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BackgroundLifestyle changes have been demonstrated to impact pathophysiology in Multiple Sclerosis (MS). Various diet and exercise protocols have been reported to improve symptoms and function in persons with MS. Evidence is accumulating that interventions as early as possible in the disease course are warranted. The objective of this study was to investigate the effect of a remotely delivered lifestyle program focusing on specific diet and exercise recommendations in persons with early MS.MethodsMS patients, with disease diagnosis no more than 2 years prior, were recruited from the patient population of the MS clinic of the Pacific Neuroscience Institute. Participants followed recommendations for diet and exercise delivered via remote heath coaching. Each participant received 6 sessions with a health coach over a 12-week period. They were given parameters of a Mediterranean-type diet to follow, and specific and individualized recommendations about duration, intensity and type of exercise and physical activity. Outcome measures included Quality of Life (QOL), cognition (Symbol Digit Modalities Test, SDMT), fatigue (Multiple Sclerosis Fatigue Impact Scale, MFIS), fitness (estimated with Metabolic equivalents, METS) and other objective and patient reported outcomes (PRO). Changes in outcomes were analyzed using mixed effects general linear models and standardized pre-post differences.(Cohen's d) RESULTS: Fifteen persons with early (≤ 2 years) MS enrolled in the study, 14 of whom completed the study. We observed significant improvements in QOL (p = 0.02), SDMT (p = 0.006), fatigue(p = 0.005), fitness (p = 0.04), and other PRO and objective metrics at the end of the protocol compared to baseline. Adherence and patient satisfaction measures were high.ConclusionsSpecific and individualized lifestyle recommendations can be effectively delivered remotely, and may produce improvement in symptoms and function in persons with early MS. Larger controlled trials of these interventions are warranted.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Abstract Interspecies pathways in the gut microbiome have been shown to metabolize levodopa, the primary treatment for Parkinson’s disease, and reduce its bioavailability. While the enzymatic reactions have been identified, the ability to establish the resulting macromolecules as biomarkers of microbial metabolism remains technically challenging. In this study, we leveraged an untargeted mass spectrometry-based approach to investigate volatile organic compounds (VOCs) produced during levodopa metabolism by Enterococcus faecalis, Clostridium sporogenes, and Eggerthella lenta. We cultured these organisms with and without their respective bioactive metabolites and detected levodopa-induced shifts in VOC profiles. We then utilized bioinformatics to identify significant differences in 2,6-dimethylpyrazine, 4,6-dimethylpyrimidine, and 4,5-dimethylpyrimidine associated with its biotransformation. Supplementing cultures with inhibitors of levodopa-metabolizing enzymes revealed specific modulation of levodopa-associated diazines, verifying their relationship to its metabolism. Furthermore, functional group analysis depicts strain-specific VOC profiles that reflect interspecies differences in metabolic activity that can be leveraged to assess microbiome functionality in individual patients. Collectively, this work identifies previously uncharacterized metabolites of microbe-mediated levodopa metabolism to determine potential indicators of this activity and further elucidate the metabolic capabilities of different gut bacteria.

Abstract Adult neurogenesis, which takes place in both vertebrate and invertebrate species, is the process by which new neurons are born and integrated into existing functional neural circuits, long after embryonic development. Most studies in mammals suggest that self-renewing stem cells are the source of the new neurons, although the extent of self-renewal is a matter of debate. In contrast, research in the crayfish Procambarus clarkii has demonstrated that the neural progenitors producing adult-born neurons are capable of both self-renewing and consuming (non-self-renewing) divisions. However, self-renewing divisions are relatively rare, and therefore the production of adult-born neurons depends heavily on progenitors that are not replenishing themselves. Because the small pool of neural progenitors in the neurogenic niche is never exhausted throughout the long lives of these animals, we hypothesized that there must also be an extrinsic source of these cells. It was subsequently demonstrated that the neural progenitors originate in hemocytes (blood cells) produced by the immune system that travel in the circulation before ultimately integrating into niches where the neural lineage begins. The current study examines the developmental lineage of the three hemocyte types — hyaline (HC), semigranular (SGC) and granular (GC) cells — with the goal of understanding the origins of the progenitor cells that produce adult-born neurons. Longstanding qualitative metrics for hemocyte classification were validated quantitatively. Then, in a longitudinal study, proliferation markers were used to label the hemocytes in vivo, followed by sampling the circulating hemocyte population over the course of two months. Hemolymph samples were taken at intervals to track the frequencies of the different hemocyte types. These data reveal sequential peaks in the relative frequencies of HCs, SGCs and GCs, which were identified using qualitative and quantitative measures. These findings suggest that the three hemocyte types comprise a single cellular lineage that occurs in the circulation, with each type as a sequential progressive stage in hemocyte maturation beginning with HCs and ending with GCs. When combined with previously published data, this timeline provides additional evidence that HCs serve as the primary neural progenitor during adult neurogenesis in P. clarkii.

Abstract Background and purpose The immune response changes during aging and the progression of Alzheimer’s disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. Methods Study participants from a University of Kentucky Alzheimer’s Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. Results CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. Conclusion These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

Daylight is essential for ecosystems and for the physical and mental well-being of people. In densely populated cities, only a small proportion of total daylight is available to support urban greenery and most people have little daily exposure to natural daylight. Despite this, many cities have followed a strategy of densification as a way of preventing urban sprawl and reducing energy consumption. In this article, we review the biological importance of daylight and show that urban densification leads to a reduction in the daylight available for both people and nature. We conclude that daylight in cities should be treated as a limiting resource that needs to be planned and managed carefully, much like water or energy. We suggest elements for a policy framework aimed at optimizing urban daylight, including how to determine daylight needs, how to determine the maximum viable urban density, and policy options for built and unbuilt areas.

IntroductionSocial isolation and loneliness are global public health concerns experienced among older adults which are commonly associated with negative physical, psychological, and social outcomes. The healthcare system has an opportunity to identify and address social isolation and loneliness in older adults. The Program of All-Inclusive Care for the Elderly (PACE) was developed to serve comprehensive social needs along with medical and behavioral needs of older adults who qualify for long-term care while still living in the community. In 2021, due to state budget reductions, Wyoming’s only PACE program (WY PACE) closed, resulting in the discharge of all participants and loss of social engagement opportunities provided by this program. The objectives of this evaluation were to (1) examine the impact of the WY PACE closure on isolation and loneliness, (2) identify how older adults adapted to the loss of services addressing isolation and loneliness, and (3) identify needs for future interventions to address isolation among clients who experienced loss of supportive programs.MethodsA mixed-methods design was used to facilitate understanding of qualitative findings while also conducting quantitative analyses to provide context for qualitative responses. Participants included 17 individuals who were either former PACE participants or their caregivers. Participants (n = 12; M = 74 years old) were predominantly non-Hispanic White (n = 8, 66%) and cisgender female (n = 7, 58%). Caregivers of participants (n = 5; M = 63 years old) were predominantly Hispanic, Latino, or of Spanish origin (n = 3, 60%) and cisgender female (n = 4, 80%).ResultsA mixed-methods design was used to facilitate understanding of qualitative findings while also conducting quantitative analyses to provide context for qualitative responses. Participants included 17 individuals who were either former PACE participants or their caregivers. Participants (n = 12; M = 74 years old) were predominantly non-Hispanic White (n = 8, 66%) and cisgender female (n = 7, 58%). Caregivers of participants (n = 5; M = 63 years old) were predominantly Hispanic, Latino, or of Spanish origin (n = 3, 60%) and cisgender female (n = 4, 80%).DiscussionThis evaluation provided preliminary insight into the impacts of the loss of programs like WY PACE on social isolation and loneliness. Creative solutions to maintain social engagement of this vulnerable population are needed.

BackgroundPatient education, hand exercises, and the use of assistive devices are recommended as first-line treatments for individuals with hand osteoarthritis (OA). However, the quality of care services for this patient group is suboptimal in primary care. ObjectiveThe overarching goal was to develop and evaluate feasibility of an app-based self-management intervention for people with hand OA. This feasibility study aims to assess self-reported usability and satisfaction, change in outcomes and quality-of-care, exercise adherence and patients’ experiences using the app. MethodsThe development and feasibility testing followed the first 2 phases of the Medical Research Council framework for the development and evaluation of complex interventions and were conducted in close collaboration with patient research partners (PRPs). A 3-month pre-post mixed methods design was used to evaluate feasibility. Men and women over 40 years of age diagnosed with painful, symptomatic hand OA were recruited. Usability was assessed using the System Usability Scale (0-100), while satisfaction, usefulness, pain, and stiffness were evaluated using a numeric rating scale (NRS score from 0 to 10). The activity performance of the hand was measured using the Measure of Activity Performance of the Hand (MAP-Hand) (1-4), grip strength was assessed with a Jamar dynamometer (kg), and self-reported quality of care was evaluated using the Osteoarthritis Quality Indicator questionnaire (0-100). Participants were deemed adherent if they completed at least 2 exercise sessions per week for a minimum of 8 weeks. Focus groups were conducted to explore participants’ experiences using the app. Changes were analyzed using a paired sample t test (mean change and 95% CI), with the significance level set at P

Summary: Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.

Abstract: Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility– and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross– validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

As many theoretical psychologists turn to the humanities to construct a psychological science that does not shortchange human subjectivity, many humanities scholars have turned to the sciences to bolster their declining standing in the academy. In juxtaposing these trends, I consider how epistemic and methodological wars in the humanities echo those that have plagued psychology and so call into question their use to remedy an allegedly scientistic “mainstream” psychology. By failing to grapple with this most relevant controversy, theoretical psychologists may be jeopardizing their efforts to put a more human face on scientific psychology.

Abstract The construction of materials regulated by chemical reaction networks requires regulatory motifs that can be stacked together into systems with desired properties. Multiple autocatalytic reactions producing thiols are known. However, negative feedback loop motifs are unavailable for thiol chemistry. Here, we develop a negative feedback loop based on the selenocarbonates. In this system, thiols induce the release of aromatic selenols that catalyze the oxidation of thiols by organic peroxides. This negative feedback loop has two important features. First, catalytic oxidation of thiols follows Michaelis-Menten-like kinetics, thus increasing nonlinearity for the negative feedback. Second, the strength of the negative feedback can be tuned by varying substituents in selenocarbonates. When combined with the autocatalytic production of thiols in a flow reactor, this negative feedback loop induces sustained oscillations. The availability of this negative feedback motif enables the future construction of oscillatory, homeostatic, adaptive, and other regulatory circuits in life-inspired systems and materials.

Abstract Carbon and chlorine isotope effects for biotransformation of chloroform by different microbes show significant variability. Reductive dehalogenases (RDase) enzymes contain different cobamides, affecting substrate preferences, growth yields, and dechlorination rates and extent. We investigate the role of cobamide type on carbon and chlorine isotopic signals observed during reductive dechlorination of chloroform by the RDase CfrA. Microcosm experiments with two subcultures of a Dehalobacter‐containing culture expressing CfrA—one with exogenous cobamide (Vitamin B12, B12+) and one without (to drive native cobamide production)—resulted in a markedly smaller carbon isotope enrichment factor (εC, bulk) for B12− (−22.1 ± 1.9‰) compared to B12+ (−26.8 ± 3.2‰). Both cultures exhibited significant chlorine isotope fractionation, and although a lower εCl, bulk was observed for B12− (−6.17 ± 0.72‰) compared to B12+ (−6.86 ± 0.77‰) cultures, these values are not statistically different. Importantly, dual‐isotope plots produced identical slopes of ΛCl/C (ΛCl/C, B12+ = 3.41 ± 0.15, ΛCl/C, B12− = 3.39 ± 0.15), suggesting the same reaction mechanism is involved in both experiments, independent of the lower cobamide bases. A nonisotopically fractionating masking effect may explain the smaller fractionations observed for the B12− containing culture.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.