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Abstract Immune receptors have emerged as critical therapeutic targets for cancer immunotherapy. Designed protein binders can have high affinity, modularity, and stability and hence could be attractive components of protein therapeutics directed against these receptors, but traditional Rosetta based protein binder methods using small globular scaffolds have difficulty achieving high affinity on convex targets. Here we describe the development of helical concave scaffolds tailored to the convex target sites typically involved in immune receptor interactions. We employed these scaffolds to design proteins that bind to TGFβRII, CTLA-4, and PD-L1, achieving low nanomolar to picomolar affinities and potent biological activity following experimental optimization. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with their respective receptors closely match the design models. These designs should have considerable utility for downstream therapeutic applications.

Abstract Background This study aimed to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, caudate nucleus, and putamen volumes previously described in children at age 2–3 years persisted to age 6–7 years in the Drakenstein Child Health Study (DCHS). Methods This neuroimaging sub-study was nested within the DCHS, a South African population-based birth cohort. Pregnant women were enrolled (2012–2015) and mother–child dyads were followed prospectively. A sub-group of children had magnetic resonance imaging at 6–7 years of age (2018–2022). Mothers had haemoglobin measurements during pregnancy and a proportion of children were tested postnatally. Maternal anaemia (haemoglobin

Abstract Background Medications for opioid use disorder (MOUD) are among the best tools available to combat the opioid epidemic. Yet, use of MOUD among people with opioid use disorder (OUD) remains low. Interventions to increase MOUD access in the United States have largely focused on improving organizational capacity and addressing funding barriers, yet stigma toward MOUD may inhibit uptake even where MOUD is readily available. Non-prescribing substance use disorder (SUD) treatment professionals (e.g. counselors) likely have considerable influence on a client’s choice to initiate and adhere to MOUD, but beliefs that counselors convey about MOUD in interaction with clients are understudied. The current study explores what advantages and disadvantages that counselors communicate about buprenorphine, methadone, and naltrexone. Methods From June to December 2021, we surveyed counselors from publicly-funded SUD treatment agencies under a municipality-wide mandate to offer MOUD to all clients with OUD. Counselors were asked to describe, in a free-response format, the most important advantages and disadvantages to communicate to their clients about taking buprenorphine, methadone, and naltrexone. Counselor responses were coded for one or more advantage and disadvantage. Results A total of 271 SUD counselors from 29 agencies in the Philadelphia Metropolitan Area completed the survey, generating 1,995 advantages and disadvantages across three types of MOUD. The most frequently reported advantage across all three types of MOUD was their ability to reduce cravings and illicit drug use. The most frequently reported disadvantage related to the potential for some types of MOUD to develop long-term medication dependence. Conclusions As the availability and variety of MOUD treatment options continue to expand, it is important that SUD counselors are equipped with evidence-based recommendations for OUD care. We identified misalignments with the MOUD-prescribing evidence base and stigmatizing language toward MOUD within counselors’ responses, highlighting the potential to refine training materials for MOUD and mitigate stigmatizing beliefs.

The recent rise in relevance and diffusion of Artificial Intelligence (AI)-based systems and the increasing number and power of applications of AI methods invites a profound reflection on the impact of these innovative systems on scientific research and society at large. The Universal Scientific Education and Research Network (USERN), an organization that promotes initiatives to support interdisciplinary science and education across borders and actively works to improve science policy, collects here the vision of its Advisory Board members, together with a selection of AI experts, to summarize how we see developments in this exciting technology impacting science and society in the foreseeable future. In this review, we first attempt to establish clear definitions of intelligence and consciousness, then provide an overview of AI’s state of the art and its applications. A discussion of the implications, opportunities, and liabilities of the diffusion of AI for research in a few representative fields of science follows this. Finally, we address the potential risks of AI to modern society, suggest strategies for mitigating those risks, and present our conclusions and recommendations.

Abstract Brain white matter disruptions have been implicated in contributing to fatigue, brain fog and other central symptoms commonly reported in inflammatory diseases. In this study, we included 252 RA patients with 756 age and sex matched controls and 240 UC patients with 720 age and sex matched controls using the UK Biobank imaging dataset. We looked for differences in total volume of white matter hyperintensities (WMH) between patients compared to controls. Then, using voxelwise analysis, we explored the spatial distribution of these white matter hyperintensities and differences in these between patients and controls and between disease groups. A significantly higher volume of WMH was observed in both the RA (p = 1.9 × 10−8, β = − 0.36, 95% CI = − 0.48, − 0.23) and UC (p = 0.003, β = − 0.18 95% CI = − 0.31, − 0.06) patients compared to their respective control groups. Voxelwise analysis revealed only a small cluster of RA associated WMH compared to controls. These results indicate an increased risk of white matter hyperintensities in patients with RA and UC. These findings help quantify the effect of inflammation from autoimmune diseases on cerebrovascular health and white matter integrity.

Abstract Aberrant caspase recruitment domain family member 14 (CARD14) signaling has been strongly associated with inflammatory skin conditions. CARD14 acts as a scaffold protein, ultimately activating the transcription factor NF-KB. Although primarily studied in the context of inflammation, recent research has suggested its potential implications in tumorigenesis. In this study, we gathered The Cancer Genome Atlas (TCGA) tumor data to gauge the involvement of CARD14 in cancer, including genetic alterations, expression patterns, survival correlations, immune cell infiltration and functional interactions across diverse cancer types. We found heightened CARD14 expression in most tumors and there was a significant correlation between CARD14 expression and the prognosis of patients for certain tumors. For instance, patients with higher CARD14 expression had a better prognosis in sarcoma, lung, cervix and head and neck cancers. Moreover, CARD14 expression positively correlated with neutrophil infiltration in most of the cancer types analyzed. Finally, enrichment analysis showed that epithelial development and differentiation pathways were involved in the functional mechanism of CARD14. Our results show that CARD14 may have the potential to become a prognostic biomarker in several cancers, hence, further prospective studies will be required for its validation.

Abstract A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma.

Starch is often chemically modified to improve its emulsification properties for food processing applications. Amylose inclusion complexes prepared using single pure fatty acid salts have been shown to be effective emulsifiers but these salts could be prohibitively expensive for industrial production. Therefore, amylose inclusion complex were prepared by steam jet cooking using more economical fatty acid salt mixtures of differing compositions derived from different plant oils. Complexes were obtained in 92–96 % yield and had good surface active properties regardless of the fatty acid salt composition. The complexes exhibited Type I 61V helical crystalline structures. Fourier transform infrared and nuclear magnetic resonance spectroscopy confirmed complex formation. Aqueous suspensions of the complexes had Newtonian behavior with viscosities and surface tensions between 0.0020 to 0.0028 Pa s and 43 and 49 mN m−1, respectively. Complexes emulsified corn oil at a 1:3 ratio of corn oil to complex suspensions, giving emulsion activity and stability indices between 180–213 m2 g−1 and 33–41 min, respectively. These complexes prepared from an array of more economical fatty acid salt mixtures performed comparably to more costly complexes prepared from pure individual fatty acid salts. These starch-based emulsifiers are produced using industrially available equipment making them desirable for food and nonfood applications.

IntroductionIn late June 2021, the Pacific Northwest region of the United States and Canada experienced an unprecedented atmospheric heatwave that co-occurred with one of the lowest day-time tide series of the year. Several consecutive days of air temperatures 10-20°C above normal, coupled with mid-afternoon low tides proved deadly for many rocky intertidal organisms, which live at the margin of land and sea.MethodsTo assess short (weeks) and longer-term (1 year) impacts of the heatwave on rocky intertidal communities, we used long-term monitoring data collected annually at 16 sites throughout Washington State.Results and discussionOur findings indicate that impacts were most severe at sites within the Salish Sea region of WA, where peak low tides occurred during the hottest, mid-afternoon hours. Focal species assemblages at Olympic coast sites, where low tides occurred in the morning, were largely spared. In addition, while the heatwave was associated with substantial short-term changes in acorn barnacle, rockweed, and California mussel assemblages, lasting impacts (1 year) were only observed in the mussel assemblage at the one Salish Sea site where this species is common. These findings will aid in forecasting both short-term and longer lasting impacts of future heatwave events and help direct potential mitigation efforts to regions and species assemblages where impacts will likely be greatest.

Abstract Semiconductor nanoplatelets are atomically flat nanocrystals which emit light with high spectral purity at wavelengths controlled by their thickness. Despite their technological potential, efforts to further sharpen the emission lines of nanoplatelets have generally failed for unknown reasons. Here, we demonstrate theoretically that the linewidth is controlled by surface chemistry—specifically, inhomogeneities in the ligand layer on the nanoplatelet surface lead to a spatially fluctuating potential that localizes excitons. This localization leads to increased scattering and optical broadening. Importantly, localization also reduces the rate of radiative emission. Our model explains the observed linewidth and predicts that a more uniform ligand layer will sharpen the lines and increase the emission rates. These findings demonstrate that light emission from nanoplatelets can be controlled by optimizing their surface chemistry, an important advantage for their eventual use in optical technologies.

Abstract Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization’s Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Abstract Background Physical function is an important indicator of physical health and predicts mortality. This study identified characteristics associated with limitations in Medicare recipients' activities of daily living. Methods 2019 Consumer Assessment of Healthcare Providers and Systems Fee-for-Service Medicare Survey data: 79,725 respondents (34% response rate) who were 65 and older and 53% female; 7% Black, 5% Hispanic, 4% Asian American, Native Hawaiian, or other Pacific Islander, 2% Multiracial, 1% American Indian/Alaskan Native; 35% with high school education or less. Walking, getting in and out of chairs, bathing, dressing, toileting, and eating (scored as having no difficulty versus being able to do with difficulty or unable to do) and a scale of these items were regressed on patient characteristics. Results After adjustment for all characteristics, function limitations were found for those who smoked (effect sizes of significant associations range .04-.13), had chronic health conditions (.02-.33), were 85 years or older (.09-.46), needed assistance completing the survey (.32–1.29), were female (.05-.07), and had low income and assets (.15-.47). Conclusions These nationally representative U.S. estimates of physical function characteristics are useful for interventions for vulnerable population subgroups.

Abstract The coherent continental-wide speleothem water isotope records are accompanied by regionally inconsistent moisture patterns within the Asian summer monsoon (ASM) region, leaving a disputed explanation of monsoonal hydroclimate variability at the orbital timescale. Here, the transient simulation forced by orbital parameters during the past 300,000 years in an isotope-enabled fully coupled model shows that the complex ASM response can be understood as a grand dipole pattern of oxygen isotope and rainfall between South Asia and Japan, with South China lying in a hybrid transition region. While the dipole monsoon rainfall change between South Asia and Japan is related to the large-scale circulation adjustment in response to Northern Hemisphere summer insolation, the dipole oxygen isotope pattern is associated with the changing contribution of moisture sources. Our results provide new clues to reconcile ASM hydroclimate patterns at orbital timescale as revealed by the water isotope records and other hydrological proxies.

Abstract Emotion studies have commonly reported impaired emotional processing in individuals with heightened anhedonic depressive symptoms, as typically measured by collecting single subjective ratings for a given emotional cue. However, the interindividual variation in moment-to-moment emotional reactivity, and associated time-varying brain networks recruitment as emotions are unfolding, remains unclear. In this study, we filled this gap by using the unique temporal characteristics of music to investigate behavioural and brain network dynamics as a function of anhedonic depressive symptoms severity. Thirty-one neurotypical participants aged 18–30 years completed anhedonic depression questionnaires and then continuously rated happy, neutral and sad pieces of music whilst undergoing MRI scanning. Using a unique combination of dynamic approaches to behavioural (i.e., emotion dynamics) and fMRI (i.e., leading eigenvector dynamics analysis; LEiDA) data analysis, we found that participants higher in anhedonic depressive symptoms exhibited increased recruitment of attentional networks and blunted emotional response to both happy and sad musical excerpts. Anhedonic depression mediated the relationship between attentional networks recruitment and emotional blunting, and the elevated recruitment of attentional networks during emotional pieces of music carried over into subsequent neutral music. Future studies are needed to investigate whether these findings could be generalised to a clinical population (i.e., major depressive disorder).

The effective management of at-risk species often requires fine-scale actions by natural resource managers. However, balancing these actions with concurrent land uses is challenging, particularly when compounded by the interplay of climate shifts, and escalating wildland–urban interface conflicts. We used spatial prioritization tools designed for biodiversity conservation to help resource managers on the Island of Lānaʻi prioritize mutually exclusive land use objectives: endangered species recovery and subsistence and recreational hunting. We weighed the current and anticipated future distributions of threatened and endangered plant species against the distribution of non-native game mammals to plan for species recovery more effectively. Prioritization results identified multiple footprints that could support recovery of all endangered species targets in climate resilient areas while retaining the majority of existing hunting areas. However, very little native vegetation was retained in conservation footprints without deliberate inclusion, which increased footprint area by 268%. Scenarios which prioritized contiguous conservation areas also dramatically increased conservation footprint area, although these scenarios may reduce associated fencing costs. This work demonstrates how spatial prioritization may guide localized species recovery efforts by supporting long-term conservation planning that addresses anticipated climate-driven increases in conflict between conservation and other land uses, with clear applicability beyond Lānaʻi.

Abstract Understanding the intricate relationship between molecular architecture and function underpins most challenges at the forefront of chemical innovation. Bond-forming reactions are particularly influenced by the topology of a chemical structure, both on small molecule scale and in larger macromolecular frameworks. Herein, we elucidate the impact that molecular architecture has on the photo-induced cyclisations of a series of monodisperse macromolecules with defined spacers between photodimerisable moieties, and examine the relationship between propensity for intramolecular cyclisation and intermolecular network formation. We demonstrate a goldilocks zone of maximum reactivity between the sterically hindered and entropically limited regimes with a quantum yield of intramolecular cyclisation that is nearly an order of magnitude higher than the lowest value. As a result of the molecular design of trifunctional macromolecules, their quantum yields can be deconvoluted into the formation of two different cyclic isomers, as rationalised with molecular dynamics simulations. Critically, we visualise our solution-based studies with light-based additive manufacturing. We formulate four photoresists for microprinting, revealing that the precise positioning of functional groups is critical for resist performance, with lower intramolecular quantum yields leading to higher-quality printing in most cases.

Abstract Background Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA. Objective To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women. Methods The proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes. Results Pathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation. Conclusion Maternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration.

Abstract Background Does preschool height predict adult stature in undernourished settings? The extent to which preschool length or height forecasts young adult stature is unclear in chronically undernourished populations. Methods In 2006-8, we assessed height in a cohort of 2074 young adults, aged 16–23 years, in rural Nepal who, as preschoolers (≤ 4 year), were measured at baseline and again 16 months later during a vitamin A supplementation trial in 1989-91. We assessed by linear regression the ability of preschool length (L, measured -1) increased from 38–40% mid-infancy to ∼ 69–74% by 6 years of age. By 3–6 years of age heights of stunted children (L/HAZ

Summary: In humans, dietary patterns impact weight and metabolism differentially across individuals. To uncover genetic determinants for differential dietary effects, we subjected four genetically diverse mouse strains to humanized diets (American, Mediterranean, vegetarian, and vegan) with similar macronutrient composition, and performed body weight, metabolic parameter, and RNA-seq analysis. We observed pronounced diet- and strain-dependent effects on weight, and triglyceride and insulin levels. Differences in fat mass, adipose tissue, and skeletal muscle glucose uptake, and gene expression changes in most tissues were strain-dependent. In visceral adipose tissue, ∼400 genes responded to diet in a strain-dependent manner, many of them in metabolite transport and lipid metabolism pathways and several previously identified to modify diet effects in humans. Thus, genetic background profoundly impacts metabolism, though chosen dietary patterns modify the strong genetic effects. This study paves the way for future mechanistic investigations into strain-diet interactions in mice and translation to precision nutrition in humans.

The páramo grassland ecosystem in the high Andes requires definition of spatially explicit and large-scale priorities for bird conservation, especially for lands outside of protected areas. Using surrogate species such as habitat specialists (e.g., páramo specialists), endemic species, or threatened species to identify potential habitat can support conservation decisions. We used MaxEnt to generate habitat suitability models for eighteen surrogate bird species in a high Andean biosphere reserve, the Macizo del Cajas (MCB). The areas of estimated suitable habitat range from 115,500 to 312,700 ha; the proportion predicted inside the national system of protected areas of MCB ranged from 12 to 29 percent. The consolidated map (i.e., the coincidence of predicted pixels for all eighteen surrogate bird species) predicted an area of 94,800 ha, with 70 percent outside the national system of protected areas. The models reveal that there are large suitable areas of MCB potentially occupied by these species outside of protected areas, especially along the eastern flank of the study area. MaxEnt models as a proxy facilitate the recognition of locations of possible habitat suitability for páramo-specialized birds and therefore identify areas of the MCB outside of the protected areas that should be considered for more formal protection.

Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB), is a zoonotic pathogen that contributes to economic losses in the cattle industry and poses a public health risk worldwide. Bacillus Calmette-Guerin, or BCG, is a live attenuated strain of M. bovis that is used for human vaccination against tuberculosis and is considered a potential vaccine candidate against bTB. However, BCG affords widely variable levels of protection against challenge and interferes with current diagnostic methods, and as such, it is not currently approved for use as a livestock or wildlife vaccine in the United States. Many efforts have been made to develop bTB vaccines that are reliable and do not interfere with diagnostic testing, but BCG continues to be the most effective option. Previous work has shown that a T helper 1 immune response is essential for protection against virulent M. bovis infection, characterized by CD4+ central and effector memory T cells. In an effort to identify an efficacious bTB intervention strategy, the study presented here used an in vitro recall response assay and concurrent evaluation of CD4+ T cell proliferation and cytokine production to characterize the surface and functional phenotypes of memory responses to BCG vaccination in cattle. Our findings enhance understanding of the bovine immune response to BCG and provide insights into the development of improved vaccines for the control of bTB.

BackgroundRheumatoid arthritis (RA) and ulcerative colitis (UC) are two autoimmune diseases where patients report high levels of fatigue, pain, and depression. The effect of systemic inflammation from these diseases is likely affecting the brain, however, it is unknown whether there are measurable neuroanatomical changes and whether these are a contributing factor to these central symptoms.MethodsWe included 258 RA patients with 774 age and sex matched controls and 249 UC patients with 747 age and sex matched controls in a case control study utilizing the UK Biobank dataset. We used imaging derived phenotypes (IDPs) to determine whether there were differences in (1) hippocampal volume and (2) additional subcortical brain volumes between patients compared to controls and if there were common regions affected between these two diseases.ResultsPatients with UC had moderately smaller hippocampi compared to age and sex matched controls (difference: 134.15 mm3, SD ± 64.76, p = 0.035). This result was not seen in RA patients. RA patients had a significantly smaller amygdala volume than age and sex matched controls (difference: 91.27 mm3, SD ± 30.85, p = 0.0021, adjusted p = 0.012). This result was not seen in UC patients. All other subcortical structures analyzed were comparable between the patients and control groups.ConclusionThese results indicate there are subcortical brain differences between UC, RA and controls but different regions of the limbic system are preferentially affected by UC and RA. This study may provide evidence for different neurodegenerative mechanisms in distinct autoimmune diseases.

Abstract Anthropogenic disturbance of stream ecosystems, often chronic in nature, has been studied extensively. However, when disturbance is driven by more than one resource policy over many decades, feedback between habitat evolution and biological adaptation can be disrupted and ecological function affected in unforeseen ways. We analyzed over 100 years of Chinook salmon (Oncorhynchus tshawytscha) length frequency trends associated with fisheries management and changes in available spawning substrate (habitat) linked to flow regulation in a highly altered California river. Over time, salmon lengths generally decreased, fluctuating with exploitation (ocean harvest) and hatchery production rates. Female size reduction, coupled with a degrading and coarsening channel, and perching peripheral habitat related to past mining activity, indicates available spawning substrate may be too large to support the current salmon population. Assuming a salmon can move material ~10% of her body length, length frequency data and current substrate size distribution suggest that increasing salmon sizes to historic distributions could increase available spawning habitat by as much as 13%. Alternatively, decreasing spawning substrate size could support a greater portion of the current population. To test the latter hypothesis and inform future management actions, we monitored two spawning riffles where large and small gravel was placed on top of a cobble. We observed an immediate spawning activity increase that was more pronounced where smaller gravel was deposited. Following a decade of habitat decline, the two sites were both replenished with medium gravel. Elevated spawning use occurred immediately at both sites, commensurate with this intermediate size, further supporting our hypotheses. Sediment coarsening and habitat disconnect below dams, combined with reduced salmon size, indicate the natural spawning process may be decoupled from available habitat below dams in the foreseeable future without continuous intervention. Actively managing salmon population demographics through modified hatchery and size‐selective harvest practices and developing a coarse sediment budget with size‐appropriate material for regulated anadromous rivers could produce immediate benefits for ecosystem services, including salmon populations. However, these management actions will require continued maintenance and informed socio‐ecological goals to remain successful.

Abstract Background In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. Methods This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. Discussion BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. Trial registration The trial was registered as ”BCI-FES Therapy for Stroke Rehabilitation” on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

Abstract Background Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. Methods We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. Results The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. Conclusions This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.

The flora and fauna of Panama is species-rich due to its location and topography, and the resulting diversity of microclimates and habitats. The last two summaries (benchmarks) of information about the caddisfly fauna (Insecta, Trichoptera) Panama were published in1992 and 2015. From 1861 to 2015, researchers from outside of Panama recorded 13 families, 45 genera, and 257 species of caddisflies. From 2015 through 2023, a series of publications by the Aquatic Invertebrate Research Group at the Universidad Autónoma de Chiriquí in David, Panamá have recorded an additional 2 families,11 genera, and 278 species. Thus, a total of 535 species of caddisflies, now recorded from the Republic of Panama, are distributed among 15 families and 56 genera. Panama’s Trichoptera fauna shows greatest affinity to other Central American countries, and to Costa Rica in particular. Indeed, 289 Costa Rican species are shared with Panama, including 91 former Costa Rican endemics now known from both countries. The Hydroptilidae is the most species rich family in Panama. Although the number of new species and new country records of macro-Trichoptera has diminished somewhat over this third benchmark period, no similar fall-off has yet been detected in the micro-Trichoptera. The caddisfly fauna of Panama is now better known, but much more work remains to define the fauna and, just as importantly, to map the surficial and altitudinal distribution of each genus and species.

Abstract Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14–3–3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14–3–3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14–3–3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14–3–3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14–3–3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14–3–3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Abstract White-tailed deer (Odocoileus virginianus) have emerged as a reservoir host for SARS-CoV-2 given their susceptibility to infection and demonstrated high rates of seroprevalence and infection across the United States. As SARS-CoV-2 circulates within free-ranging white-tailed deer populations, there is the risk of transmission to other wildlife species and even back to the human population. The goal of this study was to determine the susceptibility, shedding, and immune response of North American elk (Cervus elaphus canadensis) to experimental infection with SARS-CoV-2, to determine if another wide-ranging cervid species could potentially serve as a reservoir host for the virus. Here we demonstrate that while North American elk do not develop clinical signs of disease, they do develop a neutralizing antibody response to infection, suggesting the virus is capable of replicating in this mammalian host. Additionally, we demonstrate SARS-CoV-2 RNA presence in the medial retropharyngeal lymph nodes of infected elk three weeks after experimental infection. Consistent with previous observations in humans, these data may highlight a mechanism of viral persistence for SARS-CoV-2 in elk.

Herein we add eight new country records to Panama’s caddisfly fauna (Insecta, Trichoptera): Hydropsychidae – Leptonema turrialbum Flint, McAlpine & Ross, 1987; Polycentropodidae – Polyplectropus bravoae Bueno-Soria, 1990; Hydroptilidae – Mayatrichia ayama Mosely, 1937 and Bredinia selva Harris, Holzenthal & Flint, 2002; Glossosomatidae – Mortoniella stilula Blahnik & Holzenthal, 2008; Anomalopsychidae – Contulma talamanca Holzenthal & Flint, 1995; Helicopsychidae – Helicospyche planata Ross, 1956; and Odontoceridae – Marilia crea Mosely, 1949. The Republic of Panama now has 533 species of caddisflies distributed among 15 families and 56 genera.

Abstract Psychological flexibility plays a crucial role in how young adults adapt to their evolving cognitive and emotional landscapes. Our study investigated a core aspect of psychological flexibility in young adults: adaptive variability and maladaptive rigidity in the capacity for behavior change. We examined the interplay of these elements with cognitive-affective processes within a dynamic network, uncovering their manifestation in everyday life. Through an Ecological Momentary Assessment design, we collected intensive longitudinal data over 3 weeks from 114 young adults ages 19 to 32. Using a dynamic network approach, we assessed the temporal dynamics and individual variability in flexibility in relation to cognitive-affective processes in this sample. Rigidity exhibited the strongest directed association with other variables in the temporal network as well as highest strength centrality, demonstrating particularly strong associations to other variables in the contemporaneous network. In conclusion, the results of this study suggest that rigidity in young adults is associated with negative affect and cognitions at the same time point and the immediate future.

Abstract Heme has a critical role in the chemical framework of the cell as an essential protein cofactor and signaling molecule that controls diverse processes and molecular interactions. Using a phylogenomics-based approach and complementary structural techniques, we identify a family of dimeric hemoproteins comprising a domain of unknown function DUF2470. The heme iron is axially coordinated by two zinc-bound histidine residues, forming a distinct two-fold symmetric zinc-histidine-iron-histidine-zinc site. Together with structure-guided in vitro and in vivo experiments, we further demonstrate the existence of a functional link between heme binding by Dri1 (Domain related to iron 1, formerly ssr1698) and post-translational regulation of succinate dehydrogenase in the cyanobacterium Synechocystis, suggesting an iron-dependent regulatory link between photosynthesis and respiration. Given the ubiquity of proteins containing homologous domains and connections to heme metabolism across eukaryotes and prokaryotes, we propose that DRI (Domain Related to Iron; formerly DUF2470) functions at the molecular level as a heme-dependent regulatory domain.

Abstract Background Treponeme-Associated Hoof Disease (TAHD) is a polybacterial, multifactorial disease affecting free-ranging wild elk (Cervus canadensis) in the Pacific Northwest. Previous studies have indicated a bacterial etiology similar to digital dermatitis in livestock, including isolation of Treponema species from lesions. The lesions appear to progress rapidly from ulcerative areas in the interdigital space or along the coronary band to severe, ulcerative, necrotic, proliferative lesions under-running the hoof wall, perforating the sole, and contributing to hoof elongation, deformity, and overgrowth. Eventually the lesions undermine the laminal structure leading to sloughing of the hoof horn capsule. The objective of this study was to characterize the bacterial communities associated with hoof lesions, which were categorized into 5 stages or disease grade severities, with 0 being unaffected tissue and 4 being sloughed hoof capsule. We also wanted to determine if the etiology of TAHD through morphological changes was dominated by Treponema, as observed in hoof diseases in livestock. Results The bacterial 16S rRNA gene was sequenced from 66 hoof skin biopsy samples representing 5 lesion grades from samples collected by Washington Department of Fish and Wildlife as part of a voluntary hunter program. Analysis of the relative abundance of bacterial sequences showed that lesions were dominated by members of the bacterial phyla Proteobacteria, Firmicutes, Spirochaetes, Bacteroidetes and Actinobacteria. In lesion samples, members of the genus Treponema, Porphyromonas, and Mycoplasma increased with lesion severity. Association analysis indicated frequent identification of Treponema with Porphyromonas, Bacteroides and other anaerobic Gram-positive cocci. Conclusions The bacterial 16S rRNA gene sequencing confirmed the presence of Treponema species at all stages of TAHD lesions, treponeme specie-specific PCR and histopathology, indicating that the morphological changes are a continual progression of disease severity with similar bacterial communities. Association and abundance of these other pathogenic genera within lesions may mean synergistic role with Treponema in hoof disease pathogenesis. Characterizing bacteria involved in lesion development, and their persistence during disease progression, provides evidence for science-based management decisions in TAHD infected elk populations.

Abstract Background Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg). Methods The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. Discussion The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. Trial registration ClinicalTrials.gov Identifier NCT04797286.

Studies have shown that the production of reactive oxygen species (ROS) is triggered by bactericidal antibiotics, which contributes significantly to the killing of bacterial cells and increasing mutations in surviving cells. In this study, we hypothesized that exposure of Salmonella to sublethal concentrations of hypochlorite (NaOCl), a commonly used sanitizer in household and food industries increases mutation rates, leading to the development of antibiotic resistance. We found that a sublethal concentration (20 ppm) of NaOCl increased the mutation rates of S. typhimurium 14028s significantly (p < 0.05), which was prevented by the ROS scavenger thiourea, supporting that the increased mutation was due to NaOCl-triggered ROS production. We further found that the exposure of S. typhimurium 14028s to the same sublethal concentration of NaOCl increases resistance to kanamycin among the 3 antibiotics evaluated. The results of this study suggest that when NaOCl applied as a sanitizer fails to kill Salmonella due to diluted local concentrations or presence of organic materials, it can cause an adverse outcome of developing antibiotic resistance of the pathogen.

This study investigates the volatile compounds that contribute to the unique flavor and aroma profiles of cured meat products using alternative ingredients, specifically focusing on commercially available, conventional, and organically produced pre-converted celery (Apium graveolens) and Swiss chard (Beta vulgaris subsp. maritima) juices and powders. Volatile compounds were isolated and analyzed using an optimized method involving steam distillation with liquid–liquid phase extraction coupled with gas chromatography–tandem mass spectrometry (GC-MS/MS). The key volatile compound identified in celery was 3-butylisobenzofuran-1(3H)-one, and in Swiss chard, 2-methoxy-4-vinylphenol. In both conventional and organic celery juice, senkyunolide, sedanolide, and limonene were the primary volatiles, listed in descending order of concentration. This pioneering work on volatile and aromatic compounds in alternative curing ingredients provides foundational knowledge for sensory and volatile compound studies in alternative meat curing. It also offers valuable insights for organic plant and meat producers, processors, and consumers. Practically, this research highlights volatile chemicals that could interact with other meat constituents or residues in finished products, informing and enlightening future studies on the sensory and aromatic properties of alternative cured meats. Overall, this study contributes to the development of alternative cured meats, supporting the research and innovation of organic meats.

The accurate quantification of Campylobacter jejuni in poultry samples is critical for ensuring food safety and compliance with regulatory standards. This study evaluated the performance of three enrichment media—Mueller–Hinton Broth (MHB), Bolton’s Blood-Free Broth 2x (BFBB2x), and Buffered Peptone Water (BPW)—in supporting C. jejuni detection and quantification using the BAX® Q7-RT PCR system and traditional plate count methods. Results demonstrated high reliability across all media types, with BFBB2x and MHB showing the strongest correlations (R2 = 0.99) for the BAX® system. BFBB2x exhibited the lowest RMSE (0.13), while MHB balanced precision (RMSE = 0.4) with sensitivity. For plate counts, MHB and BPW achieved the highest correlations (R2 = 0.99) and precision (RMSE = 0.26), with MHB demonstrating the lowest detection limit (2.56 log10 CFU/mL) compared to BFBB2x (2.93 log10 CFU/mL) and BPW (3.31 log10 CFU/mL). The findings underscore MHB’s robustness as an enrichment medium, offering consistent performance across both molecular and culture-based methods. The current study supports MHB as the more effective medium for the reliable and precise quantification of C. jejuni in poultry-associated matrices, highlighting its utility in minimizing contamination risks and enhancing food safety. Future research should explore its applicability in diverse poultry products and production environments.

IntroductionSpecial Operations Forces (SOF) often conduct operations in physiologically stressful environments such as severe heat, cold, or hypoxia, which can induce decreases in a variety of cognitive abilities. Given the promising empirical demonstration of the efficacy of exogenous ketone monoester (KME) supplementation in attenuating cognitive performance decrease during hypoxia at rest in a laboratory setting, we conducted a real-world, field experiment examining KME’s efficacy during high-altitude mountaineering, an austere environment in which US SOF have conducted increasing numbers of operations over the past two decades.MethodsSpecifically, 34 students and cadre at the US Army 10th Special Forces Group Special Operations Advanced Mountaineering School (SOAMS) participated in a randomized, double-blind, placebo (PLA)–controlled crossover trial (KME vs. PLA) over 2 days of tactical mountain operations training. The participants ascended from 7,500 ft in altitude (basecamp) to 12,460 ft on 1 day and 13,627 ft the other day (in randomized order), while performing various training activities inducing high physical and cognitive loads over 8–12 h, and consumed six doses of KME or PLA 2–3 h apart throughout each training day.Results and DiscussionWhile KME increased blood ketone levels and decreased glucose levels, there were no clear indications that the elevated ketone level enhanced physical or cognitive performance. KME also produced a greater incidence of heartburn, nausea, and vomiting. In these elite operators, high-altitude mountaineering had a limited impact on cognitive performance, and KME supplementation did not demonstrate any benefit.

This review compared the efficacy of personalized psychological interventions to standardized interventions for adolescents. We conducted a scoping review and meta-analysis of randomized controlled trials that compared personalized interventions with standardized interventions in adolescents. Data was analyzed using Bayesian multilevel random effects meta-analysis. Eligible studies were identified through five databases: Scopus, PsycINFO, MEDLINE, Web of Science, and EMBASE. Moderation analysis was conducted to explain potential sources of effect size heterogeneity. Eight studies across 13 articles (participant N = 2,490) met inclusion criteria for the review with seven studies across 10 articles (N = 1,347) providing sufficient data for inclusion in the meta-analysis. A small but significant effect size favoring personalized interventions was found (d = 0.21, 95% CrI [0.02, 0.39]), indicating that personalized interventions are associated with superior treatment outcomes compared to standardized interventions. Moderate between-study heterogeneity was found (I2 = 53.3%). There was no evidence of publication bias. The review also found significant variation in methods of treatment personalization. This review provides evidence that personalization of adolescent psychological interventions is an effective way to improve treatment outcomes. Given the large number of adolescents worldwide who will experience some sort of mental health problem, personalization could have a significantly large impact on global mental health outcomes.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/XRNCG.

ABSTRACT Leptospirosis, caused by pathogenic bacteria from the genus Leptospira, is a global zoonosis responsible for more than one million human cases and 60,000 deaths annually. The disease also affects many domestic animal species. Historically, genetic manipulation of Leptospira has been difficult to perform, resulting in limited knowledge on pathogenic mechanisms of disease and the identification of virulence factors. The application of CRISPR/Cas9 and its variations have helped fill these gaps but the generation of knockout mutants remains challenging because double-strand breaks (DSBs) inflicted by Cas9 nuclease are lethal to Leptospira cells. The novel CRISPR prime editing (PE) strategy is the first precise genome-editing technology that allows deletions, insertions, and base substitutions without introducing DSBs. This revolutionary technique utilizes a nickase Cas9 that cleaves a single strand of DNA, coupled with an engineered reverse transcriptase and a modified single-guide RNA (termed prime editing guide RNA) containing an extended 3′ end with the desired edits. We demonstrate the application of CRISPR-PE in both saprophytic and pathogenic Leptospira from multiple species and serovars by introducing deletions or insertions into target DNA with a remarkable precision of just one nucleotide. Additionally, we demonstrate the ability to genetically manipulate Leptospira borgpetersenii, a prevalent pathogenic species of humans, domestic cattle, and wildlife animals. Rapid plasmid loss by mutated strains in liquid culture allows for the generation of knockout strains without selective markers, which can be readily used to elucidate virulence factors and develop optimized bacterin and/or live vaccines against leptospirosis.IMPORTANCELeptospirosis is a geographically widespread bacterial zoonosis. Genetic manipulation of pathogenic Leptospira spp. has been laborious and difficult to perform, limiting our ability to understand how leptospires cause disease. The application of the CRISPR/Cas9 system to Leptospira enhanced our ability to generate knockdown and knockout mutants; however, the latter remains challenging. Here, we demonstrate the application of the CRISPR prime editing technique in Leptospira, allowing the generation of knockout mutants in several pathogenic species, with mutations comprising just a single nucleotide resolution. Notably, we generated a mutant in the Leptospira borgpetersenii background, a prevalent pathogenic species of humans and cattle. Our application of this method opens new avenues for studying pathogenic mechanisms of Leptospira and the identification of virulence factors across multiple species. These methods can also be used to facilitate the generation of marker-less knockout strains for updated and improved bacterin and/or live vaccines.

Summary:. A 71-year-old man who had hip abductor insufficiency due to a chronic injury to the right superior gluteal nerve injury after lipoma resection presented to our outpatient clinic 1.5 years postoperatively with persistent pain, atrophy of the gluteus medius muscle, and Trendelenburg sign with a corresponding limp. A magnetic resonance imaging scan and neurophysiological diagnostics confirmed a chronic lesion of the superior gluteal nerve with completed reinnervation and absent pathological spontaneous activity, excluding neurosurgical options to restore hip abduction. Following interdisciplinary evaluation of the patient’s case, we performed a vastus lateralis transfer in May 2023 to stabilize the right hip joint. The entire vastus lateralis muscle was carefully freed from the surrounding tissue, and its attachment to the quadriceps tendon was separated. The proximal section of the lateral vastus was then fixed to the ilium and greater trochanter, while the muscle’s distal portion was sutured to a more proximal part of the quadriceps muscle. The postoperative course was without any complications, and the patient left the hospital with an abduction splint 10 days after surgery. When he presented to our outpatient clinic 10 weeks after surgery, he reported a significantly improved gait and reduction of pain. Trendelenburg sign was now absent, but right knee function was not impaired and the patient was able to ambulate without the regular need for an orthosis. A transfer of the vastus lateralis muscle is therefore a valuable option to restore hip abductor function in cases of chronic nerve lesions which exclude neurosurgical options.

Background Despite the ubiquity of multilevel sampling, design, and analysis in mental health implementation trials, few resources are available that provide reference values of design parameters (e.g., effect size, intraclass correlation coefficient [ICC], and proportion of variance explained by covariates [covariate R 2 ]) needed to accurately determine sample size. The aim of this study was to provide empirical reference values for these parameters by aggregating data on implementation and clinical outcomes from multilevel implementation trials, including cluster randomized trials and individually randomized repeated measures trials, in mental health. The compendium of design parameters presented here represents plausible values that implementation scientists can use to guide sample size calculations for future trials. Method We searched NIH RePORTER for all federally funded, multilevel implementation trials addressing mental health populations and settings from 2010 to 2020. For all continuous and binary implementation and clinical outcomes included in eligible trials, we generated values of effect size, ICC, and covariate R 2 at each level via secondary analysis of trial data or via extraction of estimates from analyses in published research reports. Effect sizes were calculated as Cohen d ; ICCs were generated via one-way random effects ANOVAs; covariate R 2 estimates were calculated using the reduction in variance approach. Results Seventeen trials were eligible, reporting on 53 implementation and clinical outcomes and 81 contrasts between implementation conditions. Tables of effect size, ICC, and covariate R 2 are provided to guide implementation researchers in power analyses for designing multilevel implementation trials in mental health settings, including two- and three-level cluster randomized designs and unit-randomized repeated-measures designs. Conclusions Researchers can use the empirical reference values reported in this study to develop meaningful sample size determinations for multilevel implementation trials in mental health. Discussion focuses on the application of the reference values reported in this study.

The 2021 FSIS Stabilization Guidelines for Meat and Poultry Products (Appendix B) Option 1.2 limits Phase 1 cooling from 48.8 to 26.7 °C in uncured meats to 1 h. However, this time restriction is impractical to achieve in large−diameter whole−muscle products. The objective of this study was to compare the inhibitory effect of commercial dry vinegars (DVs) and cultured sugar-vinegar blends (CSVs) on Clostridium perfringens and Bacillus cereus in uncured beef and poultry products during extended cooling. Treatments (beef: 72–73% moisture, pH 6.2–6.3, 0.85–0.95% NaCl; turkey: 76–77% moisture, pH 6.5–6.7, 1.3–1.6% NaCl) included Controls without antimicrobials, and four DV and four CSV, each tested at 0.75 and 1.25%. Batches were inoculated with 2.5-log C. perfringens or B. cereus spores, vacuum-packaged, and cooked to 73 °C. Packages were cooled from 48.8 to 27 °C (Phase 1) in 3, 4, or 5 h; Phase 2 (27–12.8 °C) and Phase 3 (12.8–4 °C) were standardized for 5-h cooling each. Pathogens were enumerated on selective agar in triplicate samples assayed at precook, postcook, and at the end of Phase 1, 2, and 3 cooling. Experiments were conducted twice. B. cereus did not grow (4.5 log) in Control treatments when Phase 1 cooling was extended to ≥3 h. All 1.25% DV ingredients limited C. perfringens growth to ≤1-log when Phase 1 cooling was extended to 3 h but supported a >1-log increase when Phase 1 cooling was extended to 5 h. All 1.25% CSV inhibited growth under 3-h Phase 1 cooling; 1.25% CSV-A and ≥0.75% CSV-D inhibited growth in turkey during 5-h Phase 1 cooling, but inhibition with 1.25% CSV-C was inconsistent in beef. This study revealed that formulating uncured meats with 1.25% DV or certain CSV can extend Phase 1 cooling to 3 h. Although all ingredients inhibited growth when used at 0.75% or greater compared to a control, greater variability of inhibition was observed among CSV than for DV.

IntroductionStartle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI.MethodsUsing silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation.ResultsOver time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9–13%). No significant neural activity for PPI was detected.DiscussionStartle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

IntroductionStroke leads to motor deficits, requiring rehabilitation therapy that targets mechanisms underlying movement generation. Cortical activity during the planning and execution of motor tasks can be studied using EEG, particularly via the Event Related Desynchronization (ERD). ERD is altered by stroke in a manner that varies with extent of motor deficits. Despite this consensus in the literature, defining precisely the temporality of these alterations during movement preparation and performance may be helpful to better understand motor system pathophysiology and might also inform development of novel therapies that benefit from temporal resolution.MethodsPatients with chronic hemiparetic post-stroke (n = 27; age 59 ± 14 years) and age-matched healthy right-handed control subjects (n = 23; 59 ± 12 years) were included. They performed a shoulder rotation task following the onset of a stimulus. Cortical activity was recorded using a 256-electrode EEG cap. ERD was calculated in the beta frequency band (15–30 Hz) in ipsilesional sensorimotor cortex, contralateral to movement. The ERD was compared over time between stroke and control subjects using permutation tests. The correlation between upper extremity motor deficits (assessed by the Fugl-Meyer scale) and ERD over time was studied in stroke patients using Spearman and permutation tests.ResultsPatients with stroke showed on average less beta ERD amplitude than control subjects in the time window of −350 to 50 ms relative to movement onset (t(46) = 2.8, p = 0.007, Cohen’s d = 0.31, 95% CI [0.22: 1.40]). Beta-ERD values correlated negatively with the Fugl-Meyer score during the time window −200 to 400 ms relative to movement onset (Spearman’s r = −0.54, p = 0.003, 95% CI [−0.77 to −0.18]).DiscussionOur results provide new insights into the precise temporal changes of ERD after hemiparetic stroke and the associations they have with motor deficits. After stroke, the average amplitude of cortical activity is reduced as compared to age-matched controls, and the extent of this decrease is correlated with the severity of motor deficits; both were true during motor programming and during motor performance. Understanding how stroke affects the temporal dynamics of cortical preparation and execution of movement paves the way for more precise restorative therapies. Studying the temporal dynamics of the EEG also strengthens the promising interest of ERD as a biomarker of post-stroke motor function.

RASopathies cause nonsarcomeric hypertrophic cardiomyopathy via dysregulated signaling through RAS and upregulated mitogen-activated protein kinase activity. We provide the first report of the successful treatment of an adult with RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK inhibitor.

Abstract Soils are a major source of nitrogen oxides, which in the atmosphere help govern its oxidative capacity. Thus the response of soil nitric oxide (NO) emissions to forcings such as warming or forest loss has a meaningful impact on global atmospheric chemistry. We find that the soil emission rate of NO in Amazonia from a common inventory is biased low by at least an order of magnitude in comparison to tower‐based observations. Accounting for this regional bias decreases the modeled global methane lifetime by 1.4%–2.6%. In comparison, a fully deforested Amazonia, representing a 37% decrease in global emissions of isoprene, decreases methane lifetime by at most 4.6%, highlighting the sensitive response of oxidation rates to changes in emissions of NO compared to those of terpenes. Our results demonstrate that improving our understanding of soil NO emissions will yield a more accurate representation of atmospheric oxidative capacity.

Brucella abortus strain RB51 is the commercial cattle vaccine used in the United States (US) and many parts of the world against bovine brucellosis. RB51 was licensed for use in 1996, and it has been shown to be safe and efficacious in cattle, eliciting humoral and cellular responses in calves and adult animals. In 2017, an epidemiological trace-back investigation performed by the Centers for Disease Control and Prevention (CDC) identified human cases of brucellosis caused by infection with RB51. These infections resulted from the consumption of unpasteurized dairy products, which were traced back to otherwise healthy animals that were shedding RB51 in their milk. At the current time, six adult Jersey cows have been identified in the U.S. that are shedding RB51 in milk. One of the RB51 shedding cattle was obtained and housed at the National Animal Disease Center (NADC) for further study. Improved understanding of host cellular and humoral immune responses to RB51 in persistently colonized cattle may be achieved by the characterization of responses in shedding animals. We hypothesized, based on the lack of RB51 clearance, that the RB51 shedder animal has a diminished adaptive cellular immune response to RB51. Our data demonstrate that in the presence of persistent RB51 infection, there is a lack of peripheral anti-RB51 CD4+ T cell responses and a concurrently high anti-RB51 IgG humoral response. By understanding the mechanisms that result in RB51 persistence, the development of improved interventions or vaccinations for brucellosis may be facilitated, which would provide public health benefits, including reducing the risks associated with the consumption of non-pasteurized milk products.

Abstract We report on a new ground-level neutron monitor design for studying cosmic rays and fluxes of solar energetic particles at the Earth’s surface. The first-of-its-kind instrument, named the NM-2023 after the year it was standardised and following convention, will be installed at a United Kingdom Meteorological Office observatory (expected completion mid 2024) and will reintroduce such monitoring in the UK for the first time since ca. 1984. Monte Carlo radiation transport code is used for the development and application of parameterised models to investigate alternative neutron detectors, their location and bulk material geometry in a realistic cosmic ray neutron field. Benchmarked against a model of the current and most widespread design standardised in 1964 (the NM-64), two main parameterisation studies are conducted; a simplified standard model and a concept slab parameterisation. We show that the NM-64 standard is well optimised for the intended large-diameter boron trifluoride (BF $$_3$$ 3 ) proportional counters but not for multiple smaller diameter counters. The new design (based on a novel slab arrangement) produces comparable counting efficiencies to an NM-64 with six BF $$_3$$ 3 counters and has the added advantage of being more compact, lower cost and avoids the use of highly toxic BF $$_3$$ 3 .