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Abstract Background Adverse events in early life can have impact lasting into adulthood. We investigated the long-term effects of systemic inflammation during postnatal development on adult microglial responses to lipopolysaccharide (LPS) in two CNS regions (cortex, cervical spinal cord) in male and female rats. Methods Inflammation was induced in Sprague-Dawley rats by LPS (1 mg/kg) administered intraperitoneally during postnatal development at P7, P12 or P18. As adults (12 weeks of age), the rats received a second LPS dose (1 mg/kg). Control rats received saline. Microglia were isolated 3 h post-LPS followed by gene expression analysis via qRT-PCR for pro-inflammatory (IL-6, iNOS, Ptgs2, C/EBPb, CD14, CXCL10), anti-inflammatory (CD68, Arg-1), and homeostatic genes (P2Y12, Tmemm119). CSF-1 and CX3CL1 mRNAs were analyzed in microglia-free homogenates. Results Basal gene expression in adult microglia was largely unaffected by postnatal inflammation. Adult cortical microglial pro-inflammatory gene responses to LPS were either unchanged or attenuated in rats exposed to LPS during postnatal development. Ptgs2, C/EBPb, CXCL10 and Arg-1 were the most affected genes, with expression significantly downregulated vs. rats without postnatal LPS. Spinal microglia were affected most by LPS at P18, with mixed and sometimes opposing effects on proinflammatory genes in males vs. females. Overall, male cortical vs. spinal microglia were more affected by postnatal LPS. Females were affected in both cortex and spinal cord, but the effect was dependent on timing of postnatal LPS. Overall, inflammatory challenge at P18 had greater effect on adult microglia vs. challenge at P12 or P7. Conclusions Long-lasting effects of postnatal inflammation on adult microglia depend on postnatal timing, CNS region and sex.

Abstract We perform a numerical bootstrap study of scalar operators in the critical 3d Gross-Neveu-Yukawa models, a family of conformal field theories containing N Majorana fermions in the fundamental representation of an O(N) global symmetry. We compute rigorous bounds on the scaling dimensions of the next-to-lowest parity-even and parity-odd singlet scalars at N = 2, 4, and 8. All of these dimensions have lower bounds greater than 3, implying that there are only two relevant singlet scalars and placing constraints on the RG flow structure of these theories.

Abstract Purpose Understanding how early adaptive schemas, cognitive flexibility, and emotional regulation influence eating disorder (ED) symptoms, and whether this differs across diagnostic subtypes is critical to optimising treatment. The current study investigated the relationship between these variables and ED symptomology in individuals self-reporting an ED diagnosis and healthy controls. Methods A dataset of 1576 online survey responses yielded subsamples for anorexia nervosa (n = 155), bulimia nervosa (n = 55), binge eating disorder (n = 33), other specified feeding or eating disorder (n = 93), and healthy participants (n = 505). The hierarchical linear regression analysis included Eating Disorder Examination Questionnaire 6.0 Global Score as the dependent variable; Young Positive Schema Questionnaire, Emotional Regulation Questionnaire, and Cognitive Flexibility Inventory subscale scores as the independent variables; and demographic measures as the covariates. Results The number of significant predictors varied considerably by ED sub-group. Amongst the anorexia nervosa, bulimia nervosa, and healthy subsamples, the adaptive schema Self-Compassion and Realistic Expectations was associated with lower ED symptom severity. In comparison, age and body mass index were the strongest predictors for binge eating disorder, whilst the Expressive Suppression (a subscale of the Emotional Regulation Questionnaire) was the strongest predictor for other specified feeding or eating disorders. Conclusion Early adaptive schemas, cognitive flexibility, and emotional regulation vary across ED subtype, suggesting the need for tailored treatment that disrupts the self-reinforcing cycle of ED psychopathology. Future research investigating how early adaptive schemas may predict or be associated with treatment response across diagnostic subtypes is needed. Level of evidence: Level IV, evidence obtained from multiple time-series with or without the intervention, such as case studies.

Abstract During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO2 pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the ‘exercise hyperpnoea dilemma’ can finally be solved. In this review, new perspectives are offered in the hope of stimulating original ideas based on modern neuroscience methods and current understanding. We first describe the ventilatory control system and the challenge exercise places upon blood‐gas regulation. We highlight relevant system properties, including feedforward, feedback and adaptive (i.e., plasticity) control of breathing. We then elaborate a seldom explored hypothesis that the exercise ventilatory response continuously adapts (learns and relearns) throughout life and ponder if the memory ‘engram’ encoding the feedforward exercise ventilatory stimulus could reside within the cerebellum. Our hypotheses are based on accumulating evidence supporting the cerebellum's role in motor learning and the numerous direct and indirect projections from deep cerebellar nuclei to brainstem respiratory neurons. We propose that cerebellar learning may be obligatory for the accurate and adjustable exercise hyperpnoea capable of tracking changes in life conditions/experiences, and that learning arises from specific cerebellar microcircuits that can be interrogated using powerful techniques such as optogenetics and chemogenetics. Although this review is speculative, we consider it essential to reframe our perspective if we are to solve the till‐now intractable exercise hyperpnoea dilemma.

This article presents art as a tool for promoting mental health in schools by examining the effects of art making in a sample of 104 school-based mental health professionals. It unites findings from unrelated disciplines to derive and test a new conceptual framework proposing that active engagement in a visual-tactile process over time mediates a shift to healthy mental states and that regular engagement in such process builds mental health capacity. Four hypotheses are tested through psychometrics with statistically significant findings for all (p < 0.05). Through this study, we advance Flow Theory in identifying a new causal mechanism for accessing Flow; and we make a novel, interdisciplinary contribution to the field of mental health in providing psychometric evidence that making visual art promotes mental health.

Abstract Roadside habitat has been touted as a conservation opportunity for insect pollinators, including the declining monarch butterfly. The spectacular monarch migration is under threat from the loss of habitat and the decline of their milkweed host plants. In the northern part of their range, roadsides could potentially produce millions of monarchs annually due to high densities of milkweed; however, roadside milkweed can accumulate chemicals from roads, such as sodium from road salt. Controlled lab studies have shown mixed effects of sodium on monarch development: small increases can be beneficial as sodium is an important micronutrient in brain and muscle development, but large increases can sometimes decrease survival. It is unclear how dietary sodium affects performance in ecologically relevant conditions and the migration itself. In this experiment, we raised monarchs outdoors, in migration‐inducing conditions, on milkweed sprayed with three levels of sodium chloride. We released 2464 tagged monarchs and held an additional 246 for further lab assays. While our recovery rates to the wintering grounds were low (N = 7 individuals), individuals from all three sodium chloride treatments made it to Mexico. Butterflies reared on control milkweed and low salt concentrated sodium in their tissues, while those on high salt diets excreted sodium, suggesting high salt levels were above a physiological optimum. There were no effects of treatment on wing coloration, survival, body size, immunity, or parasite prevalence. Taken together, our results suggest that monarchs are robust to levels of sodium in milkweeds found along roadsides, which is promising with respect to the toxicity of roadside plants.

Abstract Diving marine mammals are a diverse group of semi‐ to completely aquatic species. Some species are targets of conservation and rehabilitation efforts; other populations are permanently housed under human care and may contribute to clinical and biomedical investigations. Veterinary medical care for species under human care, at times, may necessitate the use of general anesthesia for diagnostic and surgical indications. However, the unique physiologic and anatomic adaptations of one representative diving marine mammal, the bottlenose dolphin, present several challenges in providing ventilatory and cardiovascular support to maintain adequate organ perfusion under general anesthesia. The goal of this review is to highlight the unique cardiopulmonary adaptations of the completely aquatic bottlenose dolphin (Tursiops truncatus), and to identify knowledge gaps in our understanding of how those adaptations influence their physiology and pose potential challenges for sedation and anesthesia of these mammals.

Abstract The plant community in roadside right‐of‐ways is an important component of transportation infrastructure. Revegetation after construction is an opportunity to improve the plant community and create pollinator habitat. However, native seed mixes are substantially more expensive than those used in conventional roadside plantings, and transportation agencies often lack resources for management. Here, we compare the actively flowering plant community across a growing season in roadside plots seeded with native seed mixes versus non‐native seed mixes in Minnesota, USA. Plots varied in age from 2 to 20 years old. We demonstrate that native seeded plots had more native flowering forbs than non‐native seeded plots, as native flowers were rare in the non‐native seeded plots. However, despite some native species establishing well, many species in native seed mixes had poor or non‐existent establishment. Furthermore, the native and non‐native seeded plots converged in the makeup of their floral communities after a few years; part of this pattern is due to colonisation of species that were never seeded at either type of plot. Practical implication. If the goal of revegetation is to produce diverse, native dominated floral communities in roadsides, agencies must invest more in long‐term management. Managers could also alter seed mixes to remove species that fail to establish, which would reduce the cost of the seed mix, but not the diversity of the plant community that ultimately establishes. The use of such streamlined seed mixes across more land area would increase the availability of pollinator habitat without substantially altering current budgets or management plans.

Summary: Beliefs—attitudes toward some state of the environment—guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Introduction: Children with type 1 diabetes require close monitoring with visits every 3–4 months. COVID-19-induced telemedicine expansion may alleviate the challenge of high visit frequency that children with type 1 diabetes face. However, telemedicine’s impact on access to care may be limited if patients lack adequate support for telemedicine. The purpose of this study was to evaluate the impact of telemedicine care coordination services on visit frequency in an urban medical center without care coordination services versus a rural outreach program with established care coordination services serviced by the same providers. Methods: We evaluated EHR data from 790 children receiving care between July 2018 and December 2021 at a single academic center in Oregon. We estimated differences in likelihood of adequately timed monitoring care over time by patient care coordination services status using Generalized Estimating Equations. Results: Just prior to telemedicine expansion, patients receiving care coordination services were 25.6 % less likely to receive adequately timed monitoring care (95 % CI: 51.6 %, 114 %). Following telemedicine expansion, likelihood of adequately timed monitoring care increased from 28.8 % to 58.2 % among those receiving care coordination services and decreased from 38.7 % to 22.0 % among those not receiving care coordination services; increases in adequately timed monitoring care were 3.55 times greater in patients receiving care coordination services relative to those not (95 % CI: 2.10, 6.01). Discussion: For pediatric patients with type 1 diabetes, telemedicine care coordination may be an important factor for increasing visit adherence and may increase the number of patients meeting goal visit frequency beyond levels seen prior to widespread telemedicine availability.

Introduction: The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods: A study was conducted across 34 clinical sites in 19 European and Middle Eastern countries from March 2021 to June 2022 to assess the effectiveness of the BIOFIRE JI Panel. Results: A total of 1527 samples were collected from patients suspected of SA or PJI, with an overall agreement of 88.4 % and 85 % respectively between the JI Panel and synovial fluid cultures (SFCs). The JI Panel detected more positive samples and microorganisms than SFC, with a notable difference on Staphylococcus aureus, Streptococcus species, Enterococcus faecalis, Kingella kingae, Neisseria gonorrhoeae, and anaerobic bacteria. The study found that the BIOFIRE JI Panel has a high utility in the real-world clinical setting for suspected SA and PJI, providing diagnostic results in approximately 1 h. The user experience was positive, implying a potential benefit of rapidity of results' turnover in optimising patient management strategies. Conclusion: The study suggests that the BIOFIRE JI Panel could potentially optimise patient management and antimicrobial therapy, thus highlighting its importance in the clinical setting.

Abstract Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three interventions: tAIH + WALKtSTIM; Placebo + WALKtSTIM; and tAIH + WALKtSHAM. Participants receive daily tAIH (fifteen 90-sec episodes at 10% O2 with 60-sec intervals at 21% O2) or daily placebo (fifteen 90-sec episodes at 21% O2 with 60-sec intervals at 21% O2) before a 45-min session of WALKtSTIM or WALKtSHAM. Our primary outcome measures assess walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up and Go Test). For safety, we also measure pain levels, spasticity, sleep behavior, cognition, and rates of systemic hypertension and autonomic dysreflexia. Assessments occur before, during, and after sessions, as well as at 1, 4, and 8 weeks post-intervention. Results from this study extend our understanding of the functional benefits of tAIH priming by investigating its capacity to boost the neuromodulatory effects of transcutaneous spinal stimulation on restoring walking after SCI. Given that there is no known cure for SCI and no single treatment is sufficient to overcome walking deficits, there is a critical need for combinatorial treatments that accelerate and anchor walking gains in persons with lifelong SCI. Trial Registration: ClinicalTrials.gov, NCT05563103.

Abstract The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit—the central automatic network—responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion.

Abstract Background Vitamin E has a positive effect in the management of osteoarthritis in humans, and in a previous study of dogs. It has been suggested to decrease C‐reactive protein concentrations and liver enzyme activities in humans and animals. Objective To assess the effect of vitamin E supplementation on lameness, pain, pain medication requirement, clinical pathology variables, and quality of life in large‐breed dogs with naturally occurring osteoarthritis. Animals Fifty‐seven client‐owned dogs with naturally occurring osteoarthritis. Methods Dogs received either vitamin E or placebo for 90 days in a randomized, placebo‐controlled, double‐blinded, prospective clinical trial. Clinical lameness scores, pain medication requirements, and owner questionnaires were used to assess response to treatment every 30 days. Blood samples were collected at enrollment and at the end of the study period. Results Vitamin E administration did not improve pain, lameness, or quality of life as assessed by owners and veterinarians. Vitamin E supplementation did not decrease the requirement for rescue pain relief. No changes in clinical pathology variables were observed after 90 days of vitamin E supplementation. Body weight was negatively associated with the lameness scores and requirement for rescue pain relief. Conclusion Vitamin E supplementation did not have any observable positive effects in dogs with naturally occurring osteoarthritis.

BackgroundTo date, most group-based diabetes self-management education (DSME) programs for type 2 diabetes (T2D) have been delivered in person. The rapid transition to remote care at the outset of the COVID-19 pandemic presented opportunities to test, evaluate, and iterate a new remote DSME program. ObjectiveWe aim to refine the delivery and evaluation of a multicomponent remote DSME program for adults living with T2D by examining several feasibility outcomes. MethodsWe recruited a convenience sample of patients from a London, Canada, outpatient diabetes clinic (serving high-risk, low-income adults) to participate in a 6-week, single cohort feasibility study from November 2020 to March 2021. This small ORBIT phase 1b feasibility study represents the first in a planned series guided by the ORBIT model for developing behavioral interventions for chronic diseases (phase 1: design; phase 2: preliminary testing; phase 3: efficacy; and phase 4: effectiveness). The feasibility of delivering and evaluating a remote DSME program, including (1) live video education classes, (2) individualized physical activity (PA) prescription and counseling, and (3) intermittently scanned continuous glucose and wearable PA monitoring, was assessed. Feasibility outcomes included recruitment and retention rates, program adherence, and acceptability (ie, technology issues and exit survey feedback). PA was assessed with Fitbit Inspire 2 (Fitbit Inc) and estimated glycated hemoglobin (HbA1c) using the FreeStyle Libre (Abbot). Given the small study sample, group- and individual-level data are reported descriptively. ResultsA total of 10 adults living with T2D were recruited (female 60%; age 49.9, SD 14.3 years; estimated HbA1c 6.2%, SD 0.5%). Recruitment and retention rates were 29% and 80%, respectively. Participants attended 83% (25/30) and 93% (37/40) of education classes and PA counseling phone calls, respectively. There were 3.2 (SD 2.6) technology issues reported per person, most of which were related to study data transfer. Exit survey responses suggest most participants (8/9, 89%) were “satisfied” with the program. Recognizing the small sample size and the fact that no inferential statistics were conducted, the mean (SD) for the weekly daily step count and estimated HbA1c are provided for illustrative purposes. Participants accumulated 7103 (SD 2900) and 7515 (SD 3169) steps per day at baseline and week 6, respectively. The estimated HbA1c was 6.2% (SD 0.5%) and 6.2% (SD 0.6%) at baseline and week 6, respectively. ConclusionsThis ORBIT phase 1b study served to refine the delivery (eg, automatic study data upload process recommended to reduce participant burden) and evaluation (eg, purposeful sampling of participants with baseline HbA1c >8% recommended to address selection bias) of a remote DSME program. Preliminary proof-of-concept testing (ORBIT phase 2) incorporating some of these learnings is now warranted. Trial RegistrationClinicalTrials.gov NCT04498819; https://clinicaltrials.gov/study/NCT04498819

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. This study’s goal was to identify the signaling drivers and pathways that modulate glomerular endothelial dysfunction in DKD via artificial intelligence-enabled literature-based discovery. Cross-domain text mining of 33+ million PubMed articles was performed with SemNet 2.0 to identify and rank multi-scalar and multi-factorial pathophysiological concepts related to DKD. A set of identified relevant genes and proteins that regulate different pathological events associated with DKD were analyzed and ranked using normalized mean HeteSim scores. High-ranking genes and proteins intersected three domains—DKD, the immune response, and glomerular endothelial cells. The top 10% of ranked concepts were mapped to the following biological functions: angiogenesis, apoptotic processes, cell adhesion, chemotaxis, growth factor signaling, vascular permeability, the nitric oxide response, oxidative stress, the cytokine response, macrophage signaling, NFκB factor activity, the TLR pathway, glucose metabolism, the inflammatory response, the ERK/MAPK signaling response, the JAK/STAT pathway, the T-cell-mediated response, the WNT/β-catenin pathway, the renin–angiotensin system, and NADPH oxidase activity. High-ranking genes and proteins were used to generate a protein–protein interaction network. The study results prioritized interactions or molecules involved in dysregulated signaling in DKD, which can be further assessed through biochemical network models or experiments.

Often, when testing for shift in location, researchers will utilize nonparametric statistical tests in place of their parametric counterparts when there is evidence or belief that the assumptions of the parametric test are not met (i.e., normally distributed dependent variables). An underlying and often unattended to assumption of nonparametric tests of location is that of identical distributions. The assumption of identical distributions requires that distributions conform to one another in terms of variability and shape (i.e., variance, skew and kurtosis). The purpose of the current study is to demonstrate, via the use of Monte Carlo simulation, the assumption of identical distribution using the Wilcoxon-Mann-Whitney (WMW) test and the Student t-test for comparison. For each of the conditions, there are several levels of sample size, variance ratio, group sample size ratio, and degree of skew in the parent distribution. Empirical Type I error rates are compared to nominal Type I error rates to determine the validity of the result for each run of the simulation. Violation of the assumption of identical distributions lead to bias in the result of the WMW test and the Student t-test. Practical implications are also discussed.

ABSTRACT Pathogenesis of Pseudomonas aeruginosa infections can include bacterial survival inside epithelial cells. Previously, we showed that this involves multiple roles played by the type three secretion system (T3SS), and specifically the effector ExoS. This includes ExoS-dependent inhibition of a lytic host cell response that subsequently enables intracellular replication. Here, we studied the underlying cell death response to intracellular P. aeruginosa, comparing wild-type to T3SS mutants varying in capacity to induce cell death and that localize to different intracellular compartments. Results showed that corneal epithelial cell death induced by intracellular P. aeruginosa lacking the T3SS, which remains in vacuoles, correlated with the activation of nuclear factor-κB as measured by p65 relocalization and tumor necrosis factor alpha transcription and secretion. Deletion of caspase-4 through CRISPR-Cas9 mutagenesis delayed cell death caused by these intracellular T3SS mutants. Caspase-4 deletion also countered more rapid cell death caused by T3SS effector-null mutants still expressing the T3SS apparatus that traffic to the host cell cytoplasm, and in doing so rescued intracellular replication normally dependent on ExoS. While HeLa cells lacked a lytic death response to T3SS mutants, it was found to be enabled by interferon gamma treatment. Together, these results show that epithelial cells can activate the noncanonical inflammasome pathway to limit proliferation of intracellular P. aeruginosa, not fully dependent on bacterially driven vacuole escape. Since ExoS inhibits the lytic response, the data implicate targeting of caspase-4, an intracellular pattern recognition receptor, as another contributor to the role of ExoS in the intracellular lifestyle of P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa can exhibit an intracellular lifestyle within epithelial cells in vivo and in vitro. The type three secretion system (T3SS) effector ExoS contributes via multiple mechanisms, including extending the life of invaded host cells. Here, we aimed to understand the underlying cell death inhibited by ExoS when P. aeruginosa is intracellular. Results showed that intracellular P. aeruginosa lacking T3SS effectors could elicit rapid cell lysis via the noncanonical inflammasome pathway. Caspase-4 contributed to cell lysis even when the intracellular bacteria lacked the entire T33S and were consequently unable to escape vacuoles, representing a naturally occurring subpopulation during wild-type infection. Together, the data show the caspase-4 inflammasome as an epithelial cell defense against intracellular P. aeruginosa, and implicate its targeting as another mechanism by which ExoS preserves the host cell replicative niche.

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigen–specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B chain 10–23 peptide presented in the context of the IAg7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR redirected NOD Treg specificity such that insulin B 10–23–peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Cotransfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In WT NOD mice, InsB-g7 CAR Tregs prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor–like CAR is a promising therapeutic approach for the prevention of autoimmune diabetes.

Rationale: Although sleep apnea occurs in over 50% of individuals with Alzheimer’s Disease (AD) or related tauopathies, little is known concerning the potential role of tauopathy in the pathogenesis of sleep apnea. Here, we tested the hypotheses that, during presumptive sleep, a murine model of tauopathy (rTg4510) exhibits: 1) increased breathing instability; 2) impaired chemoreflex function; and 3) exacerbation of these effects with tauopathy progression.Methods: rTg4510 mice initially develop robust tauopathy in the hippocampus and cortex, and eventually progresses to the brainstem. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh, and hypopnea incidence were measured in young adult (5–6 months; n = 10–14/group) and aged (13–15 months; n = 22–24/group) non-transgenic (nTg), monogenic control tetracycline transactivator, and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep (i.e., eyes closed, curled/laying posture, stable breathing for >200 breaths) while breathing room air (21% O2). Peripheral and central chemoreceptor sensitivity were assessed with transient exposures (5 min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2 in 21% O2), respectively.Results: We report significant increases in Type I, II, and III apneas (all p < 0.001), sighs (p = 0.002) and hypopneas (p < 0.001) in aged rTg4510 mice, but only Type III apneas in young adult rTg4510 mice (p < 0.001) versus age-matched nTg controls. Aged rTg4510 mice exhibited profound chemoreflex impairment versus age matched nTg and tTA mice. In rTg4510 mice, breathing frequency, tidal volume and minute ventilation were not affected by hyperoxic or hypercapnic challenges, in striking contrast to controls. Histological examination revealed hyperphosphorylated tau in brainstem regions involved in the control of breathing (e.g., pons, medullary respiratory column, retrotrapezoid nucleus) in aged rTg4510 mice. Neither breathing instability nor hyperphosphorylated tau in brainstem tissues were observed in young adult rTg4510 mice.Conclusion: Older rTg4510 mice exhibit profound impairment in the neural control of breathing, with greater breathing instability and near absence of oxygen and carbon-dioxide chemoreflexes. Breathing impairments paralleled tauopathy progression into brainstem regions that control breathing. These findings are consistent with the idea that tauopathy per se undermines chemoreflexes and promotes breathing instability during sleep.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Inflammasomes are cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a critical role in host defense and inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1PR). HIV-1PR cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes regulated by Toll-like receptor stimulation prior to viral infection. In acutely infected cells, CARD8 senses the activity of both de novo translated HIV-1PR and packaged HIV-1PR that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1PR cleavage site in human CARD8 arose after the divergence of chimpanzees and humans. Although chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz), SIVcpz does cleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans. Our findings suggest a unique role for CARD8 inflammasome activation in response to lentiviral infection of humans.

Summary: The thalamus and cortex are anatomically interconnected, with the thalamus providing integral information for cortical functions. The anteroventral thalamic nucleus (AV) is reciprocally connected to retrosplenial cortex (RSC). Two distinct AV subfields, dorsomedial (AVDM) and ventrolateral (AVVL), project differentially to granular vs. dysgranular RSC, respectively. To probe if functional responses of AV neurons differ, we recorded single neurons and local field potentials from AVDM and AVVL in rats during foraging. We observed place cells (neurons modulated by spatial location) in both AVDM and AVVL. Additionally, we characterized neurons modulated by theta oscillations, heading direction, and a conjunction of these. Place cells and conjunctive Theta-by-Head direction cells were more prevalent in AVVL; more non-conjunctive theta and directional neurons were prevalent in AVDM. These findings add further evidence that there are two thalamocortical circuits connecting AV and RSC, and reveal that the signaling involves place information in addition to direction and theta.

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.

The ability to translate Generative Adversarial Networks (GANs) and Variational Autoencoders (VAEs) into different modalities and data types is essential to improve Deep Learning (DL) for predictive medicine. This work presents DACMVA, a novel framework to conduct data augmentation in a cross-modal dataset by translating between modalities and oversampling imputations of missing data. DACMVA was inspired by previous work on the alignment of latent spaces in Autoencoders. DACMVA is a DL data augmentation pipeline that improves the performance in a downstream prediction task. The unique DACMVA framework leverages a cross-modal loss to improve the imputation quality and employs training strategies to enable regularized latent spaces. Oversampling of augmented data is integrated into the prediction training. It is empirically demonstrated that the new DACMVA framework is effective in the often-neglected scenario of DL training on tabular data with continuous labels. Specifically, DACMVA is applied towards cancer survival prediction on tabular gene expression data where there is a portion of missing data in a given modality. DACMVA significantly (p << 0.001, one-sided Wilcoxon signed-rank test) outperformed the non-augmented baseline and competing augmentation methods with varying percentages of missing data (4%, 90%, 95% missing). As such, DACMVA provides significant performance improvements, even in very-low-data regimes, over existing state-of-the-art methods, including TDImpute and oversampling alone.

OBJECTIVE:The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative. METHOD:The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT). RESULTS:After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain. CONCLUSIONS:KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β-estradiol, compared with placebo, on 48-month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48-month CAC score was >0 or if baseline CAC score was >0 and

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β-estradiol, compared with placebo, on 48-month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48-month CAC score was >0 or if baseline CAC score was >0 and

Cet article présente l'art comme un outil pour promouvoir la santé mentale dans les écoles. Il examine les effets de la création artistique auprès de 104 professionnels de la santé mentale en milieu scolaire. Il réunit les résultats de diverses disciplines afin de dégager et de tester un nouveau cadre conceptuel proposant que l'engagement actif dans un processus visuel tactile au fil du temps facilite une bonne santé mentale, et qu'un engagement constant dans un tel processus renforce la capacité de santé mentale. Quatre hypothèses sont testées au moyen de mesures psychométriques, et elles obtiennent toutes des résultats statistiquement significatifs (p < .05). Grâce à cette étude, nous faisons progresser la théorie du flux (Flow Theory) en identifiant un nouveau mécanisme causal pour accéder à ce flux ; et nous apportons une contribution novatrice et interdisciplinaire au domaine de la santé mentale en fournissant des preuves psychométriques que les arts visuels favorisent la santé mentale, Mots-clés : santé mentale, effets de la création artistique, psychométrie, théorie du flux This article presents art as a tool for promoting mental health in schools by examining the effects of art making in a sample of 104 school-based mental health professionals. It unites findings from unrelated disciplines to derive and test a new conceptual framework proposing that active engagement in a visual-tactile process over time mediates a shift to healthy mental states and that regular engagement in such process builds mental health capacity. Four hypotheses are tested through psychometrics with statistically significant findings for all (p < .05). Through this study, we advance Flow Theory in identifying a new causal mechanism for accessing Flow; and we make a novel, interdisciplinary contribution to the field of mental health in providing psychometric evidence that making visual art promotes mental health. Keywords: mental health, effects of art making, psychometrics, flow theory, Introduction The mental health crisis needs new thinking--now--especially in schools. In Canada, mental health issues affect nearly half of the population by the age of 40, and youth are notably [...]

Objectives To identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees.Design Prospective cohort study.Setting A public university in California from June to August 2020.Participants 2180 university students and 738 university employees.Primary outcome measures At baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes.Results Over the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study.Conclusions Our findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

A major bottleneck preventing the extension of deep learning systems to new domains is the prohibitive cost of acquiring sufficient training labels. Alternatives such as weak supervision, active learning, and fine-tuning of pretrained models reduce this burden but require substantial human input to select a highly informative subset of instances or to curate labeling functions. REGAL (Rule-Enhanced Generative Active Learning) is an improved framework for weakly supervised text classification that performs active learning over labeling functions rather than individual instances. REGAL interactively creates high-quality labeling patterns from raw text, enabling a single annotator to accurately label an entire dataset after initialization with three keywords for each class. Experiments demonstrate that REGAL extracts up to 3 times as many high-accuracy labeling functions from text as current state-of-the-art methods for interactive weak supervision, enabling REGAL to dramatically reduce the annotation burden of writing labeling functions for weak supervision. Statistical analysis reveals REGAL performs equal or significantly better than interactive weak supervision for five of six commonly used natural language processing (NLP) baseline datasets.

With the emergence of additive manufacturing technology, patient-specific cranial implants using 3D printing have massively influenced the field. These implants offer improved surgical outcomes and aesthetic preservation. However, as additive manufacturing in cranial implants is still emerging, ongoing research is investigating their reliability and sustainability. The long-term biomechanical performance of these implants is critically influenced by factors such as implant material, anticipated loads, implant-skull interface geometry, and structural constraints, among others. The efficacy of cranial implants involves an intricate interplay of these factors, with fixation playing a pivotal role. This study addresses two critical concerns: determining the ideal number of fixation points for cranial implants and the optimal curvilinear distance between those points, thereby establishing a minimum threshold. Employing finite element analysis, the research incorporates variables such as implant shapes, sizes, materials, the number of fixation points, and their relative positions. The study reveals that the optimal number of fixation points ranges from four to five, accounting for defect size and shape. Moreover, the optimal curvilinear distance between two screws is approximately 40 mm for smaller implants and 60 mm for larger implants. Optimal fixation placement away from the center mitigates higher deflection due to overhangs. Notably, a symmetric screw orientation reduces deflection, enhancing implant stability. The findings offer crucial insights into optimizing fixation strategies for cranial implants, thereby aiding surgical decision-making guidelines.

Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin–angiotensin–aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%.

This paper documents a novel method for the design and construction of unfolded, folded, and dielectrically-loaded sleeve baluns using additive manufacturing to achieve an electrically small form factor for size and weight constrained applications. Single and double-folded sleeve baluns were constructed, tested, and compared to standard sleeve baluns. The baluns decreased 40% in size with each successive folding, with the smallest air-core baluns being 36% the size of a standard sleeve balun. Dielectric-loading was utilized to further miniaturize, resulting in a balun that is only 21% the size of a standard sleeve balun. The double-folded balun constructed using additive manufacturing is also only 40% of the weight of a standard sleeve balun. The Common Mode Rejection Ratio (CMRR) was above 38 dB for all baluns. These baluns achieve a small form factor, similar to ferrite beads, making them usable as inline components in systems where traditional sleeve baluns are too large and heavy.

Our goal was to survey people with epilepsy (PWE) about their interest in and factors that may influence willingness and ability to participate in an exercise randomized controlled trial (RCT). A brief survey was administered to 100 PWE asking if they would take part in a hypothetical 6-week exercise intervention RCT. Follow-up questions queried reasons for and against participation and why participation would be difficult. Sixty-nine percent of respondents indicated willingness to participate. The top reason for participation was “to improve overall health with exercise” (n = 49). The top reason for why participation would be difficult was they “do not have a reliable source of transportation” (n = 27). The top reason for not participating was “not interested in research participation” (n = 19). Preliminary results were used to budget for transportation in a prospective RCT (NCT04959019). Of the first 27 PWE enrolled (63 % female; 44 % African American/Black), six (50 % female; 50 % African American/Black) have used the transportation service. The majority of PWE surveyed were interested in participating in an exercise RCT, but some indicated barriers. Accommodating transportation in an ongoing RCT has facilitated recruitment of PWE who would otherwise not be able to participate. Barriers to participation should be accounted for when designing studies.