem [1], which states that a bulk scattering process implies the existence of O(1/G N ) entanglement between associated boundary subregions. In this paper, we study the connected wedge theorem in two asymptotically AdS2+1 spacetimes: the conical defect and BTZ black hole geometries. In these settings, we find that bulk scattering processes require not just large entanglement, but also additional restrictions related to candidate RT surfaces which are non-minimal. We argue these extra relationships imply a certain CFT entanglement structure involving internal degrees of freedom. Because bulk scattering relies on sub-AdS scale physics, this supports the idea that sub-AdS scale locality emerges from internal degrees of freedom. While the new restriction that we identify on non-minimal surfaces is stronger than the initial statement of the connected wedge theorem, we find that it is necessary but still not sufficient to imply bulk scattering in mixed states.

Abstract Methyl bromide (CH3Br) is an important ozone-depleting substance whose use is regulated under the Montreal Protocol. Quantifying emissions on the national scale is required to assess compliance with the Montreal Protocol and thereby ensure the timely recovery of the ozone layer. However, the spatial-temporal patterns of China’s national CH3Br emissions remain unclear. Here we estimate the national emissions of CH3Br in China during 2011−2020 using atmospheric observations at 10 sites across China combined with an inversion technique (top-down) and compare those with an updated inventory of identified emission sources (bottom-up). Measured CH3Br mole fractions are enhanced well above the background mole fractions, especially at sites in eastern China. Top-down emission estimates exceed bottom-up estimates by 5.5 ± 1.4 gigagrams per year, with the largest fraction (60%) of observationally derived CH3Br emissions arising from underestimated or unidentified emissions sources. This study shows the potential impacts of the unaccounted emissions on stratospheric ozone depletion, with implications for the Montreal Protocol.

Abstract Flow cytometry is a useful and efficient method for the rapid characterization of a cell population based on the optical and fluorescence properties of individual cells. Ideally, the cell population would consist of only healthy viable cells as dead cells can confound the analysis. Thus, separating out healthy cells from dying and dead cells, and any potential debris, is an important first step in analysis of flow cytometry data. While gating of debris can be conducted using measured optical properties, identifying dead and dying cells often requires utilizing fluorescent stains (e.g. Sytox, a nucleic acid stain that stains cells with compromised cell membranes) to identify cells that should be excluded from downstream analyses. These stains prolong the experimental preparation process and use a flow cytometer’s fluorescence channels that could otherwise be used to measure additional fluorescent markers within the cells (e.g. reporter proteins). Here we outline a stain-free method for identifying viable cells for downstream processing by gating cells that are dying or dead. AutoGater is a weakly supervised deep learning model that can separate healthy populations from unhealthy and dead populations using only light-scatter channels. In addition, AutoGater harmonizes different measurements of dead cells such as Sytox and CFUs.

Abstract The renewable energy industry is heavily reliant on rare earth elements, underscoring the need to develop resources and production. The objective of this work was to estimate coal ash resources and potential for extraction of rare earth elements using data for the US. Data on spatiotemporal variability in coal ash resources and disposition were compiled from various federal databases and rare earth elements levels in ash were compiled from the literature. Results show that ~ 52 gigatons (Gt) of coal were produced in the US (1950–2021). Power plants account for most of the coal use, particularly since 1980. Coal ash (5.3 Gt) represents a mean of 10% of coal by weight, ranging from 6% for subbituminous to 14% for lignite. About 70% of coal ash is potentially accessible for rare earth element extraction (1985–2021) and was disposed in landfills and ponds with the remaining coal ash used onsite or sold. Median values of total rare earth elements are much higher in ashes derived from the Appalachian Basin (median 431 mg/kg) than in the Illinois (282 mg/kg) or Powder River basins (264 mg/kg). Considering the market value of rare earth oxides, potentially accessible ash volumes, and percent rare earth element extraction (30% Appalachian and Illinois Basins; 70% Powder River Basin) results in an estimated $8.4 billion value. This study provides fundamental information on accessible coal ash resources in the US, linkages to coal sources, and preliminary estimates of rare earth element levels for future development within the US.

Abstract In this study, we analyze the effects of technology availability, political coordination, and behavioral change on transformation pathways toward net-zero greenhouse gas emissions in the European Union by 2050. We implemented an iterative stakeholder dialogue to co-design the scenarios that were calculated using a global multi-regional energy-economy-land-climate model. We find that in scenarios without behavioral change and with restriction of technologies, the target of greenhouse gas neutrality in the European Union cannot be reached. Already a target of 200 Mt CO2eq/yr requires CO2 prices above 100 €/tCO2 in 2030 across all sectors in all scenarios. The required CO2 price can increase to up to 450 €/tCO2 by 2030 if technologies are constrained, if no complementary regulatory measures are implemented, and if changes in consumer behavior towards a more sustainable lifestyle do not materialize.

Evaluating the effects of environmental events across both biophysical and social dimensions is important in establishing a holistic view of such events. This study focuses on the impact of a devastating heat stress incident that occurred in many locations across the Caribbean region and South Atlantic during the 2023 summer season. The survey and focus of data collection was within Monroe County, a unique nature-based setting south of Miami, Florida, USA. The impact of the heat wave is still being calculated at the time of submission of this paper, but indications are that there was a major negative impact. The survey and data collection sought to understand recreationists’ perceptions, knowledge, and behavior changes as result of the heat stress impact in the Florida Keys. Respondents were interviewed during community workshops in person and through an online sample of boating/angler license holders. The results indicated a change in behavior by some respondents, which may have a longer-term economic impact, along with trends of satisfaction with outdoor recreation over time. This rapid survey method can be applied to future scenarios where social and economic data are needed to fully contextualize environmental impacts in addition to biological endpoints.

Abstract Serial CA125 and second line transvaginal ultrasound (TVS) screening in the UKCTOCS indicated a shift towards detection of earlier stage ovarian cancer (OvCa), but did not yield a significant mortality reduction. There remains a need to establish additional biomarkers that can complement CA125 for even earlier and at a larger proportion of new cases. Using a cohort of plasma samples from 219 OvCa cases (59 stage I/II and 160 stage III/IV) and 409 female controls and a novel Sensitivity Maximization At A Given Specificity (SMAGS) method, we developed a blood-based metabolite-based test consisting of 7 metabolites together with CA125 for detection of OvCa. At a 98.5% specificity cutpoint, the metabolite test achieved sensitivity of 86.2% for detection of early-stage OvCa and was able to capture 64% of the cases with low CA125 levels (

Abstract Researchers examining conflict between intimate partners believe that the experience and expression of emotion drives aggressive behaviour. Intra-personally, increases in negative affect make aggression more likely. Inter-personally, theoretical models suggest that each individuals’ perception of their partners’ emotion also influences aggression, potentially creating a Violence Escalation Cycle. Here, using a lab-based aggression task across a primary study (n = 104, number of trials = 3095) and a replication (n = 58, number of trials = 3167), we show that both intra- and inter-personal experiences of negative emotion predict reactive aggression within couples, revealing retaliation but not escalation. Critically, analyses of facial affect reveal that prototypic displays of negative emotions have a compounding effect, leading to dramatic changes in aggression depending on whether one, both, or neither partner expressed negative emotion. We propose a mechanism by which temporal delays (i.e., experimentally imposed forced breaks) reduce aggression by decreasing negative emotional arousal and limiting impulsive action. Our results show that both forced breaks and elective breaks (i.e., extra participant-initiated extensions of the forced break time) reduce aggression, providing exciting evidence that interventions focused on preventing impulsive action when people are in a provoked state can reduce aggression within couples.

In this academic interview, Yale law professor Robert C. Post elucidates the distinction between freedom of expression and academic freedom, emphasizing that universities are communities guided by the twin missions of education and knowledge production. At their best, universities function as ‘disciplinary communities’ who must act in professionally competent ways. Post characterizes academic freedom as a ‘two-faced coin’. On the one hand, academic freedom embodies the values and principles essential for the governance of a healthy university community; on the other hand, it shields universities from external regulations that might hinder their mission of advancing education and research. Post also addresses the significant challenges to freedom of expression posed by the cosmopolitan public sphere, particularly in the age of social media and AI. As a trustee of Meta’s Oversight Board, Post highlights the complex issue of harmful speech online, noting that it is not only a matter of scale but also of scale, producing harms that are stochastic in nature.

Abstract Museum genomics provide an opportunity to investigate population demographics of extinct species, especially valuable when research prior to extinction was minimal. The Bachman’s warbler (Vermivora bachmanii) is hypothesized to have gone extinct due to loss of its specialized habitat. However, little is known about other potential contributing factors such as natural rarity or changes to connectivity following habitat fragmentation. We examined mitochondrial DNA (mtDNA) and genome-wide SNPs using specimens collected from breeding and migration sites across the range of the Bachman’s warbler. We found no signals of strong population structuring across the breeding range of Bachman’s warblers in both mtDNA and genome-wide SNPs. Thus, long-term population isolation did not appear to be a significant contributor to the extinction of the Bachman’s warbler. Instead, our findings support the theory that Bachman’s warblers underwent a rapid decline likely driven by habitat destruction, which may have been exacerbated by the natural rarity, habitat specificity and low genetic diversity of the species.

Abstract Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Abstract Electrokinetic convection-enhanced delivery (ECED) utilizes an external electric field to drive the delivery of molecules and bioactive substances to local regions of the brain through electroosmosis and electrophoresis, without the need for an applied pressure. We characterize the implementation of ECED to direct a neutrally charged fluorophore (3 kDa) from a doped biocompatible acrylic acid/acrylamide hydrogel placed on the cortical surface. We compare fluorophore infusion profiles using ECED (time = 30 min, current = 50 µA) and diffusion-only control trials, for ex vivo (N = 18) and in vivo (N = 12) experiments. The linear intensity profile of infusion to the brain is significantly higher in ECED compared to control trials, both for in vivo and ex vivo. The linear distance of infusion, area of infusion, and the displacement of peak fluorescence intensity along the direction of infusion in ECED trials compared to control trials are significantly larger for in vivo trials, but not for ex vivo trials. These results demonstrate the effectiveness of ECED to direct a solute from a surface hydrogel towards inside the brain parenchyma based predominantly on the electroosmotic vector.

Abstract We employ double holography to examine a system of two entangled gravitating universes that live on two codimension-one branes in an asymptotically AdS3 spacetime with two disjoint conformal boundaries. There are distinct brane configurations depending on the temperature of the thermofield double (TFD) state between the left and right systems. The topology transition between two branes is naturally identified with the emergence of an Einstein-Rosen bridge connecting the two entangled universes. This doubly holographic construction offers a holographic perspective on gravitational collapse and black hole formation in brane universes. Through this holographic framework, we analyze the quantum information structure of the two gravitating universes. Specifically, we calculate the mutual information between defects present in the boundary theories on the left and right sides. Furthermore, we investigate the decoupling process in the Hayden-Preskill protocol applied to the two copies of the defect field theory and discuss the interpretation of the Yoshida-Kitaev decoding protocol.

Abstract Liquid formulations are ubiquitous yet have lengthy product development cycles owing to the complex physical interactions between ingredients making it difficult to tune formulations to customer-defined property targets. Interpolative ML models can accelerate liquid formulations design but are typically trained on limited sets of ingredients and without any structural information, which limits their out-of-training predictive capacity. To address this challenge, we selected eighteen formulation ingredients covering a diverse chemical space to prepare an open experimental dataset for training ML models for rinse-off formulations development. The resulting design space has an over 50-fold increase in dimensionality compared to our previous work. Here, we present a dataset of 812 formulations, including 294 stable samples, which cover the entire design space, with phase stability, turbidity, and high-fidelity rheology measurements generated on our semi-automated, ML-driven liquid formulations workflow. Our dataset has the unique attribute of sample-specific uncertainty measurements to train predictive surrogate models.

Investigation of the analyte soaking conditions on the crystalline sponge {[(ZnI2)3(tpt)2·x(solvent)]n} method using a statistical design of experiments model has provided fundamental insights into the influence of experimental variables. This approach focuses on a single analyte tested via 60 experiments (20 unique conditions) to identify the main effects for success and overall guest structure quality. This is employed as a basis for the development of a novel molecular structure grading system that enables the quantification of guest exchange quality.

Abstract Introduction A survey was conducted by The Harris Poll on behalf of Arcutis Biotherapeutics in the USA to understand perspectives and burden of patients with psoriasis using prescription topical treatments for their disease. This manuscript presents results from the subset of patients with intertriginous psoriasis. Methods The survey was conducted online October 21–November 24, 2021, among 507 US adults aged 18+ years with psoriasis diagnosed by a healthcare provider and currently using prescription topical treatment. Participants with intertriginous psoriasis were patients with plaque psoriasis reporting symptoms in the armpit, groin, under breast, stomach fold, or between the buttocks. Results Of the 507 respondents, 320 (64%) reported symptoms in intertriginous areas at some point, typically between the buttocks (31%). Most patients with intertriginous psoriasis reported it made them feel embarrassed (80%), anxious (79%), or depressed (69%). In addition, 45% of these patients reported intertriginous psoriasis caused a negative impact on sexual anxiety or distress. Quality of life impact was reported as “very strong negative impact” in 16% of patients with groin involvement vs. 6% in patients with no groin involvement and 15% in women vs. 6% in men. Patients with intertriginous psoriasis reported that itch (61%), scaling (53%), redness (49%), and skin cracking (46%) related to intertriginous psoriasis had the greatest negative impact on quality of life. Most (86%) of these patients said they would be more adherent if a single treatment option could be used to treat all affected areas of their body. Conclusion Psoriasis involvement in intertriginous areas over the course of disease is common and has a negative impact on these patients’ quality of life, particularly emotional well-being and sexual health.

Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug’s safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11–16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3–15.4%), neutropenia was 7.1% (95% CI, 4.6–10.4%), and anemia was 11.3% (95% CI, 8.0–15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians.

Abstract Anxiety disorders are the most prevalent worldwide mental health disorder, resulting in high societal costs. Emotion regulation and sleep quality are associated with the development of psychopathologies including anxiety. However, it is unknown whether habitual emotion regulation strategy use can mediate the influence of sleep quality on anxiety symptomology. An opportunity sample in a healthy population completed the Pittsburgh Sleep Quality Index to provide a measure of sleep quality, the Emotion Regulation Questionnaire to assess habitual use of emotion regulation strategies, and the Generalized Anxiety Disorder Scale to record anxiety symptomology. Data were analysed using correlation and regression-based mediation analyses. Improved sleep quality was predictive of reduced habitual use of expressive suppression and reduced anxiety symptomology. Additionally, increased use of expressive suppression was predictive of greater anxiety symptomology. Cognitive reappraisal was not associated with sleep quality or anxiety severity. Further, novel findings using mediation analyses show that expressive suppression partially mediated the relationship between sleep quality and anxiety. Whilst longitudinal and experimental research are needed to establish causality, these findings suggest that simultaneously targeting improvements in sleep quality and the use of specific emotion regulation strategies, including expressive suppression, may improve the efficacy of interventions focussed on reducing anxiety-related symptomology.

Abstract Advanced manufacturing of 3D‐structured materials enables the production of biomimetic muscle tissues. While models of muscle tissue exist, current approaches possess a limited ability to capture essential elements of the muscle tissue microarchitecture. Therefore, this paper aims to engineer the intrinsically complex muscle spindle‐like ellipsoid geometry using a polymer melt‐based electrohydrodynamic (EHD) printing system. EHD systems have conventionally reported fiber deposition in a layerwise fashion. However, without mitigation, the observed fiber sagging and residual charge phenomena for the melt electrowriting (MEW) process limit the ability to produce layered fibrous 3D constructs with in‐plane fiber alignment. However, in this work, fiber sagging and residual charge phenomena are leveraged as part of the design intent to deposit nonoverlapping suspended fibers between two stationary walls toward spindle‐like construct fabrication. Specifically, herein the structural and mechanical properties of the MEW‐enabled spindle‐like constructs are analyzed as a function of the process and design parameters that govern control over fiber sagging and residual charge. The results indicate that the collector speed and wall‐to‐wall distance are the key parameters for tuning the spindle morphology. Moreover, cycle number and fiber diameter are identified as effective parameters for tuning the spindle mechanical properties.

Arctic ecosystems are especially vulnerable to the impacts of climate change because of the limit to possible northward shifts for species dependent on land or continental shelf and because the rate of warming of the region has been 2-4 x the global average in recent decades. The decline in sea ice in the Arctic has both direct and indirect impacts on the species that live in association with ice, breeding on it, traveling over it, feeding on other ice-dependent species or avoiding competition with subarctic species that cannot exploit resources in ice-covered areas. Herein, we present a metamodel of a top-level predator, the polar bear (Ursus maritimus), and two of its key prey species, ringed seals (Pusa hispida) and bearded seals (Erignathus barbatus), which are important in maintaining current polar bear densities and in turn are strongly influenced by bear predation. We used a metamodel that links Population Viability Analyses of the three species in order to examine how the impacts of declining spring land-fast sea ice on the fjords of Svalbard (Norway) and Frans Josef Land (Russia) can cascade through this predator-prey system. As the ice conditions that allow ringed seals to raise pups in snow-covered lairs on the frozen fjords diminish, or even disappear, ringed seal populations using the land-fast sea ice will collapse due to lack of successful recruitment. Consequently, the polar bear population, which relies heavily on hunting ringed seals in the land-fast sea ice to be able to raise their own offspring is also likely to decline. Our models suggest time-lags of decades, with the polar bear population not entering into decline until the lack of recruitment of ringed seals results in the depletion of breeding age ringed seals – starting in the third decade from the start point of the model and dropping below the initial population size only some decades later. Although lags between climate change and impacts on the ice-associated fauna are expected, the sea ice conditions have already changed dramatically in the northern Barents Sea region, including the Svalbard Archipelago, and the collapse of this Arctic species assemblage might already be underway.

Summary: Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype–phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp. Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with ‘monogenic’ epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Ischiofemoral impingement (IFI) is a significant but often underdiagnosed source of deep posterior hip pain and functional impairment, frequently associated with narrowing of the ischiofemoral space (IFS) between the ischial tuberosity and the lesser trochanter of the femur. Traditionally, diagnostic approaches for IFI have relied on clinical examination and magnetic resonance imaging (MRI). However, the advent of diagnostic musculoskeletal ultrasound (MSKUS) has transformed the evaluation process. MSKUS offers a non-invasive, cost-effective, and dynamic method for assessing the IFS and associated musculature in real time, allowing for high-resolution visualization of soft tissues, bones, and neurovascular structures. For rehabilitation providers, understanding the application, strengths, and limitations of MSKUS can enhance diagnostic accuracy, guide targeted therapeutic interventions, and potentially expedite recovery. This article reviews the anatomy of the IFS, the pathophysiology of IFI, and the use of MSKUS in diagnosing IFI, equipping rehabilitation professionals with the knowledge to integrate this valuable diagnostic tool into clinical practice.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

ABSTRACT The animal gut microbiome can have a strong influence on the health, fitness, and behavior of its hosts. The composition of the gut microbial community can be influenced by factors such as diet, environment, and evolutionary history (phylosymbiosis). However, the relative influence of these factors is unknown in most bird species. Furthermore, phylosymbiosis studies have largely focused on clades that diverged tens of millions of years ago, and little is known about the degree of gut microbiome divergence in more recent species radiations. This study explores the drivers of microbiome variation across the unique and recent Hawaiian honeycreeper radiation (Fringillidae: Drepanidinae). Fecal samples were collected from 14 extant species spanning the main islands of the Hawaiian archipelago and were sequenced using three metabarcoding markers to characterize the gut microbiome, invertebrate diet, and plant diet of Hawaiian honeycreepers. We then used these metabarcoding data and the honeycreeper host phylogeny to evaluate their relative roles in shaping the gut microbiome. Microbiome variation across birds was highly individualized; however, source island had a small but significant effect on microbiome structure. The microbiomes did not recapitulate the host phylogenetic tree, indicating that evolutionary history does not strongly influence microbiome structure in the honeycreeper clade. These results expand our understanding of the roles of diet, geography, and phylogeny on avian microbiome structure, while also providing important ecological information about the diet and gut microbiota of wild Hawaiian honeycreepers.

ABSTRACT Early mortality syndrome (EMS) or acute hepatopancreatic necrosis syndrome (AHPND) is an epizootic bacterial infection of shrimp that has had significant negative impact on the global shrimp aquaculture industry. This disease is largely attributed to pathogenic Vibrio parahaemolyticus EMS strains (VP‐EMS). Application of probiotics was examined for control of pathogenic VP‐EMS infections in Pacific white shrimp (Litopenaeus vannamei) under laboratory‐scale conditions. Two probiotic products, a single strain (O14VRQ) of Bacillus subtilis and a blend (Plus10) of five strains of Bacillus from four different species (Bacillus amyloliquifaciens, Bacillus megaterium, Bacillus brevis, and two distinct strains of Bacillus subtilis), were evaluated at various concentrations as feed additives (applied as a top coat on commercial feed) or dosed directly into the culture water. Two trials were conducted in which shrimp were fed either a control feed (no probiotics) or probiotic‐coated feed for 7 days prior to be being challenged with VP‐EMS. Shrimp were observed for clinical signs of disease and mortalities during the disease challenge study. These experiments demonstrated that while both Bacillus probiotic products were shown to significantly (p < 0.05) improve shrimp survival, the O14VRQ strain provided the most consistent protection across the trials in top‐coated feed. Overall, better efficacy was observed with probiotic‐coated feeds. Findings were directly and positively correlated with concentration for top‐coated and even more so for direct in‐tank applications. Collectively, these findings contribute to our understanding about how probiotic strains could be applied to enhance shrimp health in aquaculture.

The focus of this selection of papers is the linkage of habitat and population dynamics for the purpose of conservation. We thus provide a general framework for making conservation decisions, emphasizing how knowledge of habitat–population linkages fits into this framework. We begin by describing structured decision-making (SDM) as a general approach to making conservation decisions. SDM requires the development of the following elements: objectives, actions, model(s), monitoring, and decision algorithm. We then describe adaptive resource management (ARM), a specific type of SDM developed for recurrent decisions characterized by potentially resolvable uncertainty. Many different classes of actions can be used to influence animal population dynamics, and modification of habitat is one class of action that is frequently used. Habitat management requires models for predicting responses of the managed system to management actions, and these models are based on our knowledge of habitat–population linkages. Frequently, these models are decomposed into two submodels: one used to predict habitat changes expected to result from management actions and another used to predict population responses to habitat changes. This latter modeling focuses generally on the influence of habitat change on vital rates governing the dynamics of population state variables (variables such as population size or density that describe the status or health of a population). Specific recommendations depend on 1) the vital rates and state variable(s) being considered, 2) the relative spatial scales of animal movement and habitat measurement, and 3) the relative temporal scales of habitat change and vital rate estimation. Finally, we present an example of an ARM program for habitat management, highlighting the role of habitat-linked population modeling in this effort.

Airport de-icing has been linked with the growth of undesirable river biofilms (URBs, formerly “sewage fungus”), a manifestation of organic pollution causing long-term ecological damage to watercourses. URBs are a polymicrobial community, with one key taxon standing out in literature: Sphaerotilus natans, a filamentous bacterium also found in sewage treatment and activated sludges. An industry often implicated in causing URBs is airport de-icing, with large biofilms often developing downstream of airport discharges in winter months. However, it is not yet clear which de-icers may cause URBs and how they influence growth. Therefore, specific objectives were to (i) determine which freeze-point depressants (FPDs) can be utilized by S. natans; (ii) examine differences in the growth kinetics between FPDs; and (iii) compare pure-FPDs to commercial airport de-icers (CADs) as carbon sources, to determine impacts of additives. This study employed a turbidimetric micro-batch culture design to conduct microbial growth experiments, using S. natans and a minimal medium supplemented with airport de-icer as the carbon source. Equimolar carbon concentrations were used to compare the effects of common FPDs and CADs – each containing a specific FPD. Growth was assessed via optical density (OD600) measurements, from which time-to-detection, maximum rate of change, and maximum optical density were derived and kinetics inferred. S. natans was found to grow effectively on all FPDs tested, although the microbial yield was heavily dependent on the carbon concentration for all FPDs and CADs. Sodium acetate generated the quickest growth, with the lowest TTD (lag-time) for all but the lowest concentrations tested. Propylene glycol produced the greatest maxOD (total growth), whereas ethylene glycol had a higher limiting concentration for maxROC (growth rate). The mixture of compounds and additives in commercial products did not significantly impact the growth of S. natans. This research provides evidence from controlled laboratory experiments that airport de-icers support the growth of S. natans. The differences in growth kinetics observed for the FPDs and CADs could inform improved mitigation or treatment to reduce the incidence and ecological impacts of URBs.

Objectives To describe the development, validation and reliability of the Oxford Vaccine Hesitancy Scale (OVHS), a new instrument to assess vaccine hesitancy in the general population.Design Cross-sectional validation study.Setting Internet-based study with participants in the UK and USA.Participants Demographically representative (stratified by age, sex and race) samples from the UK and USA recruited through the Prolific Academic platform.Main outcome measures To demonstrate OVHS development, exploratory factor analysis with categorical variables and a polychoric correlation matrix followed by promax oblique rotation on the UK sample was performed. Confirmatory factor analysis with a Satorra-Bentler scaled test statistic evaluating goodness of fit statistics including the root mean squared error of approximation (RMSEA), standardised root mean squared residual (SRMR) and comparative fit index (CFI) was performed on the US sample. Reliability as internal consistency was assessed using McDonald’s omega. Evidence in support of the predictive, convergent and discriminant validity of the scale was assessed using logistic regression ORs of association (OR) or Pearson correlation coefficients.Results Data for factor analysis were obtained from 1004 respondents, 504 in the UK and 500 in the USA. A scree plot, minimum average partial correlation analysis and parallel analysis suggested a three-factor 13-item scale with domains of vaccine beliefs (seven items), pain (three items) and personal deliberation (three items). Responses were recorded on a Likert scale ranging from disagree completely to agree completely, with higher score reflecting greater hesitancy. Potential total scores ranged from 13 to 65. Goodness of fit was excellent, with RMSEA=0.044, SRMR=0.041 and CFI=0.977. Predictive validity for COVID-19 vaccination status was excellent, with logistic regression ORs of association (95% CI) of 0.07 (0.04, 0.13), p

Abstract BackgroundGrowing evidence suggests that severe acute COVID-19 illness increases the risk of long COVID (also known as post–COVID-19 condition ObjectiveThis study aimed to examine associations between acute COVID-19 symptom profiles and long COVID prevalence using a population-based sample. MethodsWe used a dual mode (phone and web-based) population-based probability survey of adults with polymerase chain reaction–confirmed SARS-CoV-2 between June 2020 and May 2022 in the Michigan Disease Surveillance System to examine (1) how acute COVID-19 symptoms cluster together using latent class analysis, (2) sociodemographic and clinical predictors of symptom clusters using multinomial logistic regression accounting for classification uncertainties, and (3) associations between symptom clusters and long COVID prevalence using modified Poisson regression. ResultsIn our sample (n=4169), 15.9% (n=693) had long COVID, defined as new or worsening symptoms at least 90 days post SARS-CoV-2 infection. We identified 6 acute COVID-19 symptom clusters resulting from the latent class analysis, with flu-like symptoms (24.7%) and fever (23.6%) being the most prevalent in our sample, followed by nasal congestion (16.4%), multi-symptomatic (14.5%), predominance of fatigue (10.8%), and predominance of shortness of breath (10%) clusters. Long COVID prevalence was highest in the multi-symptomatic (39.7%) and predominance of shortness of breath (22.4%) clusters, followed by the flu-like symptom (15.8%), predominance of fatigue (14.5%), fever (6.4%), and nasal congestion (5.6%) clusters. After adjustment, females (vs males) had greater odds of membership in the multi-symptomatic, flu-like symptom, and predominance of fatigue clusters, while adults who were Hispanic or another race or ethnicity (vs non-Hispanic White) had greater odds of membership in the multi-symptomatic cluster. Compared with the nasal congestion cluster, the multi-symptomatic cluster had the highest prevalence of long COVID (adjusted prevalence ratio [aPR] 6.1, 95% CI 4.3‐8.7), followed by the predominance of shortness of breath (aPR 3.7, 95% CI 2.5‐5.5), flu-like symptom (aPR 2.8, 95% CI 1.9‐4.0), and predominance of fatigue (aPR 2.2, 95% CI 1.5‐3.3) clusters. ConclusionsResearchers and clinicians should consider acute COVID-19 symptom profiles when evaluating subsequent risk of long COVID, including potential mechanistic pathways in a research context, and proactively screen high-risk patients during the provision of clinical care.

Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.

Abstract Electrohydrodynamic processes have emerged as promising methods for fabricating polymetric fiber‐based artificial tubular tissues. Existing review articles focus on the biological applications and processing materials associated with electrohydrodynamic processes in artificial tubular constructs, while overlooking the design and fabrication of these constructs. To address this gap, this review article emphasizes the design and fabrication of tubular tissue constructs enabled by employing electrohydrodynamic processes. This article begins by presenting an overview of two electrohydrodynamic processes: solution electrospinning (SE) and melt electrowriting (MEW). It then delves into the control of the fiber diameter enabled by SE and MEW, offering insights into the manipulation of processing parameters to achieve desired fiber diameters. Additionally, the review highlights cutting‐edge strategies for electrohydrodynamic processes to create tubular structures with customized microarchitectures. This includes fiber alignment control for SE and pore morphology design for MEW. Moreover, the review covers the creation of customized macroscale tubular geometries through collector geometry design. Lastly, a comprehensive survey is presented for designing multiphasic tubular structures specifically for electrohydrodynamic techniques or in tandem with other techniques. The objective of this review is to offer a thorough understanding of the design considerations and potential applications of tubular structures fabricated by electrohydrodynamic processes.

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells.

IntroductionMillions of women worldwide annually undergo manual vacuum aspiration (MVA) with no pain medication, which is a violation of their basic human dignity. We designed a novel device (Chloe SED®) to administer paracervical block (PCB) during MVA in countries where pain medication is not typically given due to the high cost of the necessary tools.MethodsWe conducted a single-blinded, randomized controlled non-inferiority trial including 61 patients at two hospitals in Kisumu, Kenya, to validate Chloe SED® for administration of PCB during MVA. PCB administered with Chloe SED® was compared to PCB administered with a standard spinal needle. Patients requiring MVA were block randomized in blocks of six, each provider completing six PCBs—three with the Chloe SED® and three with the standard spinal needle. The trial was registered with the Kenya Pharmacy and Poisons Board, ECCT/19/03/01 (https://ctr.pharmacyboardkenya.org/applications/index/protocol_no:RUNDVC8xOS8wMy8wMQ__/filter:/investigator:/sites:/pages:5/start_date:/end_date:/disease_condition:/users:/ercs:/stages). An intention-to-treat analysis was completed. The primary outcome was the non-inferiority of the pain score during uterine evacuation with a non-inferiority margin of 2 points on an 11-point numerical rating scale. Secondary outcomes included the non-inferiority of the pain score at four other time points and patient satisfaction.ResultsChloe SED® showed non-inferiority of the primary outcome with a mean pain score during evacuation of 3.8 [90% confidence interval (CI): 3.1–4.6] compared with the spinal needle at 4.1 (90% CI: 3.5–4.7). Non-inferiority of the pain score was shown at all time points. Most patients expressed a desire for the continued use of the device to administer PCB for MVA. No adverse events were noted.ConclusionIn summary, the Chloe SED® appears non-inferior to the spinal needle and desirable for the administration of PCB during MVA.

BackgroundWearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor. ObjectiveThe objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs. MethodsQuantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported. ResultsThe median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies. ConclusionsParticipant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user.

Medial collateral ligament (MCL) injuries are prevalent in sports and other physical activities and constitute a significant cause of knee pain and dysfunction. Traditional diagnostic modalities such as magnetic resonance imaging (MRI) are often utilized for their detailed visualization capabilities. However, musculoskeletal ultrasound (MSK-US) has emerged as a pivotal diagnostic tool in the evaluation of MCL injuries due to its non-invasive nature, cost-effectiveness, and dynamic imaging capabilities. This article reviews the utility and advantages of MSK-US in diagnosing MCL injuries, with a specific focus on its implications for rehabilitation providers. We discuss the technical aspects of ultrasound (US) imaging, including the sonographic appearance of MCL injuries across various grades, and compare its diagnostic accuracy with other imaging modalities such as MRI. Additionally, the role of US in monitoring the healing process and guiding rehabilitation strategies is explored. This review emphasizes the practical application of MSK-US in clinical settings, offering rehabilitation providers a comprehensive understanding of how US can be integrated into patient management protocols to enhance outcomes in patients with MCL injuries.

Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2E79Q expression, one of the most common activating mutations in human SCCs, on tumor promotion and progression in the mouse skin multistage carcinogenesis model using a DMBA-initiation/TPA-promotion protocol where the Hras A->T mutation (Q61L) is the canonical driver mutation. Nrf2E79Q expression was temporally and conditionally activated in the epidermis at two stages of tumor development: 1) after DMBA initiation in the epidermis but before cutaneous tumor development and 2) in pre-existing DMBA-initiated/TPA-promoted squamous papillomas. Expression of Nrf2E79Q in the epidermis after DMBA initiation but before tumor occurrence inhibited the development/promotion of 70% of squamous papillomas. However, the remaining papillomas often displayed non-canonical Hras and Kras mutations and enhanced progression to SCCs compared to control mice expressing wildtype Nrf2. Nrf2E79Q expression in pre-existing tumors caused rapid regression of 60% of papillomas. The remaining papillomas displayed the expected canonical Hras A->T mutation (Q61L) and enhanced progression to SCCs. These results demonstrate that mutant Nrf2E79Q enhances the promotion and progression of a subset of skin tumors and alters the frequency and diversity of oncogenic Ras mutations when expressed early after initiation.

Abstract Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

Abstract Neonates and young infants are known to have limited responses to pediatric vaccines due to reduced germinal center formation. Extended vaccine antigen dosing was previously shown to expand germinal center formation and improve humoral responses in adult mice. We report that sustained antigen delivery through sequential dosing overcomes neonatal limitations to form germinal center reactions and improves humoral immunity. Thus, vaccine strategies that extend the release of vaccine antigens may reduce the number of doses, and time needed, to achieve protective immunity in neonates and young infants.

Abstract Background Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. Methods Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. Results In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p

Abstract Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.

Abstract Background Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD. Results We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10−5, for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD. Conclusion In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. Video Abstract

Abstract Background Aspergillus flavus is an important agricultural and food safety threat due to its production of carcinogenic aflatoxins. It has high level of genetic diversity that is adapted to various environments. Recently, we reported two reference genomes of A. flavus isolates, AF13 (MAT1-2 and highly aflatoxigenic isolate) and NRRL3357 (MAT1-1 and moderate aflatoxin producer). Where, an insertion of 310 kb in AF13 included an aflatoxin producing gene bZIP transcription factor, named atfC. Observations of significant genomic variants between these isolates of contrasting phenotypes prompted an investigation into variation among other agricultural isolates of A. flavus with the goal of discovering novel genes potentially associated with aflatoxin production regulation. Present study was designed with three main objectives: (1) collection of large number of A. flavus isolates from diverse sources including maize plants and field soils; (2) whole genome sequencing of collected isolates and development of a pangenome; and (3) pangenome-wide association study (Pan-GWAS) to identify novel secondary metabolite cluster genes. Results Pangenome analysis of 346 A. flavus isolates identified a total of 17,855 unique orthologous gene clusters, with mere 41% (7,315) core genes and 59% (10,540) accessory genes indicating accumulation of high genomic diversity during domestication. 5,994 orthologous gene clusters in accessory genome not annotated in either the A. flavus AF13 or NRRL3357 reference genomes. Pan-genome wide association analysis of the genomic variations identified 391 significant associated pan-genes associated with aflatoxin production. Interestingly, most of the significantly associated pan-genes (94%; 369 associations) belonged to accessory genome indicating that genome expansion has resulted in the incorporation of new genes associated with aflatoxin and other secondary metabolites. Conclusion In summary, this study provides complete pangenome framework for the species of Aspergillus flavus along with associated genes for pathogen survival and aflatoxin production. The large accessory genome indicated large genome diversity in the species A. flavus, however AflaPan is a closed pangenome represents optimum diversity of species A. flavus. Most importantly, the newly identified aflatoxin producing gene clusters will be a new source for seeking aflatoxin mitigation strategies and needs new attention in research.

Background: Cardiovascular disease is a leading cause of illness and death globally, primarily due to atherosclerosis. This disease reduces blood flow and oxygen delivery to organs, and when it affects the carotid arteries, it can lead to cognitive impairment and dementia. In a population of 104 individuals, comprising both healthy controls and individuals at elevated risk for developing cardiovascular diseases (CVD) due to identified risk factors, we used PET imaging with 18F-fluorodeoxyglucose (FDG) to assess cerebral glucose metabolism and 18F-sodium fluoride (NaF) to detect atherosclerotic calcification. Our statistical analysis revealed significant differences in metabolic activity between healthy and at-risk individuals in specific brain regions. 18F-FDG uptake in the brain varied inversely with respect to the clinical assessment of cardiovascular risk in regions such as the cuneus (β = −0.030, SE = 0.014, p = 0.035), middle occipital gyrus (β = −0.032, SE = 0.011, p = 0.005), and posterior cingulate gyrus (β = −0.032, SE = 0.015, p = 0.044). In contrast, areas including the basis pontis (β = 0.025, SE = 0.012, p = 0.038) and the pons (β = 0.034, SE = 0.013, p = 0.008) exhibited direct correlations. Notably, carotid 18F-NaF uptake had inverse associations with 18F-FDG uptake in the cerebellum (β = −0.825, SE = 0.354, p = 0.021), medulla (β = −0.888, SE = 0.405, p = 0.029), and posterior cingulate gyrus (β = −1.253, SE = 0.567, p = 0.028), while increased carotid calcification influenced metabolic activity in the fusiform gyrus (β = 1.660, SE = 0.498, p = 0.001) and globus pallidus (β = 1.505, SE = 0.571, p = 0.009). We observed that atherosclerotic plaque accumulation, especially in the carotid arteries, has potential implications for metabolic changes in brain regions governing cognition, emotion, sensory perception, and motor activities. Our findings underscore the possible early interventions that can be used to preempt or delay cognitive deterioration linked with cardiovascular ailments.