Search

CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca2+-NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in CRACR2A [paternal allele c.834 gaG> gaT (p.E278D) and maternal alelle c.430 Aga > Gga (p.R144G) c.898 Gag> Tag (p.E300*)], the gene encoding CRACR2A. The 33-year-old patient of East-Asian origin exhibited late onset combined immunodeficiency characterised by recurrent chest infections, panhypogammaglobulinemia and CD4+ T cell lymphopenia. In vitro exposure of patient B cells to a T-dependent stimulus resulted in normal generation of antibody-secreting cells, however the patient's T cells showed pronounced reduction in CRACR2A protein levels and reduced proximal TCR signaling, including dampened SOCE and reduced JNK phosphorylation, that contributed to a defect in proliferation and cytokine production. Expression of individual allelic mutants in CRACR2A-deleted T cells showed that the CRACR2AE278D mutant did not affect JNK phosphorylation, but impaired SOCE which resulted in reduced cytokine production. The truncated double mutant CRACR2AR144G/E300* showed a pronounced defect in JNK phosphorylation as well as SOCE and strong impairment in cytokine production. Thus, we have identified variants in CRACR2A that led to late-stage combined immunodeficiency characterized by loss of function in T cells.

The purpose of this study was to determine whether university students with physical disabilities (SWD) gained similar benefits from recreational physical activity participation as able-bodied (AB) university students as reported in the literature. Researchers designed an inclusive, university-offered aquatic exercise class for SWD. Six SWD volunteered for participation and six SWD volunteered for the control group. Quantitative survey measures were used to compare group changes in exercise self-efficacy, quality of life, and social inclusion following the five-week testing period. Qualitative interviews were used to explore the experiences of intervention participants. Independent t-tests revealed no significant differences in pre/post changes between groups, however thematic analysis of qualitative interviews indicated intervention participants perceived numerous positive outcomes and experiences resulted from the intervention, very similar to those found in AB university students. Results from this study provide important information on participant experiences, outcomes, and assist in future recommendations for recreational physical activity for SWD.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.

Background: Functional assessments easy to administer within the clinic to identify non-ambulatory individuals with spinal cord injury at risk of recurrent falls are needed. Purpose: To examine the ability of functional balance and transfer quality to predict recurrent falls. Methods: This 6-month prospective study examined remote assessments of transfer quality using the Transfer Assessment Instrument and functional sitting balance with the Function in Sitting Test and the Trunk Control Test. Then, participants prospectively monitored their falls for 6-month using fall diaries. Frequency of falls was categorized as infrequent fallers (≤2 falls) and recurrent fallers (>2 falls). A multivariable logistic regression analysis was conducted. A Receiver Operating Characteristic curve was performed to determine the area under the curve, the sensitivity, and the specificity of the model. Results: Eighteen non-ambulatory individuals (mean age = 44 ± 16 years, mean time since injury = 7.8 ± 32.6 years) participated in the study. Poor balance (lower Function in Sitting Test score) was associated with higher odds of future recurrent falls (Odds Ratio = 0.70, 95% CI, 0.48 to 1.00, p = 0.05), area under the receiving operating curve = 0.87, sensitivity = 88%, and specificity = 70%. Conclusions: A comprehensive sitting balance assessment that includes the static, proactive, and reactive components of balance with the integration of sensorial functions as evaluated within the Function in Sitting Test may be useful for predicting recurrent falls among non-ambulatory individuals with spinal cord injury. Replication of the findings in a larger sample is warranted. [ABSTRACT FROM AUTHOR]

Recent research has highlighted cerebellar involvement in cognition and several psychiatric conditions such as mood and anxiety disorders and schizophrenia. Attention‐deficit/hyperactivity disorder and autism spectrum disorder have been linked to reduced cerebellar volume as well. Cerebellar alterations are frequently present after early adversity in humans and animals, but a systematic integration of results is lacking. To this end, a systematic literature search was conducted in PubMed, Web of Science, and EBSCO databases using the keywords "early adversity OR early life stress" AND "cerebellum OR cerebellar." A total of 45 publications met the inclusion criteria: 25 studies investigated human subjects and 20 reported results from animal models. Findings in healthy subjects show bilateral volume reduction and decreased functional connectivity within the cerebellum and between the cerebellum and frontal regions after adversity throughout life, especially when adversity was assessed with the Childhood Trauma Questionnaire. In clinical populations, adults demonstrate increased cerebellar volume and functional connectivity after adversity, whereas pediatric patients show reduced cerebellar volume. Animal findings reveal cerebellar alterations without necessarily co‐occurring pathological behavior, highlighting alterations in stress hormone receptor levels, cell density, and neuroinflammation markers. Cerebellar alterations after early adversity are robust findings across human and animal studies and occur independent of clinical symptoms. [ABSTRACT FROM AUTHOR]

Background: Falls are prevalent among people living with Multiple Sclerosis (PwMS) and Spinal Cord Injury (PwSCI) who use wheelchairs or scooters (WC/S) full time, however, there is a scarcity of evidence-based fall prevention and management programs. Objective: To describe the systematic translation of an in-person fall prevention and management program (Individualized Reduction Of FaLLs - iROLL) for PwMS to an online platform, extending its scope to include PwSCI, and to evaluate the preliminary useability, usefulness, and safety of the intervention. Methods: iROLL was systematically translated to an online platform (iROLL-O). PwMS and PwSCI who use a WC/S full time, experienced at least one fall within the past 36 months, and could transfer independently or with minimal to moderate assistance, enrolled in iROLL-O. Usability, usefulness, and safety were evaluated through 1:1 semi-structured interviews, gathering feedback on: perceived impact of the intervention on falls and functional mobility, program experiences, adverse events, and recommendations for improvement. Results: Five participants successfully completed the iROLL-O program. No safety concerns were raised by participants. Themes emerging from the semistructured interviews included: (1) barriers and facilitators to program access, (2) motivation for participation, (3) program outcomes, and (4) program content and structure. Participants reported reduced concerns about falling, enhanced functional mobility skills, and highlighted the supportive nature of synchronous group meetings for learning. Conclusion: No adverse events occurred during the implementation of iROLL-O and participants found the program to be useable and useful. Further testing is needed to examine efficacy among a large and diverse population. [ABSTRACT FROM AUTHOR]

Colleges of agriculture in the US have been challenged to produce candidates prepared with the knowledge, skills, and disposition to engage in a global agricultural industry. Studies show that one of the most influential factors in secondary student perceptions and outlook is their secondary teachers. The adult learning theory of transformative learning by Mezirow indicates a process of making a new or revised interpretation of the meaning of an experience, which guides subsequent understanding, appreciation, and action that is anchored in life experience. To have the most impact, experiences should be grounded in a context that students can relate. Nineteen teacher candidates participated in a course with a short term study abroad component that was grounded in global school-based agricultural education. Students were administered a researcher-developed instrument measuring knowledge, skills and dispositions of global competency three times: round I -prior to the course, round II -after the course prior to the travel experience, and round III after the travel experience. Findings indicated substantial, sustained change in the candidate knowledge, candidate perceptions of knowledge, candidate perceptions of skills, and candidate perceptions of dispositions related to global competency. Further research is recommended to measure impact on practice in the secondary agriscience classroom.

Lack of disability awareness of fitness professionals is a well-established barrier to exercise participation among people with disabilities that is likely related to the lack of disability awareness training for group fitness instructors. The purposes of this study were to develop, implement, and evaluate a disability awareness training for group fitness instructors. A 90-min video training and resource manual were developed. We recruited 10 group fitness instructors from one recreation center to participate. Participants completed baseline, posttraining, and 2-month follow-up testing on survey-based outcomes including disability attitudes, confidence in exercise adaptations, and training satisfaction. Participants' confidence to adapt fitness classes was significantly improved; however, disability attitudes were high in the pretest and not significantly different posttraining. Semistructured interviews were conducted posttraining and revealed three themes: Formal disability training is needed, Managing inclusive class dynamics, and Training suggestions and satisfaction. This training demonstrated a feasible intervention for increasing disability awareness among community-based group fitness instructors. [ABSTRACT FROM AUTHOR]

To examine the differences in demographics, fear of falling (FOF), transfer quality and participation enfranchisement between manual and power wheelchair users with multiple sclerosis (MS) and spinal cord injury (SCI). Secondary data analysis including 126 manual or power wheelchair users with MS and SCI (median age, 53.00 years, IQR = 24.00). Demographic information including age, gender, height, weight and disability duration was collected. Body mass index (BMI) was calculated for all participants. Participation enfranchisement was examined using both subscales (Importance and Control) of the enfranchisement scale of the Community Participation Indicator (CPI). FOF was assessed using the Spinal Cord Injury-Falls Concern Scale (SCI-FCS) and transfer quality was assessed using the Transfer Assessment Instrument (TAI) 3.0 and 4.0. Mann–Whitney's U-tests or independent samples t-tests and chi-square were used to analyse the differences between continuous variables and categorical variables, respectively. Fifty-seven percent of participants were manual wheelchair users. There were significant differences in most demographic information except for weight and disability duration. Significant differences were also found for BMI (t = 1.06, p = 0.04), CPI-Importance (U = 1282.50, p < 0.01), CPI-Control (U = 1165.50, p < 0.01) and SCI-FCS (t = 4.08, p < 0.01). Manual wheelchair users outperformed power wheelchair users in all outcomes analysed except the TAI (p = 0.18). Power wheelchairs users presented with a higher BMI, reported lower participation enfranchisement, and reported higher levels of FOF compared to manual wheelchair users. The findings may help clinicians to develop targeted rehabilitation goals specific for power and manual wheelchair users with MS and SCI. Significant functional differences exist between manual and power wheelchair users. Compared to manual wheelchair users, power wheelchair users had higher body mass index, reported lower community participation and reported higher levels of fear of falling. These findings can help clinicians to develop targeted interventions specific for power and manual wheelchair users. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD‐relevant functional networks. The goal of this study is to compare resting‐state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro‐cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN). Methods: Twenty‐eight participants completed a resting‐state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole‐brain approach, was used to identify regions with significant differences in FC between groups. Seed‐based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance. Results: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro‐cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST. Conclusions: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long‐term heavy drinking alters cerebro‐cerebellar FC, particularly within networks that are involved in executive function. [ABSTRACT FROM AUTHOR]

Gait and balance impairments are associated with falls and reduced quality of life among survivors of stroke (SS). Effective methods to assess these impairments at-home and in-clinic can help reduce fall risks and improve functional outcomes. Smartphone technology may be able to evaluate these impairments. This review aims to summarize the validity, reliability, sensitivity, and specificity of smartphone applications for determining gait and balance disorders in SS. Database search through PubMed, Web of Science, Scopus, CINAHL, and SportDiscuss was conducted to retrieve studies that explored the use of smartphone-based applications for assessing gait and balance disorders in SS. Two independent reviewers screened potential articles to determine eligibility for inclusion. Eligible studies were summarized for participant and study characteristics, validity, reliability, sensitivity, and specificity of smartphone assessments. Methodological quality assessment of studies was performed using the NIH Quality Assessment Tool. Seven cross-sectional studies were included in the review. Quality assessment revealed all studies had low risk of bias. Three of the included studies examined the validity, four examined the reliability, and two examined the specificity and sensitivity of smartphone-based application assessments of gait and balance in SS. Studies revealed that smartphones were valid, reliable, specific, and sensitive. Six of the seven included studies intended their use for SS and one study for clinicians. Preliminary evidence supports that smartphone-based gait and balance assessments are valid, reliable, sensitive, and specific in SS in laboratory settings. Future research is needed to test smartphone-based gait and balance assessments in home settings and determine optimal wear sites for assessments. Smartphone-based gait and balance assessments are feasible, valid and reliable for survivors of stroke The findings may guide future research to standardize the use of smartphone to assess gait and balance in this population. The remote use of smartphone-based assessments to predict fall risk in survivors of stroke needs to be explored. [ABSTRACT FROM AUTHOR]