Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia.

We performed a comprehensive study of the morphological, functional, and genetic features of moonwalker (MWK) mice, a mouse model of spinocerebellar ataxia caused by a gain of function of the TRPC3 channel. These mice show numerous behavioral symptoms including tremor, altered gait, circling behavior, impaired motor coordination, impaired motor learning and decreased limb strength. Cerebellar pathology is characterized by early and almost complete loss of unipolar brush cells as well as slowly progressive, moderate loss of Purkinje cell (PCs). Structural damage also includes loss of synaptic contacts from parallel fibers, swollen ER structures, and degenerating axons. Interestingly, no obvious correlation was observed between PC loss and severity of the symptoms, as the phenotype stabilizes around 2 months of age, while the cerebellar pathology is progressive. This is probably due to the fact that PC function is severely impaired much earlier than the appearance of PC loss. Indeed, PC firing is already impaired in 3 weeks old mice. An interesting feature of the MWK pathology that still remains to be explained consists in a strong lobule selectivity of the PC loss, which is puzzling considering that TRPC is expressed in every PC. Intriguingly, genetic analysis of MWK cerebella shows, among other alterations, changes in the expression of both apoptosis inducing and resistance factors possibly suggesting that damaged PCs initiate specific cellular pathways that protect them from overt cell loss.

Life cycle exposure to titanium dioxide nanoparticles (TiO2-NPs) induces filial toxicity and population decline in the nematode Caenorhabditis elegans.

Titanium dioxide nanoparticle (TiO2-NP) exposure has raised significant concern due to their potential toxicity and adverse ecological impacts. Despite their ubiquitous presence in various environmental compartments, the long-term consequences of TiO2-NPs remain poorly understood. In this study, we combined data of in vivo toxicity and modeling to investigate the potential negative impacts of TiO2-NP exposure. We employed the nematode Caenorhabditis elegans, an environmental organism, to conduct a full life cycle TiO2-NP toxicity assays. Moreover, to assess the potential impact of TiO2-NP toxicity on population dynamics, we applied a stage-constructed matrix population model (MPM). Results showed that TiO2-NPs caused significant reductions in reproduction, survival, and growth of parental C. elegans (P0) at the examined concentrations. Moreover, these toxic effects were even more pronounced in the subsequent generation (F1) when exposed to TiO2-NPs. Furthermore, parental TiO2-NP exposure resulted in significant toxicity in non-exposed C. elegans progeny (TiO2-NPs free), adversely affecting their reproduction, survival, and growth. MPM analysis revealed decreased transition probabilities of surviving (Pi), growth (Gi), and fertility (Fi) in scenarios with TiO2-NP exposure. Additionally, the population growth rate (λmax) was found to be less than 1 in both P0 and F1, indicating a declining population trend after successive generations. Sensitivity analysis pinpointed L1 larvae as the most vulnerable stage, significantly contributing to the observed population decline in both P0 and F1 generations under TiO2-NP exposure. Our findings provide insight into the potential risk of an environmental organism like nematode by life cycle exposure to TiO2-NPs.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

The Effect of Social Robots on Depression and Loneliness for Older Residents in Long-Term Care Facilities: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Depression and loneliness are challenges facing older residents living in long-term care facilities. Social robots might be a solution as nonpharmacologic interventions. The purpose of this study was to explore the effects of concrete forms of social robots on depression and loneliness in older residents in long-term care facilities by a systematic review and meta-analysis of randomized controlled trials. DESIGN: This is a systematic review and meta-analysis. SETTING AND PARTICIPANTS: Older residents in long-term care facilities. METHODS: Six electronic databases of PubMed, Embase, Scopus, Web of Science, MEDLINE, and CINAHL plus were searched in August 2023. Random effect models of meta-analyses, subgroup analyses, and meta-regressions were performed for statistical analyses. RESULTS: After evaluation, 8 studies were selected for both qualitative and quantitative synthesis. Social robot interventions had significant positive effects on decreasing depression and loneliness with large effect sizes. Group-based robot activities had a better effect on improving depression than individual-based robot activities. Longer durations of interventions produced significantly more improvement in depression. CONCLUSION AND IMPLICATION: Social robots with physical manifestation provide the opportunity for older adults' social engagement and interactions with robots and others. Social robot interventions are recommended for older residents in long-term care facilities to promote psychosocial well-being in daily care routines.

Actual and Virtual Parks Benefit Quality of Life and Physical Activity: A Cluster Trial.

Urban parks provide connectedness to nature as a health resilience environment for promoting health. Virtual reality can provide opportunities for urban citizens to be exposed to natural elements with health benefits. The purpose was to explore the effects of actual and virtual parks on the quality of life and physical activity of urban residents. The study design was a cluster trial. Participants were healthy adults aged 20-50 years, recruited from three college campuses, and randomly assigned to two experimental groups (n = 30, 32) and one control group (n = 30). The intervention with virtual or actual parks was conducted for 30 min a session once a week for 12 weeks. Outcomes were measured using self-reported questionnaires, including the World Health Organization Quality-of-Life Scale-BREF and International Physical Activity Questionnaire-Short Form. In total, 84 participants completed the interventions and post-intervention measures. Results showed that participants who experienced actual parks had significant increases in the social quality of life and light-intensity physical activity and had decreased body weight. Participants who experienced the virtual parks experienced a significant increase in their mental quality of life. Participants in the experimental groups of both kinds of parks had significant improvements in their self-rated health, physical and environmental quality of life, and sedentary time after the intervention. Urban parks are an important natural resource for citizens' health and physical activity promotion. Virtual parks can simulate actual parks and have similar health benefits and are thus are recommended for citizens who lack opportunities and motivation to go to actual parks.

Dual regulation of cytochrome P450 gene expression by two distinct small RNAs, a novel tasiRNA and miRNA, in Marchantia polymorpha.

The miR390-derived TAS3 trans-acting short-interfering RNAs (tasiRNAs) module represents a conserved RNA silencing pathway in the plant kingdom; however, its characterization in the bryophyte Marchantia polymorpha is limited. This study elucidated that MpDCL4 processes MpTAS3 double-stranded RNA (dsRNA) to generate tasiRNAs, primarily from the 5'- and 3'-ends of dsRNA. Notably, we discovered a novel tasiRNA, tasi78A, can negatively regulate a cytochrome P450 gene, MpCYP78A101. Additionally, tasi78A was abundant in MpAGO1, and transient expression assays underscored the role of tasi78A in repressing MpCYP78A101. A microRNA, miR11700, also regulates MpCYP78A101 expression. This coordinate regulation suggests a role in modulating auxin signaling at apical notches of gemma, influencing the growth and sexual organ development of M. polymorpha and emphasizing the significance of RNA silencing in MpCYP78A101 regulation. However, phylogenetic analysis identified another paralog of the CYP78 family, Mp1g14150, which may have a redundant role with MpCYP78A101, explaining the absence of noticeable morphological changes in loss-of-function plants. Taken together, our findings provide new insights into the combined regulatory roles of miR390/MpTAS3/miR11700 in controlling MpCYP78A101 and expand our knowledge about the biogenesis and regulation of tasiRNAs in M. polymorpha.

Household physical activity and subjective well-being: An international comparison among East Asian older adult populations.

PURPOSE: Engaging in lifelong physical activity has multiple health benefits for older populations. Household physical activity occupies older adults' awake time, and they can be an important energy expenditure during the day. The purpose of this study was to investigate the association between older adults' household physical activity and subjective well-being in four East Asian societies. METHODS: The study design was a secondary data analysis. Data were retrieved from the module of Families 2016 in the database of the East Asian Social Survey. Participants were community-dwelling older adults with a mean age of 70.30±7.50 years and who lived in China, Japan, Korea, and Taiwan. Data were collected by interviews via structured questionnaires between 2016 and 2018. Descriptive analyses, independent t-tests, and an analysis of covariance were performed for the statistical analyses. RESULTS: In total, there were 3,432 valid responses. Participants who lived in Taiwan had significantly lower levels of total household physical activity than those living in other societies. Older adults' household physical activity was found to significantly differ by age, educational degree, gender, religion, marital status, occupation, and whether living alone. Older adults with high levels of household physical activity had significantly higher self-rated health and marital satisfaction than those with low levels. CONCLUSIONS: Household physical activity has potential benefits for subjective well-being across international older adult populations. Increasing household physical activity is recommended for older married couples to maintain marital satisfaction.

Leisure Participation for Mental Health Promotion in Later Life: A Six-Year Longitudinal Study.

Engaging in leisure activities is essential for mental health in older adults. This longitudinal study (n = 1,101, mean age = 69.20 ± 6.23 years at baseline) examined the associations between leisure participation and mental health over 6 years in three waves: 2016, 2018, and 2020. Pearson's correlation analyses and generalized estimating equations were performed for data analyses. The frequency of participation in physical and social activities was significantly positively associated with happiness, life satisfaction, and self-rated health, and significantly negatively associated with depression. Passive activities were significantly positively associated with happiness, life satisfaction, and self-rated health but not with depression. The time effect had no significant association with any mental health outcomes. These findings highlight the importance of leisure activities in promoting mental health among older adults. Policy makers should encourage older adults to engage in physical and social leisure activities.

CBAP regulates the function of Akt-associated TSC protein complexes to modulate mTORC1 signaling.

The Akt-Rheb-mTORC1 pathway plays a crucial role in regulating cell growth, but the mechanisms underlying the activation of Rheb-mTORC1 by Akt remain unclear. In our previous study, we found that CBAP was highly expressed in human T-ALL cells and primary tumors, and its deficiency led to reduced phosphorylation of TSC2/S6K1 signaling proteins as well as impaired cell proliferation and leukemogenicity. We also demonstrated that CBAP was required for Akt-mediated TSC2 phosphorylation in vitro. In response to insulin, CBAP was also necessary for the phosphorylation of TSC2/S6K1 and the dissociation of TSC2 from the lysosomal membrane. Here we report that CBAP interacts with AKT and TSC2, and knockout of CBAP or serum starvation leads to an increase in TSC1 in the Akt/TSC2 immunoprecipitation complexes. Lysosomal-anchored CBAP was found to override serum starvation and promote S6K1 and 4EBP1 phosphorylation and c-Myc expression in a TSC2-dependent manner. Additionally, recombinant CBAP inhibited the GAP activity of TSC2 complexes in vitro, leading to increased Rheb-GTP loading, likely due to the competition between TSC1 and CBAP for binding to the HBD domain of TSC2. Overexpression of the N26 region of CBAP, which is crucial for binding to TSC2, resulted in a decrease in mTORC1 signaling and an increase in TSC1 association with the TSC2/AKT complex, ultimately leading to increased GAP activity toward Rheb and impaired cell proliferation. Thus, we propose that CBAP can modulate the stability of TSC1-TSC2 as well as promote the translocation of TSC1/TSC2 complexes away from lysosomes to regulate Rheb-mTORC1 signaling.

Prevalence of sarcopenia and its association with diet and physical activity in older adults with type 2 diabetes: A cross-sectional study.

This cross-sectional study explored the prevalence of sarcopenia in older adults with type 2 diabetes and investigated the effects of diet and physical activity on sarcopenia. In total, 577 older adults with diabetes were recruited from a teaching hospital in Taiwan. Diet and physical activity were assessed using self-rated questionnaires, including the Healthy Diet Inventory, the Mini Nutritional Assessment-Short Form, and the International Physical Activity Questionnaire-Short Form. Sarcopenia was defined in accordance with the Asian Working Group for Sarcopenia 2019 guidelines. In total, 51.12% of participants had either possible sarcopenia, sarcopenia, or severe sarcopenia. Participants who were female, old age, prolonged sedentary times, poor nutritional status, and lower level of moderate-to-vigorous physical activity were identified as risk factors for possible to severe sarcopenia. Older adults with diabetes and possible to severe sarcopenia had poor nutrition status and engaged in inadequate physical activity. The findings indicate that sarcopenia may be related to nutrition status and physical activity, especially in older adults with diabetes.

RAD51 paralogs synergize with RAD51 to protect reversed forks from cellular nucleases.

Fork reversal is a conserved mechanism to prevent stalled replication forks from collapsing. Formation and protection of reversed forks are two crucial steps in ensuring fork integrity and stability. Five RAD51 paralogs, namely, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which share sequence and structural similarity to the recombinase RAD51, play poorly defined mechanistic roles in these processes. Here, using purified BCDX2 (RAD51BCD-XRCC2) and CX3 (RAD51C-XRCC3) complexes and in vitro reconstituted biochemical systems, we mechanistically dissect their functions in forming and protecting reversed forks. We show that both RAD51 paralog complexes lack fork reversal activities. Whereas CX3 exhibits modest fork protection activity, BCDX2 significantly synergizes with RAD51 to protect DNA against attack by the nucleases MRE11 and EXO1. DNA protection is contingent upon the ability of RAD51 to form a functional nucleoprotein filament on DNA. Collectively, our results provide evidence for a hitherto unknown function of RAD51 paralogs in synergizing with RAD51 nucleoprotein filament to prevent degradation of stressed replication forks.

Atypical Presentation of Klebsiella pneumoniae Necrotizing Fasciitis of the Lower Extremities: Silent but Deadly: A Case Report.

CASE: There has been an emerging trend of Klebsiella pneumoniae necrotizing fasciitis (KP-NF). We report a 50-year-old Chinese woman with rapidly progressive KP-NF, presenting atypically with innocuous skin symptoms. She had newly diagnosed diabetes mellitus. She had extensive subcutaneous crepitus in her lower limbs with subcutaneous gas on x-rays. Despite aggressive surgical debridement, she succumbed to septic shock and multiorgan failure. CONCLUSION: KP-NF is an emerging clinical entity and is associated with a compromised host immunity and high mortality rates. Clinicians must be aware that not all may present with the typical fulminant features and should maintain a high index of suspicion.

Associations between older adults' social media use behaviors and psychosocial well-being.

BACKGROUND: Research examining associations between social media use behaviors and psychosocial well-being among older adults are limited. AIMS: To explore associations between older adults' social media (social networking services and instant messaging applications) use behaviors and psychosocial well-being. METHODS: This was a secondary data analysis. All data were retrieved from the Taiwan Communication Survey database, an annual survey that examines trends in Taiwanese residents' communication behaviors and social media use. The original investigation was conducted in Taiwan from September to December 2019. Data from 647 older adults aged over 60 years were extracted for the analyses. Social media use behaviors (users/non-users and time spent using), positive psychosocial outcomes (life satisfaction, self-determination, subjective well-being, and happiness), negative psychosocial outcomes (loneliness, depression, and anxiety), and demographic variables were included. RESULTS: Social media users had significantly higher levels of subjective well-being and lower levels of depression, anxiety, and loneliness compared with non-users. Time spent on social networking services was significantly and positively correlated with negative psychosocial outcomes (ß = 0.103, p = 0.044, f2 = 0.011), and it was significantly and inversely correlated with positive psychosocial outcomes (ß = - 0.063, p = 0.049, f2 = 0.004). Time spent using an instant messaging application was significantly positively associated with positive psychosocial outcomes (ß = 0.068, p = 0.031, f2 = 0.005). The proposed path model had an acceptable model fit. DISCUSSION: Study results indicated that older adults' social media use behaviors were associated with their psychosocial well-being. CONCLUSIONS: Older adults are recommended to use social media for appropriate time periods as an important way to promote social engagement for their psychosocial well-being.

Health comparisons between active and inactive transport modes in urban adults with chronic conditions: A cross-sectional study.

An active transport mode provides an opportunity for integrating physical activity into one's daily life through walking, cycling, and the use of public transportation. The purpose of this study was to compare urban adults with chronic conditions who used active and inactive transport modes and to find differences in their health outcomes. A cross-sectional study was conducted from September 2019 to May 2020. Participants were urban adults who self-reported being overweight or obese, or having a diagnosis of chronic disease. Anonymous structured self-reported questionnaires were used for data collection, including the World Health Organization Quality-of-Life Scale, International Physical Activity Questionnaire Short-Form, and the frequency of eight modes of transportation. According to differences between the frequency score of weekly active and inactive transportation, participants were categorized into inactive, balanced, and active transport modes. In total, 617 valid responses were obtained. Participants who engaged in an active transport mode were found to have significantly less sedentary time, and better comprehensive, social, and environmental aspects of quality of life than those with an inactive transport mode. Engaging in active transportation and avoiding inactive transportation are recommended for urban adults with chronic diseases.

Infrared Multiphoton Dissociation Enables Top-Down Characterization of Membrane Protein Complexes and G Protein-Coupled Receptors.

Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical limit to the amount of energy which can be applied, which often precludes subsequent characterization by top-down MS. To overcome this barrier, we have applied a modified Orbitrap Eclipse Tribrid mass spectrometer coupled to an infrared laser within a high-pressure linear ion trap. We show how tuning the intensity and time of incident photons enables liberation of membrane proteins from detergent micelles. Specifically, we relate the ease of micelle removal to the infrared absorption of detergents in both condensed and gas phases. Top-down MS via infrared multiphoton dissociation (IRMPD), results in good sequence coverage enabling unambiguous identification of membrane proteins and their complexes. By contrasting and comparing the fragmentation patterns of the ammonia channel with two class A GPCRs, we identify successive cleavage of adjacent amino acids within transmembrane domains. Using gas-phase molecular dynamics simulations, we show that areas prone to fragmentation maintain aspects of protein structure at increasing temperatures. Altogether, we propose a rationale to explain why and where in the protein fragment ions are generated.

White Cord Syndrome: A Treatment Dilemma.

Spinal cord reperfusion injury following decompressive surgery is extremely rare. This complication is known as white cord syndrome (WCS). A 61-year-old male presented with chronic neck stiffness associated with left C6/C7 radiculopathy and numbness. Magnetic resonance imaging (MRI) of the cervical spine reported a severely narrowed left C6/C7 neural exit canal. C6/C7 anterior cervical decompression and fusion (ACDF) was performed. There was no significant intraoperative injury. On postoperative day 6, the patient developed bilateral C8 numbness, which started post-operation. He was treated for surgical site inflammation and was prescribed prednisolone and amitriptyline. However, his condition progressively worsened. At postoperative six weeks, there was right hemisensory loss, right triceps atrophy, and positive right Lhermitte's and Hoffman's tests. This subsequently progressed to right C7 weakness and bilateral lower limb radiculopathy at postoperative eight weeks. Postoperative MRI of the cervical spine revealed a new focal gliosis/edema within the spinal cord at C6/C7. The patient was treated conservatively with pregabalin and was referred for rehabilitation. Early diagnosis and treatment initiation are crucial in the management of WCS. Surgeons should be aware of this potential complication and counsel patients on the risk prior to surgery. Magnetic resonance imaging (MRI) remains the gold standard in the diagnosis of WCS. The current mainstay of treatment is high-dose steroids, intraoperative neurophysiological monitoring, and early recognition of postoperative WCS.

Sex-specific genetic variants associated with adult-onset inguinal hernia in a Taiwanese population.

Introduction: Inguinal hernia repair is one of the most common surgeries worldwide. However, there is limited information on its underlying genetic mechanism. Studies on the genetic factors related to inguinal hernia in Han Chinese are lacking. Therefore, we aimed to conduct a hospital-based study to assess the genetic factors and comorbidities underlying inguinal hernia in Taiwan. Materials and Methods: This was a retrospective case-control study. Utilizing data from the Taiwan Precision Medicine Initiative, we identified 1000 patients with inguinal hernia and 10,021 matched controls without inguinal hernia between June 2019 and June 2020. Four susceptibility loci (rs2009262, rs13091322, rs6991952, and rs3809060) associated with inguinal hernia were genotyped by the Taiwan Biobank version 2 (TWBv2) array. Inguinal hernia, surgery types, and comorbidities were obtained from the electronic health records of Taichung Veterans General Hospital. Results: Adult-onset inguinal hernia was associated with WT1 rs3809060 GT/TT genotype in males and EFEMP1 rs2009262 TC/CC genotype in females. In addition, we identified sex-specific risk factors associated with inguinal hernia; benign prostatic hyperplasia in males (OR: 3.19, 95% CI: 2.73 - 3.73, p< 0.001), chronic obstructive pulmonary disease in females (OR: 2.34, 95% CI: 1.33 - 4.11, p = 0.003) and overweight, defined by body mass index ≧24 kg/m2 (OR: 0.75, 95% CI: 0.65 - 0.86, p<0.001 in males, and OR: 0.60, 95% CI:0.37 - 0.98, p = 0.042 in females), were inversely associated with inguinal hernia. After stratifying BMI, overweight males with EFEMP1 rs2009262 TC/CC genotype exhibited a higher risk of inguinal hernia (OR: 1.31, 95% CI: 1.07 - 1.61, p = 0.01). Additionally, rs3809060 was specifically associated with male patients with direct-type inguinal hernia (OR: 1.62, 95% CI: 1.19 - 2.22, p = 0.002). Conclusion: Genetic susceptibility appears to participate in the pathogenesis of inguinal hernia in the Taiwanese population in a sex-specific manner. Future studies are needed to illuminate the complex interplay between heredity and comorbidities.

Awareness of and subjective needs for post-discharge healthcare services among older adult patients.

BACKGROUND: Increasing patient awareness of post-discharge care resources is an effective strategy to reduce rehospitalization rates and medical costs. Therefore, the purpose of this study was to explore hospitalized older adult patients' awareness of and subjective demands for post-discharge healthcare services. METHODS: A cross-sectional study design was conducted from November 2018 to May 2020. STROBE statement was completed. Participants were inpatients over 65 years of age in the general ward of a medical center in northern Taiwan. A questionnaire was used to collect data by face-to-face interviews. Two hundred and twelve participants were recruited. Home nursing care, home rehabilitation, home respiratory therapy, home services, assistive devices rental, and transportation were the main post-discharge healthcare services in this study. RESULTS: Overall, 83.5% of older adult patients were aware of and 55.7% of the older adult patients demanded at least one post-discharge healthcare services. Logistic regression results found that, patients experiencing moderate to severe disability and cognitive impairment, and those hospitalized in the past year had significantly higher demands for services. CONCLUSIONS: Developing post-discharge healthcare services for older adult patients provides continuous patient-centered services for assisting patients and their families in adapting to the transition period of the post-acute stage. Satisfying these demands is beneficial for older adult patients and their families, as well as for reducing readmissions and medical costs.