Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions

A multi-biometric iris recognition system based on a deep learning approach

YesMultimodal biometric systems have been widely applied in many real-world applications due to its ability to deal with a number of significant limitations of unimodal biometric systems, including sensitivity to noise, population coverage, intra-class variability, non-universality, and vulnerability to spoofing. In this paper, an efficient and real-time multimodal biometric system is proposed based on building deep learning representations for images of both the right and left irises of a person, and fusing the results obtained using a ranking-level fusion method. The trained deep learning system proposed is called IrisConvNet whose architecture is based on a combination of Convolutional Neural Network (CNN) and Softmax classifier to extract discriminative features from the input image without any domain knowledge where the input image represents the localized iris region and then classify it into one of N classes. In this work, a discriminative CNN training scheme based on a combination of back-propagation algorithm and mini-batch AdaGrad optimization method is proposed for weights updating and learning rate adaptation, respectively. In addition, other training strategies (e.g., dropout method, data augmentation) are also proposed in order to evaluate different CNN architectures. The performance of the proposed system is tested on three public datasets collected under different conditions: SDUMLA-HMT, CASIA-Iris- V3 Interval and IITD iris databases. The results obtained from the proposed system outperform other state-of-the-art of approaches (e.g., Wavelet transform, Scattering transform, Local Binary Pattern and PCA) by achieving a Rank-1 identification rate of 100% on all the employed databases and a recognition time less than one second per person

Stability of domain structures in multi-domain proteins

Multi-domain proteins have many advantages with respect to stability and folding inside cells. Here we attempt to understand the intricate relationship between the domain-domain interactions and the stability of domains in isolation. We provide quantitative treatment and proof for prevailing intuitive ideas on the strategies employed by nature to stabilize otherwise unstable domains. We find that domains incapable of independent stability are stabilized by favourable interactions with tethered domains in the multi-domain context. Stability of such folds to exist independently is optimized by evolution. Specific residue mutations in the sites equivalent to inter-domain interface enhance the overall solvation, thereby stabilizing these domain folds independently. A few naturally occurring variants at these sites alter communication between domains and affect stability leading to disease manifestation. Our analysis provides safe guidelines for mutagenesis which have attractive applications in obtaining stable fragments and domain constructs essential for structural studies by crystallography and NMR

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations:Experience from the MJFF Global Genetic Parkinson's Disease Project

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.</p

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Using global team science to identify genetic parkinson's disease worldwide.

No abstract available

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Hydrogeochemical evolution of groundwater in a Quaternary sediment and Cretaceous sandstone unconfined aquifer in Northwestern China

A better understanding of the hydrogeochemical evolution of groundwater in vulnerable aquifers is important for the protection of water resources. To assess groundwater chemistry, groundwater sampling was performed from different representative aquifers in 2012–2013. A Piper trilinear diagram showed that the groundwater types can be classified into Na–SO4 and Na–Cl types. Only one groundwater sample was Na–HCO3 type. The dominant cations for all samples were Na+. However, the dominant anions varied from HCO3− to SO42−, and as well Cl−. The mean total dissolved solid (TDS) content of groundwater in the region was 1889 mg/L. Thus, only 20% of groundwater samples meet Chinese drinking water standards (< 1000 mg/L). Principal component analysis (PCA) combined with hierarchical cluster analysis (HCA) and self-organizing maps (SOM) were applied for the classification of the groundwater geochemistry. The three first principal components explained 58, 20, and 16% of the variance, respectively. The first component reflects sulfate minerals (gypsum, anhydrite) and halite dissolution, and/or evaporation in the shallow aquifer. The second and third components are interpreted as carbonate rock dissolution. The reason for two factors is that the different aquifers give rise to different degree of hydrogeochemical evolution (different travel distances and travel times). Identified clusters for evolution characteristic and influencing factors were confirmed by the PCA–HCA methods. Using information from eight ion components and SOM, formation mechanisms and influencing factors for the present groundwater quality were determined

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception