Functional Level Research Articles

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

Reduced Glycolysis and Cytotoxicity in Staphylococcus aureus Isolates from Chronic Rhinosinusitis as Strategies for Host Adaptation.

Chronic rhinosinusitis (CRS) is a multifactorial infection of the nasal cavity and sinuses. In this study, nasal swabs from control donors (N = 128) and patients with CRS (N = 246) were analysed. Culture methods and metagenomics revealed no obvious differences in the composition of the bacterial communities between the two groups. However, at the functional level, several metabolic pathways were significantly enriched in the CRS group compared to the control group. Pathways such as carbohydrate transport metabolism, ATP synthesis, cofactors and vitamins, photosynthesis and transcription were highly enriched in CRS. In contrast, pathways related to lipid metabolism were more representative in the control microbiome. As S. aureus is one of the main species found in the nasal cavity, staphylococcal isolates from control and CRS samples were analysed by microarray and functional assays. Although no significant genetic differences were detected by microarray, S. aureus from CRS induced less cytotoxicity to lung cells and lower rates of glycolysis in host cells than control isolates. These results suggest the differential modulation of staphylococcal virulence by the environment created by other microorganisms and their interactions with host cells in control and CRS samples. These changes were reflected in the differential expression of cytokines and in the expression of Agr, the most important quorum-sensing regulator of virulence in S. aureus. In addition, the CRS isolates remained stable in their cytotoxicity, whereas the cytotoxic activity of S. aureus isolated from control subjects decreased over time during in vitro passage. These results suggest that host factors influence the virulence of S. aureus and promote its adaptation to the nasal environment during CRS.

A mutation in F-actin polymerization factor suppresses the distal arthrogryposis type 5 PIEZO2 pathogenic variant in Caenorhabditis elegans.

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a candidate suppressor allele in the C. elegans gene gex-3. This gene is an ortholog of human NCKAP1 (NCK-associated protein 1), a subunit of the Wiskott-Aldrich syndrome protein (WASP)-verprolin homologous protein (WAVE/SCAR) complex, which regulates F-actin polymerization. Depletion of gex-3 by RNAi, or with the suppressor allele gex-3(av259[L353F]), significantly increased brood size and ovulation rate, as well as alleviating the crushed oocyte phenotype of the pezo-1(R2405P) mutant. Expression of GEX-3 in the soma is required to rescue the brood size defects in pezo-1(R2405P) animals. Actin organization and orientation were disrupted and distorted in the pezo-1 mutants. Mutation of gex-3(L353F) partially alleviated these defects. The identification of gex-3 as a suppressor of the pathogenic variant pezo-1(R2405P) suggests that the PIEZO coordinates with the cytoskeleton regulator to maintain the F-actin network and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.

Neurocognitive Concussion Test Performance for Student Athletes on the Autism Spectrum.

To examine baseline neurocognitive functioning among adolescent athletes on the autism spectrum based on self-reported level of academic performance. Participants in this cross-sectional, observational study were 6,441 adolescent athletes with a self-reported diagnosis of autism who completed pre-season neurocognitive testing using Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT); 4,742 reported a co-occurring learning disorder (LD), and 6,612 individuals without autism or LD were included as a control group. The majority (57%) self-reported Average Academic Performance, 39% Above Average, and 4% Below Average performance. Athletes with self-reported autism (with or without LD; 12.2%) were 2.74x (95% CI: 2.17-2.82) more likely to fall below cutoffs for ImPACT Embedded Invalidity Indicators (EVIs), with a significant interaction between self-reported Diagnosis and Academic Performance; individuals with co-occurring autism and LD who reported Below Average Academic Performance had the greatest likelihood of scoring below cutoffs (22%), followed by ASD without LD (14.8%) and Controls (14.6%) with Below Average Academic Performance. Analyses of variance (ANOVAs) revealed main effects of Diagnosis and Academic Performance on neurocognitive performance, with interactions on all ImPACT Composite Scores except Processing Speed. Athletes with self-reported ASD are more likely to fall below ImPACT EVIs and score worse on ImPACT, with greater likelihood/worse performance related to level of academic functioning. Academic performance should be considered when interpreting neurocognitive testing data, to best index neuropsychological functioning associated with concussion in this population. The current findings highlight the importance of individual participant baseline neuropsychological testing for individuals on the autism spectrum.

The potential causal path between periodontitis stage diagnosis and vegetable consumption is mediated by loss of posterior functional tooth units and masticatory function.

Emerging evidence points to a two-way relationship between periodontitis and dietary choices and, thus, nutrition. This study aimed to assess the potential cause-effect relationship between the periodontitis stage, loss of functional tooth units (FTUs), masticatory function, and intake of different food groups using path analysis. A single calibrated examiner determined the periodontitis stage of a consecutive sample of 241 Chinese subjects reporting for tooth replacement. Their masticatory function was quantified by the mixing ability of a two-colour chewing gum. Validated food frequency questionnaires were used to calculate the intake of 33 food group items by an experienced calibrated rater. After verification of assumptions, visual structural equation modeling was performed with Amos 23. The consistency of results and the potential modifying effect of age were assessed in 9043 subjects from the NHANES database. Highly significant models were constructed using periodontitis stage and age as exogenous factors. Periodontitis stage diagnosis significantly affected the number of posterior FTUs and oral health-related quality of life (OHRQoL, path coefficient [PC] = -0.55 and -0.20, p < .05, respectively). In the model, FTUs also had an independent effect on OHRQoL (PC = 0.23, p < .05). FTUs determined the level of masticatory function (PC = -0.38, p < .05), which in turn affected vegetable intake but not fruit or meat intake (PC = -0.18, p < .0.5, PC = 0.06, NS and PC = 0.11, NS, respectively). The effect of age was significant for vegetable and meat intake and was also correlated with periodontitis stage diagnosis. Analysis of the NHANES database confirmed the negative impact of periodontitis on the number of occluding pairs and vegetable consumption for the 18-44, 45-60 and >60 age groups. Periodontitis showed a potential cause-effect pathway affecting vegetable intake across cultures and age groups. The size of the effect is potentially of clinical and public health significance. Additional studies, including intervention trials, are required to test this potential mechanism linking oral health to nutrition.

Multi-omics revealed rumen microbiota metabolism and host immune regulation in Tibetan sheep of different ages.

The rumen microbiota and metabolites play an important role in energy metabolism and immune regulation of the host. However, the regulatory mechanism of rumen microbiota and metabolite interactions with host on Tibetan sheep's plateau adaptability is still unclear. We analyzed the ruminal microbiome and metabolome, host transcriptome and serum metabolome characteristics of Tibetan sheep at different ages. Biomarkers Butyrivibrio, Lachnospiraceae_XPB1014_group, Prevotella, and Rikenellaceae_RC9_gut_group were found in 4 months, 1.5 years, 3.5 years, and 6 years Tibetan sheep, respectively. The rumen microbial metabolites were mainly enriched in galactose metabolism, unsaturated fatty acid biosynthesis and fatty acid degradation pathways, and had significant correlation with microbiota. These metabolites further interact with mRNA, and are co-enriched in arginine and proline metabolism, metabolism of xenobiotics by cytochrome P450, propanoate metabolism, starch and sucrose metabolism, gap junction pathway. Meanwhile, serum metabolites also have a similar function, such as chemical carcinogenesis - reactive oxygen species, limonene and pinene degradation, and cutin, suberine and wax biosynthesis, thus participating in the regulation of the body's immune and energy-related metabolic processes. This study systematically revealed that rumen microbiota, metabolites, mRNA and serum metabolites of Tibetan sheep were involved in the regulation of fermentation metabolic function and immune level of Tibetan sheep at different ages, which provided a new perspective for plateau adaptability research of Tibetan sheep at different ages.

Molecular insight into thymoquinone mechanism of action against Mycobacterium tuberculosis.

Natural products are promising antimicrobials, usually having multiple and different cellular targets than synthetic antibiotics. Their influence on bacteria at various metabolic and functional levels contributes to higher efficacy even against drug-resistant strains. One such compound is a naturally occurring p-benzoquinone - thymoquinone. It is effective against different bacteria, including multidrug-resistant and extremely drug-resistant Mycobacterium tuberculosis. Its antibacterial mechanism of action was studied in several bacterial species except mycobacteria. To get an insight into the antimycobacterial activity of thymoquinone at the molecular level, we performed metabolomic and transcriptomic analyzes of bacteria exposed to this compound. The expression of genes coding stress-responsive sigma factors revealed that thymoquinone rapidly induces the production of sigE transcripts. At the same time, prolonged influence results in the overexpression of all sigma factor genes and significantly upregulates sigF. The metabolomic analysis confirmed that the antimycobacterial activity of thymoquinone was related to the depletion of NAD and ATP pools and the downregulation of plasma membrane lipids. This state was observed after 24 h and was persistent the next day, suggesting that bacteria could not activate catabolic mechanisms and produce energy. Additionally, the presence of a thymoquinone nitrogen derivative in the bacterial broth and the culture was reported.

20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

Engagement With Remote Delivery Channels in a Physical Activity Intervention for Senior Women in the US.

Identify the effects of engagement with different intervention delivery channels on physical activity (PA), and the participant subgroups engaging with the different channels, among Women's Health Initiative Strong and Healthy (WHISH) PA trial participants. Secondary analysis of data from WHISH, a pragmatic trial that used passive randomized consent. United States (remote intervention in all 50 states). 18,080 U.S. women, aged 68-99 years, assigned to the WHISH PA intervention arm. 6 dichotomous variables operationalized engagement: Engagement with Targeted Inserts, Email (opened), Email (clicked links), Website (logging in), Website (tracking), Interactive Voice Response (IVR). PA was measured using the CHAMPS PA questionnaire. Linear regressions evaluated effects of engagement on PA. Conditional Inference Trees identified subgroups of participants engaging with different channels based on demographic and psychosocial variables. Engagement with each channel, except IVR, was associated with significantly more hours/week of PA (square root coefficients .29 - .13, P values <.001). Consistently across channels, features that identified subgroups of participants with higher engagement included younger age, and higher levels of PA and physical function. Subgroups with the highest engagement differed from those with the lowest in most participant characteristics. For equitable population-level impact via large-scale remotely-delivered PA programs, it may be necessary to identify strategies to engage and target harder to reach subgroups more precisely. The WHISH trial is registered at ClinicalTrials.gov (No. NCT02425345).

Design and manufacturing by fused filament technique of novel YSZ porous grafts infiltrated with PCL/PVA/AgNPs for large bone defects repairing

Addressing large bone segmental defects remains a profound challenge in orthopaedic surgery, demanding graft designs that mirror patient-specific defects while ensuring vascularization, osteoconduction, and structural integrity. Conventional approaches fall short in achieving this level of customization and functionality. This work leverages fuse filament fabrication (FFF) to fabricate innovative yttria stabilize zirconia graft designs that combine several strategies to tackle these multifaceted challenges. Graft designs ingeniously incorporate dense and porous structures mimicking the intricate architecture of natural bone for improved structural integrity and different ridges and protrusions to enhance the fixation. Additionally, these grafts undergo infiltration with PCL/PVA/AgNPs composite polymers, enriching biocompatibility, structural integrity, and antibacterial properties, fostering conducive conditions for optimal bone growth. Attaining printable filaments with YSZ powders below 50 nm and loads reaching 50 vol% marks a pioneering advancement in bone graft fabrication via Fused Filament Fabrication (FFF). This enabled high densification and low grain size at reduced sintering temperatures, imperative to achieve high mechanical performance. The biodegradation capacity of biopolymers in PBS and their role in the mechanical behaviour of grafts have been assessed, demonstrating the beneficial potential of the multicomponent graft proposed reaching strength values of 90–105 MPa.

Effects of Circuit Class Training Versus Individual, Task Specific Training on Upper Extremity Function in Chronic Stroke Patients

Background: Stroke is a leading contributor to disability globally, emphasizing the need for effective rehabilitation techniques. Circuit class training (CCT) and individual, task-specific training (ITST) have emerged as potential approaches for enhancing upper extremity function in stroke survivors. Comparative analyses of their efficacy, especially among chronic stroke patients, are scant. Objective: This study aimed to evaluate and compare the impacts of CCT and ITST on upper extremity spasticity, motor function, and quality of life in individuals with chronic stroke. Methods: In a randomized controlled trial, 36 chronic stroke patients were allocated to either CCT or ITST groups. Participants were aged 45-70 years, had experienced a single stroke episode, and were at least 6 months post-stroke, with specific inclusion criteria regarding spasticity and motor function levels. The interventions were delivered for 1.5 hours daily, five days a week, over eight weeks. Outcomes were measured using the Modified Ashworth Scale (MAS) for spasticity, Functional Independence Measure for Upper Extremity (FMA-UE) for motor function, and Stroke-Specific Quality of Life (SS-QOL) scale for quality of life, analyzed using SPSS version 25. Results: Post-intervention, both CCT and ITST participants exhibited significant improvements in their outcomes. MAS scores showed a reduction in spasticity, with average improvements not significantly differing between the groups. FMA-UE scores increased by an average of 10 points in both groups, indicating enhanced motor function without a significant difference between the groups (p &gt; 0.05). SS-QOL scores improved by an average of 20 points in each group, reflecting better quality of life, with no significant intergroup difference observed. Conclusion: The study concludes that CCT and ITST are equally effective in ameliorating upper extremity spasticity, motor function, and quality of life among chronic stroke patients. The selection between CCT and ITST can thus be personalized based on patient preferences, available resources, and logistical considerations, maintaining rehabilitation efficacy.

Efficient bicycle networks and expansion strategies

&#x0D; &#x0D; &#x0D; This article explains some of the key attributes and factors relating to efficient bicycle networks and their expansion strategies. Varying from a network scale to brief discussion about the streetscape design, many scientific publications are referenced to explain the crucial aspects which must be taken into consideration when planning an attractive cycling network. Modal switch from other transport modes, especially from cars is one of the goals of this cycling promotion. Various methods such as building new bicycle facilities, improving the quality of existing ones and increasing the comfort and safety of the connections were found to improve the attractiveness of cycling in urban context. Additionally, this article analyses the reasons behind cyclists’ route choice as well as the metrics such as connectedness, directedness and coverage which can be used to measure the level of network functionality. Lastly, network growth under limited resources is considered and an equitable distribution of cycleways across the city is found to be important in preventing neighbourhood segregation while not being too far from a utilitarian kind of distribution in terms of return to investment. &#x0D; &#x0D; &#x0D;

Incorporating functional annotation with bilevel continuous shrinkage for polygenic risk prediction

BackgroundGenetic variants can contribute differently to trait heritability by their functional categories, and recent studies have shown that incorporating functional annotation can improve the predictive performance of polygenic risk scores (PRSs). In addition, when only a small proportion of variants are causal variants, PRS methods that employ a Bayesian framework with shrinkage can account for such sparsity. It is possible that the annotation group level effect is also sparse. However, the number of PRS methods that incorporate both annotation information and shrinkage on effect sizes is limited. We propose a PRS method, PRSbils, which utilizes the functional annotation information with a bilevel continuous shrinkage prior to accommodate the varying genetic architectures both on the variant-specific level and on the functional annotation level.ResultsWe conducted simulation studies and investigated the predictive performance in settings with different genetic architectures. Results indicated that when there was a relatively large variability of group-wise heritability contribution, the gain in prediction performance from the proposed method was on average 8.0% higher AUC compared to the benchmark method PRS-CS. The proposed method also yielded higher predictive performance compared to PRS-CS in settings with different overlapping patterns of annotation groups and obtained on average 6.4% higher AUC. We applied PRSbils to binary and quantitative traits in three real world data sources (the UK Biobank, the Michigan Genomics Initiative (MGI), and the Korean Genome and Epidemiology Study (KoGES)), and two sources of annotations: ANNOVAR, and pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and demonstrated that the proposed method holds the potential for improving predictive performance by incorporating functional annotations.ConclusionsBy utilizing a bilevel shrinkage framework, PRSbils enables the incorporation of both overlapping and non-overlapping annotations into PRS construction to improve the performance of genetic risk prediction. The software is available at https://github.com/styvon/PRSbils.

Differentiation of Wharton's Jelly-derived mesenchymal stem cells into insulin-producing beta cells with the enhanced functional level on electrospun PRP-PVP-PCL/PCL fiber scaffold

Diabetes is a global problem that threatens human health. Cell therapy methods using stem cells, and tissue engineering of pancreatic islets as new therapeutic approaches have increased the chances of successful diabetes treatment. In this study, to differentiate Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) into insulin-producing cells (IPCs) with improved maturity, and function, platelet-rich plasma (PRP)-Polyvinylpyrrolidone (PVP)-Polycaprolactone (PCL)/PCL scaffold was designed. The two-dimensional (2D) control group included cell culture without differentiation medium, and the experimental groups included 2D, and three-dimensional (3D) groups with pancreatic beta cell differentiation medium. WJ-MSCs-derived IPCs on PRP-PVP-PCL/PCL scaffold took round cluster morphology, the typical pancreatic islets morphology. Real-time PCR, immunocytochemistry, and flowcytometry data showed a significant increase in pancreatic marker genes in WJ-MSCs-derived IPCs on the PRP-PVP-PCL/PCL scaffold compared to the 2D-experimental group. Also, using the ELISA assay, a significant increase in the secretion of insulin, and C-peptide was measured in the WJ-MSCs-derived IPCs of the 3D-experimental group compared to the 2D experimental group, the highest amount of insulin (38 µlU/ml), and C-peptide (43 pmol/l) secretion was in the 3D experimental group, and in response to 25 mM glucose solution, which indicated a significant improvement in the functional level of the WJ-MSCs-derived IPCs in the 3D group. The results showed that the PRP-PVP-PCL/PCL scaffold can provide an appropriate microenvironment for the engineering of pancreatic islets, and the generation of IPCs.

Exploring the potential of the sit-to-stand test for self-assessment of physical condition in advanced knee osteoarthritis patients using computer vision.

Knee osteoarthritis (KOA) is a prevalent condition often associated with a decline in patients' physical function. Objective self-assessment of physical conditions poses challenges for many advanced KOA patients. To address this, we explored the potential of a computer vision method to facilitate home-based physical function self-assessments. We developed and validated a simple at-home artificial intelligence approach to recognize joint stiffness levels and physical function in individuals with advanced KOA. One hundred and four knee osteoarthritis (KOA) patients were enrolled, and we employed the WOMAC score to evaluate their physical function and joint stiffness. Subsequently, patients independently recorded videos of five sit-to-stand tests in a home setting. Leveraging the AlphaPose and VideoPose algorithms, we extracted time-series data from these videos, capturing three-dimensional spatiotemporal information reflecting changes in key joint angles over time. To deepen our study, we conducted a quantitative analysis using the discrete wavelet transform (DWT), resulting in two wavelet coefficients: the approximation coefficients (cA) and the detail coefficients (cD). Our analysis specifically focused on four crucial joint angles: "the right hip," "right knee," "left hip," and "left knee." Qualitative analysis revealed distinctions in the time-series data related to functional limitations and stiffness among patients with varying levels of KOA. In quantitative analysis, we observed variations in the cA among advanced KOA patients with different levels of physical function and joint stiffness. Furthermore, there were no significant differences in the cD between advanced KOA patients, demonstrating different levels of physical function and joint stiffness. It suggests that the primary difference in overall movement patterns lies in the varying degrees of joint stiffness and physical function among advanced KOA patients. Our method, designed to be low-cost and user-friendly, effectively captures spatiotemporal information distinctions among advanced KOA patients with varying stiffness levels and functional limitations utilizing smartphones. This study provides compelling evidence for the potential of our approach in enabling self-assessment of physical condition in individuals with advanced knee osteoarthritis.

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder

BackgroundProtein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder.ResultsThirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains.ConclusionsThe GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.

Effects of Land Cover on the Taxonomic and Functional Diversity of the Bird Communities on an Urban Subtropical Mountain

Mountain ecosystems are crucial for global biodiversity conservation. However, their landscape features are constantly changing owing to urban expansion. Understanding the relationships between biotic communities and landscape features is essential for biodiversity conservation. This study aimed to examine the effect of land cover type on avian communities in Lishui, a mountainous urban area in eastern China. Avian surveys were conducted using 168 line transects in total across different land cover types once per season from December 2019 to January 2021. We assessed the diversity of bird communities by calculating various metrics at both taxonomic and functional levels. Among the land cover types measured, woodland, built-up land, cultivated land, and water bodies significantly influenced bird community diversity and composition. Species richness, species abundance, and functional richness were negatively correlated with the proportion of woodland but were positively correlated with the proportion of non-natural land cover, such as built-up and cultivated land. In contrast, functional evenness was positively correlated with the proportion of woodland and grassland but negatively correlated with the proportion of non-natural land cover. Land cover type also exhibited significant correlations with avian functional characteristics such as diet, foraging strata, and body mass, thereby influencing the overall community structure. Our results indicated that mountainous landscape patterns substantially affect avian communities. Different land cover types possess varying resource endowments that affect the distribution of avian species. Therefore, urban landscape planning in mountainous areas should carefully consider the various functions provided to organisms by different types of land cover to promote biodiversity.

The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage.

It is well-established that, through canonical functions in transcription and DNA repair, the tumor suppressor p53 plays a central role in safeguarding cells from the consequences of DNA damage. Recent data retrieved in tumor and stem cells demonstrated that p53 also carries out non-canonical functions when interacting with the translesion synthesis (TLS) polymerase iota (POLι) at DNA replication forks. This protein complex triggers a DNA damage tolerance (DDT) mechanism controlling the DNA replication rate. Given that the levels of p53 trigger non-binary rheostat-like functions in response to stress or during differentiation, we explore the relevance of the p53 levels for its DDT functions at the fork. We show that subtle changes in p53 levels modulate the contribution of some DDT factors including POLι, POLη, POLζ, REV1, PCNA, PRIMPOL, HLTF and ZRANB3 to the DNA replication rate. Our results suggest that the levels of p53 are central to coordinate the balance between DDT pathways including (i) fork-deceleration by the ZRANB3-mediated fork reversal factor, (ii) POLι-p53-mediated fork-slowing, (iii) POLι- and POLη-mediated TLS and (iv) PRIMPOL-mediated fork-acceleration. Collectively, our study reveals the relevance of p53 protein levels for the DDT pathway choice in replicating cells.

Impact of folic acid supplementation on ischemia‒reperfusion-induced kidney injury in rats: folic acid prophylactic role revisited

Folic acid (FA), with its anti-inflammatory and antioxidant properties, may offer protection against ischemia–reperfusion (IR) injury. This study investigated whether FA safeguards rat kidneys from IR by targeting high mobility group box-1 (HMGB1), a key inflammatory mediator. Fifty adult male Wistar rats were randomly allocated into four groups: control, IR, IR + FA pretreatment, and FA alone. Compared to controls, IR significantly impaired renal function and elevated levels of malondialdehyde, HMGB1, NF-κB, and caspase 3. FA pretreatment effectively reversed these detrimental changes, protecting renal function and minimizing tissue damage. The FA-alone group showed no significant differences compared to the control group, indicating no adverse effects of FA treatment. Mechanistically, FA inhibited HMGB1 expression and its downstream activation of NF-κB and caspase 3, thereby quelling inflammation and cell death. FA shields rat kidneys from IR-induced injury by suppressing HMGB1-mediated inflammation and apoptosis, suggesting a potential therapeutic avenue for IR-associated kidney damage.

Student Homelessness in High School: Prevalence, Individual Characteristics, and Profiles of Risk and Multidomain Functioning

We estimated the prevalence of high school homelessness and examined associations among homelessness, demographic factors, victimization experiences, and poor functioning using variable- and person-centered approaches. Anonymous self-report survey data from the 2019 Youth Risk Behavior Surveillance System represented approximately 6.5 million high school students in 29 regions of the United States. An estimated 9.32% of students experienced homelessness. Path analysis found homelessness was related to poor functioning, accounting for victimization and demographic factors. Latent class analysis found the highest risk profiles had high levels of homelessness, victimization, and poor functioning and an overrepresentation of multiracial, Native, and Hispanic/Latino students, and students with LGBT identities. Interventions to prevent, identify, and respond to youth homelessness should address sources of marginalization and adversity.