Distinct roles of SOX9 in self-renewal of progenitors and mesenchymal transition of the endothelium.

Regenerative capabilities of the endothelium rely on vessel-resident progenitors termed endothelial colony forming cells (ECFCs). This study aimed to investigate if these progenitors are impacted by conditions (i.e., obesity or atherosclerosis) characterized by increased serum levels of oxidized low-density lipoprotein (oxLDL), a known inducer of Endothelial-to-Mesenchymal Transition (EndMT). Our investigation focused on understanding the effects of EndMT on the self-renewal capabilities of progenitors and the associated molecular alterations. In the presence of oxLDL, ECFCs displayed classical features of EndMT, through reduced endothelial gene and protein expression, function as well as increased mesenchymal genes, contractility, and motility. Additionally, ECFCs displayed a dramatic loss in self-renewal capacity in the presence of oxLDL. RNA-sequencing analysis of ECFCs exposed to oxLDL validated gene expression changes suggesting EndMT and identified SOX9 as one of the highly differentially expressed genes. ATAC sequencing analysis identified SOX9 binding sites associated with regions of dynamic chromosome accessibility resulting from oxLDL exposure, further pointing to its importance. EndMT phenotype and gene expression changes induced by oxLDL in vitro or high fat diet (HFD) in vivo were reversed by the silencing of SOX9 in ECFCs or the endothelial-specific conditional knockout of Sox9 in murine models. Overall, our findings support that EndMT affects vessel-resident endothelial progenitor's self-renewal. SOX9 activation is an early transcriptional event that drives the mesenchymal transition of endothelial progenitor cells. The identification of the molecular network driving EndMT in vessel-resident endothelial progenitors presents a new avenue in understanding and preventing a range of condition where this process is involved.

Review of antibiotic use and resistance in food animal production in WHO South-East Asia Region.

Antimicrobial resistance is an emerging global threat to public health. The resistant bacteria in food animals can be transferred to humans through the food chain. Limited information on antimicrobial usage and resistance in food animals is available in Southeast Asia due to inadequate monitoring or surveillance systems. A literature review was conducted on antimicrobial use and resistance in food animal production in Southeast Asia for the period 2011-2020, to assess the scope and extent of antibiotic use and resistance. The countries included in the study were Bangladesh, Bhutan, Democratic People's Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. The information was categorised by country, production type and findings regarding antibiotic use and resistance. A total of 108 publications were included in the review. Results showed widespread use of critically and highly important antibiotics in livestock, poultry and aquacultured fish and their products. To curb the growing threat of antibiotic resistance, Southeast Asian countries need to strengthen surveillance and regulatory controls of antimicrobial use in food animal production through "One Health" approach.

Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Dietary trends among young adults during the COVID-19 lockdown: socioeconomic and gender disparities.

BACKGROUND: Healthy eating is vital to well-being and during the COVID-19 pandemic, it was especially important for boosting immunity and protecting against viral infections. Yet, by many accounts, keeping a nutritious diet was a casualty of the pandemic rather than a means to fight it. Young adults experienced disproportionate pandemic-related disruptions during a formative stage of development while little is still known about dietary outcomes. METHODS: We employed a cross-sectional design to examine dietary disparities targeting young adults (ages 18-28) during the COVID-19 lockdown period. Participants (N = 254) responded to a 15-20-min online survey with questions related to food composition and sources of food, perceptions of healthy eating, weight change, physical activity, and food insecurity. Comparisons were made by household income and gender. Multiple regression analyses were conducted to investigate factors that predicted perceptions of healthy eating behaviors while controlling for other sociodemographic factors. RESULTS: A clear overall trend toward unhealthy behaviors was found while positive changes were also identified. Consumption of junk food significantly increased (+ 3%), 40% gained weight, a third were less active, and 5-8% were food insecure on a regular basis. Meanwhile, eating food from restaurants declined and, for some, home-based cooking increased. Lower income participants were overly represented in unhealthy changes and higher income participants were disproportionately represented in healthy changes. Males reported more changes in dietary composition while females reported more fluctuation in weight. Reduced activity, weight gain, and food insecurity predicted unhealthy eating behaviors. Living with friend(s)/roommate(s) predicted healthier eating, but only among lower income participants. CONCLUSIONS: It is recommended that pandemic minded public health interventions account for negative dietary trends with particular attention to low-income young adults. Solutions should be geared toward reshaping fiscal, social and physical environments, rather than relying solely on behavioral interventions.

Macrophages in Skin Wounds: Functions and Therapeutic Potential.

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed re-epithelization and abated post-healing fibrosis and scar formation. However, in some animal species, oral mucosa and foetal life, cutaneous wounds can heal normally and remain scarless without any involvement of macrophages. These paradoxical observations have created much controversy on macrophages' indispensable role in skin wound healing. Advanced knowledge gained by characterising macrophage subsets, their plasticity in switching phenotypes and molecular drivers provides new insights into their functional importance during cutaneous wound healing. In this review, we highlight the recent findings on skin macrophage subsets, their functional role in adult cutaneous wound healing and the potential benefits of targeting them for therapeutic use.

Myeloid Wls expression is dispensable for skin wound healing and blood vessel regeneration.

Wnt signaling controls blood vessel growth, regression and patterning during embryonic and postnatal life. Macrophages are major producers of Wnt ligands and angiogenic growth factors. It regulates vascular development and specification during embryogenesis and wound healing. Macrophage dysregulation in wound healing impairs vessel regeneration and delay wound closure. During cutaneous wound healing, the endovascular progenitors (EVPs) proliferate and differentiate into mature endothelial (D) cells in response to signals produced by perivascular cells, including macrophages, governing blood vessels regeneration. However, the role of macrophage's Wnt production on endothelial cells, especially the EVPs during wound healing is currently unknown. Here we used a cutaneous excisional wound model in mice with conditional deletion of Wnt secretion by myeloid cells (Wlsfl/flLysM-Cre+ ) to assess the kinetics of endothelial subpopulations (including EVP), myeloid infiltration, collagen deposition and wound closure. Deletion of Wls expression by myeloid cells did not affect wound closure and collagen deposition, indicating that myeloid Wls expression does not promote wound healing and regeneration. Myeloid-specific Wls deletion elevated the EVP population during the peak of angiogenesis, yet without affecting blood vessel density. Wounds in Wlsfl/flLysM-Cre+ animals showed unperturbed myeloid infiltration and differentiation. Overall, our data indicate that macrophage Wnt production shapes EVP kinetics without major relevance to wound healing. These findings extend the knowledge of macrophage and endothelial molecular crosstalk and position myeloid-derived Wnt production as a regulator of endovascular progenitor.

Prevalence, molecular characterization, and antimicrobial resistance profile of Clostridium perfringens from India: A scoping review.

Clostridium perfringens is one of the most important foodborne pathogens that causes histotoxic diseases and intestinal infections in both humans and animals. The present scoping review has been designed to analyze the literature published during 2000-2021 from India on the prevalence, molecular characterization, and antimicrobial resistance profile of C. perfringens isolates recovered from humans, animals, animal-based foods, and associated environmental samples. The peer-reviewed articles retrieved from four electronic databases (Google Scholar, PubMed, Science Direct, and Web of Science) were assessed using PRISMA-ScR guidelines. A total of 32 studies from India were selected on the basis of their relevance and inclusion criteria. The overall prevalence of C. perfringens among domestic animals having history of clinical symptoms and among healthy animals was found to be 65.8% (508/772) and 42.8% (493/1152), respectively. The pathogen was also detected in clinically affected wild animals (75%), healthy wild animals (35.4%), and captive birds (24.5%). The detection of C. perfringens among poultry having necrotic enteritis and among healthy birds was found to be 66.8% (321/480) and 25.6% (80/312), respectively. The detection of pathogen among animal-based foods (i.e., meat, milk, and fish and their products) and environmental samples depicted a prevalence of 20.8% (325/1562) and 30.2% (23/76), respectively. However, the prevalence of C. perfringens among humans having history of diarrhea and among healthy humans was found to be 25% (70/280) and 23.2% (36/155), respectively. The genotyping of C. perfringens isolates revealed that toxin type A was found to be the most prevalent genotype. Along with the alpha toxin gene (cpa), beta (cpb), epsilon (etx), iota (itx), enterotoxin (cpe), beta-2 toxin (cpb2), and NetB (netB) toxins were also detected in different combinations. Antimicrobial resistance profile of C. perfringens isolates recovered from different sources demonstrated that the highest resistance was detected against sulphonamides (76.8%) and tetracycline (41.3%) by phenotypic and genotypic detection methods, respectively. Comprehensive scientific studies covering different geographical areas at the human-animal-environment interface are crucial to generalize the real magnitude of C. perfringens-associated problem in India and for establishing a reliable database.

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues.

Mouse hematopoietic tissues contain abundant tissue-resident macrophages that support immunity, hematopoiesis, and bone homeostasis. A systematic strategy to characterize macrophage subsets in mouse bone marrow (BM), spleen, and lymph node unexpectedly reveals that macrophage surface marker staining emanates from membrane-bound subcellular remnants associated with unrelated cells. Intact macrophages are not present within these cell preparations. The macrophage remnant binding profile reflects interactions between macrophages and other cell types in vivo. Depletion of CD169+ macrophages in vivo eliminates F4/80+ remnant attachment. Remnant-restricted macrophage-specific membrane markers, cytoplasmic fluorescent reporters, and mRNA are all detected in non-macrophage cells including isolated stem and progenitor cells. Analysis of RNA sequencing (RNA-seq) data, including publicly available datasets, indicates that macrophage fragmentation is a general phenomenon that confounds bulk and single-cell analysis of disaggregated hematopoietic tissues. Hematopoietic tissue macrophage fragmentation undermines the accuracy of macrophage ex vivo molecular profiling and creates opportunity for misattribution of macrophage-expressed genes to non-macrophage cells.

Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model.

Osteal macrophages (osteomacs) support osteoblast function and promote bone anabolism, but their contribution to osteoporosis has not been explored. Although mouse ovariectomy (OVX) models have been repeatedly used, variation in strain, experimental design and assessment modalities have contributed to no single model being confirmed as comprehensively replicating the full gamut of osteoporosis pathological manifestations. We validated an OVX model in adult C3H/HeJ mice and demonstrated that it presents with human postmenopausal osteoporosis features with reduced bone volume in axial and appendicular bone and bone loss in both trabecular and cortical bone including increased cortical porosity. Bone loss was associated with increased osteoclasts on trabecular and endocortical bone and decreased osteoblasts on trabecular bone. Importantly, this OVX model was characterized by delayed fracture healing. Using this validated model, we demonstrated that osteomacs are increased post-OVX on both trabecular and endocortical bone. Dual F4/80 (pan-macrophage marker) and tartrate-resistant acid phosphatase (TRAP) staining revealed osteomacs frequently located near TRAP+ osteoclasts and contained TRAP+ intracellular vesicles. Using an in vivo inducible macrophage depletion model that does not simultaneously deplete osteoclasts, we observed that osteomac loss was associated with elevated extracellular TRAP in bone marrow interstitium and increased serum TRAP. Using in vitro high-resolution confocal imaging of mixed osteoclast-macrophage cultures on bone substrate, we observed macrophages juxtaposed to osteoclast basolateral functional secretory domains scavenging degraded bone byproducts. These data demonstrate a role for osteomacs in supporting osteoclastic bone resorption through phagocytosis and sequestration of resorption byproducts. Overall, our data expose a novel role for osteomacs in supporting osteoclast function and provide the first evidence of their involvement in osteoporosis pathogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors.

Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of Sox9 from the vasculature (Sox9fl/fl/Cdh5-CreER RosaYFP) depletes EVP while enhancing Rbpj expression and canonical Notch signalling. Additionally, skin wound analysis from Sox9 conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with Rbpj conditionally knocked-out from the murine vasculature (Rbpjfl/fl/Cdh5-CreER RosaYFP) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced Sox9 and EndMT related gene (Snail, Slug, Twist1, Twist2, TGF-ß) expression. Similarly, increased endothelial hedgehog signaling (Ptch1fl/fl/Cdh5-CreER RosaYFP), that upregulates the expression of Sox9 in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased Sox9, reduced Rbpj and enhanced EndMT. Importantly, using topical administration of siRNA against Sox9 on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of Rbpj or Notch signalling and Sox9, highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.

Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.

KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A,a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport in vivo by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity.

Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice.

BACKGROUND: Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. METHODS: We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. RESULTS: CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48-CD150+ HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48-CD150+ HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. CONCLUSION: These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.

Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer.

Breast cancer is the most prominent, frequently diagnosed and leading cause of death among women. Estrogen is an agonist of estrogen receptor alpha (ER-α), expressed in mammary glands and is responsible for initiating many signalling pathways that lead to differentiation and development of breast tissue. Any mutations in these signalling pathways result in irregular growth of mammary tissue, leading to the development of tumour or cancer. All these observations attract the attention of researchers to antagonize ER-α receptor either by developing selective estrogen receptor modulators or by selective estrogen receptor degraders. Therefore, this article provides a brief overview of various factors that are responsible for provoking breast cancer in women and design strategies recently used by the various research groups across the world for antagonizing or demodulating ER-α.

Comparative analysis of Methicillin-Resistant Staphylococcus aureus (MRSA) and Borderline Oxacillin Resistant Staphylococcus aureus (BORSA) in community and food of animal origin.

The aim of this study was to illustrate the relative pervasiveness of Borderline Oxacillin Resistant Staphylococcus aureus (BORSA) and Methicillin-Resistant Staphylococcus aureus (MRSA) in community and food of animal origin and their relationship with other genetic determinants. Staphylococcus aureus isolates were subjected to E-test using the antibiotics: oxacillin, ceftriaxone, cotrimoxazole, vancomycin, genotypic tests for the genes mecA, vanA, blaZ, pvl gene and SCCmec typing. The prevalence of S. aureus (MRSA) in the food of animal origin and community settings was 21% (1.8% MRSA) and 21.9% (7.4% MRSA), respectively. SCCmec type V was prevalent among the food of animal origin, while SCCmec type IVa among the community isolates. The likelihood of MRSA presence among community isolates was three times more than in isolates from chicken and milk samples. Likewise, the likelihood of detecting pvl positive MRSA (pvl+MRSA) isolates was 4-fold higher in the community setting than in the food of animal origin. The mecA negative BORSA (mecA-BORSA) was a frequently observed phenotype among S. aureus isolates. Also, co-detection of pvl and cotrimoxazol resistance was reported in this study although there was no noteworthy correlation of cotrimoxazol resistance with the type of sample. Isolates from milk and community settings exhibit higher minimum inhibitory concentration to vancomycin (Vancomycin MIC creep, 2-4 µg/mL). SIGNIFICANCE: Current study provides the information on the statistical relationship between the genetic determinants of S. aureus with respect to sample type, and additionally the correlation that exists between the pvl and MRSA, pvl and cotrimoxazol resistance, vancomycin MIC and MRSA/Methicillin-Susceptible S. aureus (MSSA).

Internet of things-inspired healthcare system for urine-based diabetes prediction.

Healthcare industry is the leading domain that has been revolutionized by the incorporation of Internet of Things (IoT) technology resulting in smart medical applications. Conspicuously, this study presents an effective system of home-centric Urine-based Diabetes (UbD) monitoring system. Specifically, the proposed system comprises of 4-layers for predicting and monitoring diabetes-oriented urine infection. The system layers including Diabetic Data Acquisition (DDA) layer, Diabetic Data Classification (DDC) layer, Diabetic-Mining and Extraction (DME) layer, and Diabetic Prediction and Decision Making (DPDM) layer allow an individual not exclusively to track his/her diabetes measure on regular basis but the prediction procedure is also accomplished so that prudent steps can be taken at early stages. Additionally, probabilistic measurement of UbD monitoring in terms of Level of Diabetic Infection (LoDI), which is cumulatively quantified as Diabetes Infection Measure (DIM) has been performed for predictive purposes using Recurrent Neural Network (RNN). Moreover, the existence of UbD is visualized based on the Self-Organized Mapping (SOM) procedure. To validate the proposed system, numerous experimental simulations were performed on datasets of 4 individuals. Based on the experimental simulation, enhanced results in terms of temporal delay, classification efficiency, prediction efficiency, reliability and stability were registered for the proposed system in comparison to state-of-the-art decision-making techniques.

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A).

Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

Synchrotron-based VUV excitation-induced ultrahigh quality cool white light luminescence from Sm-doped ZnO.

We report that the rare-earth (RE) ion, Sm-doped ZnO, acts as white light emitting vacuum ultraviolet (VUV) phosphors and possesses an ultrahigh color rendering index (CRI) and color quality scale (CQS). The VUV-excited emission spectra measured from the synchrotron source reveal the emergence of multi-color emission bands in the visible-IR region and substantially depend on the concentration of Sm3+ ions. A mechanism is proposed to elucidate the origin behind the high-energy bandgap excitation of the host charge carrier and subsequent energy transfer to the Sm3+ states leading to additional green-yellow-orange emission bands of Sm3+(4G5/2→6HJ(J=5/2,7/2,and9/2)). High-quality cool white light (correlated color temperature 5600 K) having CIE coordinates (0.33, 0.35) with a CRI as high as 95.89 and a CQS value of 94.49 is achieved for Zn0.985Sm0.015O under synchrotron VUV radiations. This Letter demonstrates that RE activated ZnO-based phosphors are expected to be a promising candidate in solid state lighting, as well as plasma display devices.