Search

While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection.

Proper progression through the cell-division cycle is critical to normal development and homeostasis and is necessarily misregulated in cancer. The key to cell-cycle regulation is the control of two waves of transcription that occur at the onset of DNA replication (S phase) and mitosis (M phase). MuvB complexes play a central role in the regulation of these genes. When cells are not actively dividing, the MuvB complex DREAM represses G1/S and G2/M genes. Remarkably, MuvB also forms activator complexes together with the oncogenic transcription factors B-MYB and FOXM1 that are required for the expression of the mitotic genes in G2/M. Despite this essential role in the control of cell division and the relationship to cancer, it has been unclear how MuvB complexes inhibit and stimulate gene expression. Here we review recent discoveries of MuvB structure and molecular interactions, including with nucleosomes and other chromatin-binding proteins, which have led to the first mechanistic models for the biochemical function of MuvB complexes.

The gender dimension of Science, Technology, Engineering and Mathematics (STEM) has intrigued social scientists for a long time. Although in India, women's entry to STEM higher education has been improving over the last few decades, the reality of premier institutions remains broadly unaltered. The current qualitative research was an attempt: (a) to explore the career-selection-related decision-making, (b) to detect whether gendered processes are evident in STEM research laboratories, and (c) to explore the psychological effects of gendered processes among female doctoral/postdoctoral researchers. This qualitative study relied on in-depth interviews with twenty female STEM academics pursuing doctoral or postdoctoral research in ten premier Indian institutions. A hybrid of theoretical and inductive thematic analysis has been used to analyse the qualitative data. The results revealed that the combination of individual (interest and self-efficacy) and contextual factors (parental support and role models) had impacted the researchers' decision to select and pursue higher studies in STEM. Furthermore, the current research shows that higher studies in STEM are characterised by the four defining features of gendering, i.e., gendered division of labour, gendered symbols, gendered identity, and gendered interactions (Acker, 1990). Gendering in STEM has led to self-doubt and diminished sense of belonging among the researchers.

This study explores the relation between yoga and prosocial behavior (PSB) of business students and evaluates the impact of yoga on their academic performance in an MBA program. The mediating role of mindfulness is also examined. The study covers a cohort of 255 MBA students. Individual MBA student's yoga practice, mindfulness, PSB, and performance in management case studies was measured before and after a 20-week yoga programme. The study found that yogic practices significantly increase PSB and academic performance. To assess the mediating role of mindfulness, PROCESS macro was used for regression analysis. It was found that mindfulness acts as a mediator between yoga and PSB. As a result of partial mediation, half the effect on PSB comes from higher mindfulness while the remaining half comes directly from the practice of yoga. Mindfulness also acts as a mediator between yoga and academic performance. In case of the grades obtained by the MBA students, 58% of increase comes through mindfulness whereas the remaining 42% comes from yogic practices directly. Increasing PSB among business school students would be a logical step toward promoting future management practices that are more comprehensive, socially responsible, value-based, and ethically-oriented. This study demonstrates how yoga can benefit MBA students who practise it as well as meet social demands.

Patients of Asian and black ethnicity face disadvantage on the renal transplant waiting list in the UK, because of lack of human leucocyte antigen and blood group matched donors from an overwhelmingly white deceased donor pool. This study evaluates outcomes of renal allografts from Asian and black donors. The UK Transplant Registry was analysed for adult deceased donor kidney only transplants performed between 2001 and 2015. Asian and black ethnicity patients constituted 12.4% and 6.7% of all deceased donor recipients but only 1.6% and 1.2% of all deceased donors, respectively. Unadjusted survival analysis demonstrated significantly inferior long-term allograft outcomes associated with Asian and black donors, compared to white donors. On Cox-regression analysis, Asian donor and black recipient ethnicities were associated with poorer outcomes than white counterparts, and on ethnicity matching, compared with the white donor–white recipient baseline group and adjusting for other donor and recipient factors, 5-year graft outcomes were significantly poorer for black donor-black recipient, Asian donor-white recipient, and white donor-black recipient combinations in decreasing order of worse unadjusted 5-year graft survival. Increased deceased donation among ethnic minorities could benefit the recipient pool by increasing available organs. However, it may require a refined approach to enhance outcomes.

Summary: RNase L is an endoribonuclease of higher vertebrates that functions in antiviral innate immunity. Interferons induce oligoadenylate synthetase enzymes that sense double-stranded RNA of viral origin leading to the synthesis of 2′,5′-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L remodels the host cell transcriptome. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A is directly introduced into cells. Here, we report that RNase L activation by 2-5A causes a ribotoxic stress response involving the MAP kinase kinase kinase (MAP3K) ZAKα, MAP2Ks, and the stress-activated protein kinases JNK and p38α. RNase L activation profoundly alters the transcriptome by widespread depletion of mRNAs associated with different cellular functions but also by JNK/p38α-stimulated induction of inflammatory genes. These results show that the 2-5A/RNase L system triggers a protein kinase cascade leading to proinflammatory signaling and apoptosis.

Objective: We provide an in-depth understanding of how governance and decision-making during the COVID-19 pandemic has been empirically characterized in the literature to identify gaps in research and highlight areas that require further inquiry.Methods: We searched peer-reviewed publications using empirical data published between Jan 1, 2020 and Jan 31, 2022 in three electronic databases to examine the process of governance and decision-making during the COVID-19 pandemic. Two authors independently screened the records and 24 publications were extracted for the review.Results: Governance is analyzed by its level at national, sub-national, community and by its aspects of process, determinants and performance. While different methodological approaches are used, governance is conceptualized in four ways 1) characteristics and elements, 2) leadership, 3) application of power and 4) models or arrangements of governance.Conclusion: For future pandemic preparedness, there is a need for more empirical research using a unified conceptual approach to governance, which integrates decision-making processes and can guide governance structures and mechanisms across different countries and contexts. We call for more inclusivity in who performs the research on governance and where.

Collagenous colitis is a form of microscopic colitis, while Collagenous Sprue (CS) is a malabsorptive disorder that mimics celiac disease. Both conditions show increased Intraepithelial Lymphocytes (IELs) and basement membrane thickening due to collagen deposition. The simultaneous occurrence of both disorders is rare, and only a few such cases have been reported in the literature. A 60-year-old female presented with chronic, non bloody diarrhoea persisting for two years. Investigations revealed megaloblastic anaemia and hypoalbuminaemia. Gastroenteroscopy showed flattening and atrophy of the small intestinal mucosa. Biopsy results showed increased IELs, normal crypt architecture, and stripping of the epithelium. There was also patchy deposition of hyalinised band subepithelially, confirmed to be collagen through Masson’s stain. As both the upper and lower Gastrointestinal (GI) tracts were involved, a diagnosis of collagenous enterocolitis was made. A 70-year-old female presented with intermittent watery diarrhoea for the past 10 days, accompanied by urgency and tenesmus. She had a history of colicky abdominal pain four years ago, which improved with steroids, but the symptoms recurred. Clinically, she was considered to have inflammatory bowel disease, with recurrent anaemia. Both gastroduodenoscopy and colonoscopy were normal. Mapping biopsy showed increased IELs and focal atrophy in the duodenum, while the colon exhibited mild mononuclear inflammation with occasional minimal activity. Focal, irregular deposition of subepithelial collagen was also observed and confirmed through Masson’s stain. A diagnosis of collagenous enterocolitis was made. She is currently being monitored for any recurrence of symptoms, after which steroid treatment will be initiated. Collagenous colitis, CS, and collagenous duodenitis share similar histological features and can rarely co-exist. Further studies are needed to better understand their aetiology and association.

Abstract Background Alzheimer’s disease involves accumulating amyloid (A) and tau (T) pathology, and progressive neurodegeneration (N), leading to the development of the AD clinical syndrome. While several markers of N have been proposed, efforts to define normal vs. abnormal neurodegeneration based on neuroimaging have been limited. Sensitive markers that may account for or predict cognitive dysfunction for individuals in early disease stages are critical. Methods Participants (n = 296) defined on A and T status and spanning the AD-clinical continuum underwent multi-shell diffusion-weighted magnetic resonance imaging to generate Neurite Orientation Dispersion and Density Imaging (NODDI) metrics, which were tested as markers of N. To better define N, we developed age- and sex-adjusted robust z-score values to quantify normal and AD-associated (abnormal) neurodegeneration in both cortical gray matter and subcortical white matter regions of interest. We used general logistic regression with receiver operating characteristic (ROC) and area under the curve (AUC) analysis to test whether NODDI metrics improved diagnostic accuracy compared to models that only relied on cerebrospinal fluid (CSF) A and T status (alone and in combination). Results Using internal robust norms, we found that NODDI metrics correlate with worsening cognitive status and that NODDI captures early, AD neurodegenerative pathology in the gray matter of cognitively unimpaired, but A/T biomarker-positive, individuals. NODDI metrics utilized together with A and T status improved diagnostic prediction accuracy of AD clinical status, compared with models using CSF A and T status alone. Conclusion Using a robust norms approach, we show that abnormal AD-related neurodegeneration can be detected among cognitively unimpaired individuals. Metrics derived from diffusion-weighted imaging are potential sensitive markers of N and could be considered for trial enrichment and as outcomes in clinical trials. However, given the small sample sizes, the exploratory nature of the work must be acknowledged.

In this study, a variety of machine-learning algorithms are used to predict the viscosity and thermal conductivity of several water-based nanofluids. Machine learning algorithms, namely decision tree, random forest, extra tree, KNN, and polynomial regression, have been used, and their performances have been compared. The input parameters for the prediction of the thermal conductivity of nanofluids include temperature, concentration, and the thermal conductivity of nanoparticles. A three-input and a two-input model were utilized in modelling the viscosity of nanofluid. Both models considered temperature and concentration as input parameters, and additionally, the type of nanoparticle was considered for the three-input model. The order of importance of the most influential parameters in predicting both viscosity and thermal conductivity was studied. A wider range of input parameters have been considered in an open-access database. With the existing experimental data, all of the developed machine learning models exhibit reasonable agreement. Extra trees were found to provide the best results for estimating thermal conductivity, with a value of 0.9403. In predicting viscosity using a three-input model, extra trees were found to provide the best result with a value of 0.9771, and decision trees were found to provide the best results for estimating the viscosity using a two-input model with a value of 0.9678. In order to study heat transport phenomena through mathematical modelling, it is important to have an explicit mathematical expression. Therefore, the formulation of mathematical expressions for predicting viscosity and thermal conductivity has been carried out. Additionally, a comparison with the Xue and Maxwell thermal conductivity models is made to validate the results of this study, and the results are observed to be reliable.

Introduction: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer globally and the seventh most common cause of cancer-related mortality. Tobacco use, alcohol consumption, and Human Papillomavirus (HPV) infection are prominent risk factors for HNSCC. HPVpositive Oral Squamous Cell Carcinoma (OSCC) differs from HPV-negative OSCC in terms of risk factors, preferential site of origin, age, histomorphological features, molecular genetic alterations, and prognosis. The prominent basaloid morphology and lobular growth of OSCCs are associated with p16 positivity and p53 negativity, respectively. Aim: To establish the immunohistochemical expression of p16 (p16INK4a) and p53 in OSCC and to assess their relationship with specific histomorphological features, in the form of solid growth of cells in a lobular configuration, small crowded cells with scant cytoplasm, dark hyperchromatic nuclei without nucleoli. Materials and Methods: The cross-sectional study involved fifty cases of OSCC over a two-year period from January 2017 to January 2019 at Army Hospital (R and R) Delhi Cantt. The intensity of p16 and p53 protein expression was graded as follows: no staining (0), weak staining (1), moderate staining (2), and strong staining (3). The proportion/percentage of staining for p16 and p53 protein expression was calculated as follows: 1-4% (1), 5-19% (2), 20-39% (3), 40-59% (4), 60-79% (5), and 80-100% (6) cells stained. A quick score of 0-1 (negative), 2-3 (weak positive), 4-5 (moderate positive), and >6 (strong positive) was assessed. Cross tables were generated and the Chi-square test was used for testing associations. The Statistical Software for Data Science (STATA)-14 was used for statistical analysis. Results: A total of 50 cases of OSCC were analysed for histomorphological features and immunohistochemical patterns of p16 and p53. The age distribution showed that 8 (16%), 9 (18%), 18 (36%), 13 (26%), and 2 (4%) of the patients were in the age groups of 31-40 years, 41-50 years, 51-60 years, 61-70 years, and above 70 years, respectively. The gender distribution noted 42 (84%) males and 8 (16%) females. Genital and nongenital mucosa are usually involved by HPV subtypes 6, 11, 16, 18, and 16, 18, 11, 13, 2, respectively. HPV-16 has been demonstrated in 90-95% of all HPV-positive HNSCC cases, followed by HPV-18, HPV-31, and HPV-33. p53 is considered the guardian of the genome and controls the expression and activity of proteins involved in cell cycle regulation, DNA repair, cellular senescence, and apoptosis. More than 50% of all primary HNSCC exhibit p53 mutation. Conclusion: A significant correlation was observed between age, dysplasia, keratinisation, basaloid morphology versus p16 expression, and lobular growth, histological grade versus p53. An inverse relationship between p16 and p53 expressions was observed. The immunohistochemical expression of p16 as an immunohistochemical marker of HPV, along with p53, is recommended. Due to the constraint of the study period, the survival of the patients could not be assessed in correlation with p16 and p53 expression.

Background: During the past 20 years, numerous publications have described the usefulness of systolic pressure variation, pulse pressure variation, stroke volume variation, etc., to guide intraoperative fluid administration. However, we still lack robust noninvasive physiological variables to successfully predict the response to fluid loading. Aims and Objectives: The present study was designed to evaluate the utility of plethysmography variability index (PVI) to optimize fluid management during intra-abdominal surgery in cancer patients. Materials and Methods: After the Institutional Ethics Committee approval and consent, 60 patients scheduled for elective lower abdominal cancer surgeries were randomized to receive fluid by either PVI-directed management (2 mL/kg/h) or using central venous pressure (8 mL/kg/h) after standardized technique of general and lumbar epidural anesthesia. The PVI was calculated by measuring changes in the PI during the respiratory cycle (PVI = [(PImax - PImin)/PImax] × 100). Arterial blood samples were taken at the time of incision and after 6 h postoperatively. Instances of intraoperative hypotension and oliguria were recorded. Results: Among the 60 patients enrolled in the study, demographic data, ASA status, duration of surgery, and hemodynamics were found to be comparable. The amount of crystalloid given was significantly lesser in Group P (984.70±51.16) as compared to Group C (2395.27±209.68) (P

BackgroundKlotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease.ObjectiveTest whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors.MethodsCirculating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics.ResultsSerum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF.ConclusionIn a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

IntroductionDementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes.MethodsTrajectories of change in memory and executive function (N = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aβ)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.ResultsMemory and executive function declined (p's ≤ 0.001) and CSF t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42 levels increased (all p's ≤ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03).DiscussionKL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

The high overlapping nature of various features across multiple mental health disorders suggests the existence of common psychopathology factor(s) (p-factors) that mediate similar phenotypic presentations across distinct but relatable disorders. In this perspective, we argue that circadian rhythm disruption (CRD) is a common underlying p-factor that bridges across mental health disorders within their age and sex contexts. We present and analyze evidence from the literature for the critical roles circadian rhythmicity plays in regulating mental, emotional, and behavioral functions throughout the lifespan. A review of the literature shows that coarse CRD, such as sleep disruption, is prevalent in all mental health disorders at the level of etiological and pathophysiological mechanisms and clinical phenotypical manifestations. Finally, we discuss the subtle interplay of CRD with sex in relation to these disorders across different stages of life. Our perspective highlights the need to shift investigations towards molecular levels, for instance, by using spatiotemporal circadian "omic" studies in animal models to identify the complex and causal relationships between CRD and mental health disorders.

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene expression.

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes.

The COVID-19 pandemic may profoundly harm the mental health and emotional well- being of many older adults. Public health interventions to minimize the spread of the virus have had the unintended consequences of worsening social isolation, financial stress, and unemployment. Results of early research efforts assessing the impact of these interventions on the mental health of older adults have been mixed. Available findings suggest that a subset of community-dwelling older adults have been less negatively impacted than younger adults, while people of color, the poor, residents of nursing homes and other communal living environments, and those living with dementia and their caregivers are more likely to suffer from COVID-related health problems. This manuscript describes two older adults for whom COVID-19 associated stresses caused significant worsening in their psychiatric illnesses, including the emergence of suicidal ideation, summarizes the literature on the impact of interactions between psychosocial stresses and biological factors on the mental health and well-being of older adults, and discusses interventions to help older adults whose mental health has worsened due to COVID-19. Timely and accurate diagnosis, prompt provision of individualized care using both pharmacologic and psychotherapeutic interventions, adoption of new technologies that permit care to be provided safely at a distance and which allow for virtual social interactions, coupled with ongoing advocacy for policy changes that address significant health care disparities and provide older adults continued access to health care and relief from financial hardship, will help older adults remaining as healthy as possible during the pandemic.

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

Abstract A prompt and modular copper(I)-catalyzed azide–alkyne cycloaddition ʼclickʼ approach has been exploited for the synthesis of galactose- and mannose-coated calixarene-cored G1 generation glycodendrimers. The developed calixarene glycodendrimers were characterized by using spectral techniques (1H NMR, 13C NMR and IR). In photophysical evaluation, UV and fluorescence spectra of the developed compounds were recorded in CH3CN/H2O.

The ability to both sensitively and specifically assess the sequence composition of a nucleic acid strand is an ever-growing field. Designing a detection scheme that can perform this function when the sequence of the target being detected deviates significantly from the canonical sequence however is difficult in part because probe/primer design is based on established Watson-Crick base-pairing rules. We present here a robust and tunable toehold-based exchange probe that can detect a sequence with a variable number of SNPs of unknown identity by inserting a series of controlled, sequential mismatches into the protector seal of the toehold probe, in an effort to make the protector seal "sloppy". We show that the mismatch-tolerant system follows predicted behavior closely even with targets containing up to four mismatches that thermodynamically deviate from the canonical sequence by up to 15 kcal/mole. The system also performs faithfully regardless of the global mismatch position on either the protector seal or target. Lastly, we demonstrate the generalizability of the approach by testing the increasingly mismatch-tolerant protectors on HIV clinical samples to show that the system is capable of resolving multiple, iteratively mutated sequences derived from numerous HIV sub-populations with remarkable precision.

In several research studies, the reactivation extinction paradigm did not effectively prevent the return of fear if administered without any intervention technique. Therefore, in this study, the authors hypothesized that playing music (high valence, low arousal) during the reconsolidation window may be a viable intervention technique for eliminating fear-related responses. A three-day auditory differential fear conditioning paradigm was used to establish fear conditioning. Participants were randomly assigned into three groups, i.e., one control group, standard extinction (SE), and two experimental groups, reactivation extinction Group (RE) and music reactivation extinction (MRE), of twenty participants in each group. Day 1 included the habituation and fear acquisition phases; on Day 2 (after 24 hours), the intervention was conducted, and re-extinction took place on Day 3. Skin conductance responses were used as the primary outcome measure. Results indicated that the MRE group was more effective in reducing fear response than the RE and SE groups in the re-extinction phase. Furthermore, there was no significant difference observed between SE and RE groups. This is the first study known to demonstrate the effectiveness of music intervention in preventing the return of fear in a healthy individual. Therefore, it might also be employed as an intervention strategy (non-pharmacological approach) for military veterans, in emotion regulation, those diagnosed with post-traumatic stress disorder, and those suffering from specific phobias.

Objectives Health and care resources are under increasing pressure, partly due to the ageing population. Physical activity supports healthy ageing, but motivating exercise is challenging. We aimed to explore staff perceptions towards a virtual reality (VR) omnidirectional treadmill (MOTUS), aimed at increasing physical activity for older adult care home residents.Design Interactive workshops and qualitative evaluation.Settings Eight interactive workshops were held at six care homes and two university sites across Cornwall, England, from September to November 2021.Participants Forty-four staff participated, including care home, supported living, clinical care and compliance managers, carers, activity coordinators, occupational therapists and physiotherapists.Interventions Participants tried the VR treadmill system, followed by focus groups exploring device design, potential usefulness or barriers for care home residents. Focus groups were audio-recorded, transcribed verbatim and thematically analysed. We subsequently conducted a follow-up interview with the technology developer (September 2022) to explore the feedback impact.Results The analysis produced seven key themes: anticipated benefits, acceptability, concerns of use, concerns of negative effects, suitability/unsuitability, improvements and current design. Participants were generally positive towards VR to motivate care home residents’ physical activity and noted several potential benefits (increased exercise, stimulation, social interaction and rehabilitation). Despite the reported potential, staff had safety concerns for frail older residents due to their standing position. Participants suggested design improvements to enhance safety, usability and accessibility. Feedback to the designers resulted in the development of a new seated VR treadmill to address concerns about falls while maintaining motivation to exercise. The follow-up developer interview identified significant value in academia–industry collaboration.Conclusion The use of VR-motivated exercise holds the potential to increase exercise, encourage reminiscence and promote meaningful activity for care home residents. Staff concerns resulted in a redesigned seated treadmill for those too frail to use the standing version. This novel study demonstrates the importance of stakeholder feedback in product design.

Abstract Background Insulin resistance (IR) and type 2 diabetes have been found to increase the risk for Alzheimer’s clinical syndrome in epidemiologic studies but have not been associated with tau tangles in neuropathological research and have been inconsistently associated with cerebrospinal fluid P-tau181. IR and type 2 diabetes are well-recognized vascular risk factors. Some studies suggest that cardiovascular risk may act synergistically with cortical amyloid to increase tau measured using tau PET. Utilizing data from largely nondemented middle-aged and older adult cohorts enriched for AD risk, we investigated the association of IR and diabetes to tau PET and whether amyloid moderated those relationships. Methods Participants were enrolled in either the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or Wisconsin Alzheimer’s Disease Research Center (WI-ADRC) Clinical Core. Two partially overlapping samples were studied: a sample characterized using HOMA-IR (n=280 WRAP participants) and a sample characterized on diabetic status (n=285 WRAP and n=109 WI-ADRC). IR was measured using the homeostasis model assessment of insulin resistance (HOMA-IR). Tau PET employing the radioligand 18F-MK-6240 was used to detect AD-specific aggregated tau. Linear regression tested the relationship of IR and diabetic status to tau PET standardized uptake value ratio (SUVR) within the entorhinal cortex and whether relationships were moderated by amyloid assessed by amyloid PET distribution volume ratio (DVR) and amyloid PET positivity status. Results Neither HOMA-IR nor diabetic status was significantly associated with tau PET SUVR. The relationship between IR and tau PET SUVR was not moderated by amyloid PET DVR or positivity status. The association between diabetic status and tau PET SUVR was not significantly moderated by amyloid PET DVR but was significantly moderated by amyloid PET positivity status. Among the amyloid PET-positive participants, the estimated marginal tau PET SUVR mean was higher in the diabetic (n=6) relative to the nondiabetic group (n=88). Conclusion Findings indicate that IR may not be related to tau in generally healthy middle-aged and older adults who are in the early stages of the AD clinicopathologic continuum but suggest the need for additional research to investigate whether a synergistic relationship between type 2 diabetes and amyloid is associated with increased tau levels.

Abstract Near-term quantum communication protocols suffer inevitably from channel noises, whose alleviation has been mostly attempted with resources such as multiparty entanglement or sophisticated experimental techniques. Generation of multiparty higher dimensional entanglement is not easy. This calls for exploring realistic solutions which are implementable with current devices. Motivated particularly by the difficulty in generation of multiparty entangled states, in this paper, we have investigated error-free information transfer with minimal requirements. For this, we have proposed a new information encoding scheme for communication purposes. The encoding scheme is based on the fact that most noisy channels leave some quantities invariant. Armed with this fact, we encode information in these invariants. These invariants are functions of expectation values of operators. This information passes through the noisy channel unchanged. Pertinently, this approach is not in conflict with other existing error correction schemes. In fact, we have shown how standard quantum error-correcting codes emerge if suitable restrictions are imposed on the choices of logical basis states. As applications, for illustration, we propose a quantum key distribution protocol and an error-immune information transfer protocol.