Miracle-dz/UniFAR-FTUs huggingface dataset:
The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs

As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways’ inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.
Functional, proteomic and bioinformatic analyses of Nrf2‐ and Keap1‐ null skeletal muscle

Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle‐specific transgenic mouse models with unbiased‐omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two‐way model to understand Nrf2 function: a tonic effect through a Keap1‐independent mechanism under basal conditions and an induced effect through a Keap1‐dependent mechanism in response to oxidative and other stresses.
Health equity considerations in COVID-19: geospatial network analysis of the COVID-19 outbreak in the migrant population in Singapore

Abstract Background Low-wage dormitory-dwelling migrant workers in Singapore were disproportionately affected by coronavirus disease 2019 (COVID-19) infection. This was attributed to communal living in high-density and unhygienic dormitory settings and a lack of inclusive protection systems. However, little is known about the roles of social and geospatial networks in COVID-19 transmission. The study examined the networks of non-work–related activities among migrant workers to inform the development of lockdown exit strategies and future pandemic preparedness. Methods A population-based survey was conducted with 509 migrant workers across the nation, and it assessed dormitory attributes, social ties, physical and mental health status, COVID-19-related variables and mobility patterns using a grid-based network questionnaire. Mobility paths from dormitories were presented based on purposes of visit. Two-mode social networks examined the structures and positions of networks between workers and visit areas with individual attributes. Results COVID-19 risk exposure was associated with the density of dormitory, social ties and visit areas. The migrant worker hub in the city centre was the most frequently visited for essential services of grocery shopping and remittance, followed by south central areas mainly for social gathering. The hub was positioned as the core with the highest degree of centrality with a cluster of workers exposed to COVID-19. Conclusions Social and geospatial networks of migrant workers should be considered in the implementation of lockdown exit strategies while addressing the improvement of living conditions and monitoring systems. Essential services, like remittance and grocery shopping at affordable prices, need to be provided near to dormitories to minimize excess gatherings.
Weaker Cerebellocortical Connectivity Within Sensorimotor and Executive Networks in Schizophrenia Compared to Healthy Controls: Relationships with Processing Speed

BACKGROUND The cognitive dysmetria theory of schizophrenia proposes that communication between the cerebellum and cerebral cortex is disrupted by structural and functional abnormalities, resulting in psychotic symptoms and cognitive deficits. METHODS Using publicly available data, resting state functional connectivity (rsFC) was calculated from 20 hemispheric cerebellar lobules as seed regions of interest to the rest of the brain. Group differences in rsFC between individuals with schizophrenia (SZ) and healthy controls (HC) were computed, and relationships between rsFC and symptom severity and cognitive functioning were explored. RESULTS HC demonstrated stronger connectivity than SZ between several cerebellar lobules and cortical regions, most robustly between motor-related cerebellar lobules (V and VIIIa/b) and temporal and parietal cortices. In addition, seven of nine lobules in which reduced cerebello-cortical connectivity was observed also showed diagnosis  processing speed interactions; HC showed a positive relationship between connectivity and processing speed, whereas SZ did not show this relationship. Other cognitive domains and symptom severity did not show relationships with connectivity. CONCLUSIONS These findings partially support the cognitive dysmetria theory and suggest that disrupted cerebello-cortical connectivity is associated with slowed processing speed in schizophrenia.
Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes.

BACKGROUND Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. OBJECTIVE In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. METHODS We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). RESULTS We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. CONCLUSION The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.
Insights into the roles of membrane pore size and feed foulant concentration in ultrafiltration membrane fouling based on collision‐attachment theory

Membrane property and feed characteristics play critical roles in membrane fouling. This paper aims to clarify the roles of membrane pore size (φ) and feed foulant concentration (Cb) in ultrafiltration fouling induced by polysaccharides. The fouling behaviors were expounded by collision‐attachment theory, where the rate of membrane fouling is mainly determined by collision frequency (JCb) and attachment efficiency (γ). At the initial fouling stage, rapid flux decline was observed at large φ or high Cb due to the great JCb and/or γ. At the later fouling stage, there existed a nearly identical maximum stable flux attributing to the same JCb and γ, which was independent of φ and Cb. Moreover, the smaller φ can lead to less foulants passed through the membrane and thus more foulants attaching on the membrane, while the higher Cb can give rise to more foulants on both the membrane surface and in the permeate. The results presented in current study provide fundamental basis in understanding membrane fouling.
Neurological immune‐related adverse events associated with immune checkpoint inhibitors: A review of the literature

Immune checkpoint inhibitors (ICIs) have made a breakthrough in cancer therapy. Patients treated with ICIs may develop immune‐related adverse events (irAEs) due to the upregulated activity of the immune system. With the increasing use of ICIs, irAEs are more frequently reported and have become important challenges in many patients. Neurological irAEs, which include encephalitis, myelitis, aseptic meningitis, peripheral neuropathy, myasthenia gravis, and myositis, consist of a distinct group of neuroinflammatory disorders. These disorders are rare but frequently severe with high mortality and morbidity. Patients with neurological irAEs are generally responsive to immune‐modulating therapy. Therefore, early recognition and treatment are the most important ways to improve their prognosis. Here, we provide a comprehensive review of neurological irAEs associated with ICIs and focus on these affecting central nervous systems.
Lower cardiorenal risk with sodium‐glucose cotransporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes without cardiovascular and renal diseases: A large multinational observational study

We compared the new use of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) versus dipeptidyl peptidase‐4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice.
The effect of carotid revascularization on the ophthalmic artery flow: systematic review and meta-analysis.

INTRODUCTION High-grade internal carotid stenosis results in impaired flow dynamics in the ocular circulation that may lead to a rare clinical entity; ophthalmic ischemic syndrome (OIS). The aim of this study was to investigate hemodynamic changes in the ophthalmic circulation after carotid revascularization, assessed with duplex ultrasonography (DUS), and their potential impact on ocular function in patients suffering from OIS. EVIDENCE ACQUISITION A systematic review of the literature was performed according to the PRISMA guidelines. MEDLINE, EMBASE and CENTRAL databases were searched. EVIDENCE SYNTHESIS The analysis included fourteen cohort studies (589 patients) reporting on the hemodynamic effect of carotid revascularization on the ophthalmic circulation using DUS. Eighty-five per cent of patients were treated for symptomatic carotid stenosis. The pre- and post-operative ophthalmological evaluation was recorded in four studies (227 out of 358 patients (63%) diagnosed with OIS). Reversed ophthalmic artery (OA) flow prior to carotid revascularization was present in 86 cases (24%). Following carotid revascularization, a significant increase in peak systolic velocity (PSV) (mean difference (MD) 14.712 cm/s, 95% confidence interval (CI) 10.566-18.858; p<0.001, I2=96%) and a significant anterograde restoration of flow in the OA (OR 2.047, 95% CI 1.72-2.42, p<0.001, Ι2=0%) were recorded. Carotid revascularization resulted in regression of ischemic symptoms in 93.1% of patients (95% CI 56.4%-99.3%), P=0.001, I2=82%). CONCLUSIONS Carotid revascularization may be associated with a significant flow restoration and PSV increase in the OA; as well as clinical improvement in ischemic ophthalmic symptoms in patients with OIS.
Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington’s Disease: Effect of mHTT on Growth

Background: The gene (Huntingtin or HTT) causing Huntington’s disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development. Objective: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. Methods: Children ages 6–18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. Results: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. Conclusion: Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology.
Wilms’ tumor 1 (WT1) promotes ovarian cancer progression by regulating E-cadherin and ERK1/2 signaling

ABSTRACT Wilms’ tumor 1 (WT1) is reported to play an important role in tumor invasion and metastasis, two hallmarks of ovarian cancer (OC) that influence treatment efficacy and prognosis. However, the specific roles and underlying mechanisms of WT1 in OC have not been fully understood. Here, we investigated the potential function and signaling pathways of WT1 in OC cells. We showed that WT1 was significantly upregulated in human OC tissues and closely associated with OC type, grade and FIGO stage. In cultured cells and xenograft mouse models, WT1 depletion significantly inhibited cell migration and invasion, reversed epithelial–mesenchymal transition (EMT), and prevented metastasis of OC cells. We further demonstrated that WT1 inhibited E-cadherin expression via targeting E-cadherin gene promoter by chromatin immunoprecipitation and luciferase reporter assay. Moreover, ERK1/2 activation was suppressed upon WT1 silencing. Inhibiting ERK1/2 phosphorylation increased E-cadherin expression and suppressed WT1-induced OC cell migration and invasion. Taken together, our study reveals WT1 exerts a tumor-promoting role in OC, enhancing EMT through negative modulation of E-cadherin expression via ERK1/2 signaling. WT1 may represent a novel therapeutic target that may improve the prognosis of OC.
Significant association between the endothelial lipase gene 584C/T polymorphism and coronary artery disease risk

Abstract Several studies have investigated a potential association between the endothelial lipase gene (LIPG) 584C/T polymorphism and susceptibility to coronary artery disease (CAD), but a uniform conclusion is yet to be reached. To better evaluate the true relationship between the LIPG 584C/T polymorphism and the risk of CAD, a meta-analysis of 14 case–control studies with 9731 subjects was performed. Relevant articles published through August 2020 were searched in the CNKI, PubMed, Embase and Web of Science databases. Thirteen articles, including 14 eligible case–control studies with 4025 cases and 5706 controls, were enrolled in the present meta-analysis. The Newcastle–Ottawa Scale (NOS) scores of the case–control studies ranged from 6 to 8. The pooled results indicated that there is a significant association between the LIPG 584C/T polymorphism and CAD in the homozygote comparison model and the allelic comparison model. Subgroup analyses revealed that the LIPG 584C/T mutation significantly decreased the risk of CAD in the subgroups of African, CAD, hospital-based (HB), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) populations in some genetic models. No publication bias was found in our meta-analysis, which certifies the robustness of the current meta-analysis. Trial sequential analysis (TSA) also confirmed the stability of our results. The results of our meta-analysis indicate that the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD. More high-quality case–control studies on various ethnicities are needed to confirm our results.
Chironomus Newsletter on Chironomidae Research 27

The spatial distribution of chironomid communities in the littoral zone (0-20 m) of the western coast of the southern Baikal basin is investigated. The fauna is composed of 16 species and forms of chironomid larvae, comprising 10 communities. It has been found that the communities are characterized by rather poor species diversity; Shannon’s index varies from 0.7 to 2.1 bit. Their distribution is affected by hydro-lithodynamic conditions, type of bottom sediments and macrophyte development. The peak of maximal biomass of chironomid larvae on the facies of non-rounded rock debris near Berezovy Cape is recorded in spring.
An artificial neural network‐based model to predict chronic kidney disease in aged cats

Abstract Background Chronic kidney disease (CKD) frequently causes death in older cats; its early detection is challenging. Objectives To build a sensitive and specific model for early prediction of CKD in cats using artificial neural network (ANN) techniques applied to routine health screening data. Animals Data from 218 healthy cats ≥7 years of age screened at the Royal Veterinary College (RVC) were used for model building. Performance was tested using data from 3546 cats in the Banfield Pet Hospital records and an additional 60 RCV cats—all initially without a CKD diagnosis. Methods Artificial neural network (ANN) modeling used a multilayer feed‐forward neural network incorporating a back‐propagation algorithm. Clinical variables from single cat visits were selected using factorial discriminant analysis. Independent submodels were built for different prediction time frames. Two decision threshold strategies were investigated. Results Input variables retained were plasma creatinine and blood urea concentrations, and urine specific gravity. For prediction of CKD within 12 months, the model had accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 88%, 87%, 70%, 53%, and 92%, respectively. An alternative decision threshold increased specificity and PPV to 98% and 87%, but decreased sensitivity and NPV to 42% and 79%, respectively. Conclusions and Clinical Importance A model was generated that identified cats in the general population ≥7 years of age that are at risk of developing CKD within 12 months. These individuals can be recommended for further investigation and monitoring more frequently than annually. Predictions were based on single visits using common clinical variables.
Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

The regulation of protein synthesis is a vital and finely tuned process in cellular physiology. In neurons, this process is very precisely regulated, as which mRNAs undergo translation is highly dependent on context. One of the most prominent regulators of protein synthesis is the enzyme eukaryotic elongation factor kinase 2 (eEF2K) that regulates the elongation stage of protein synthesis. This kinase and its substrate, eukaryotic elongation factor 2 (eEF2) are important in processes such as neuronal development and synaptic plasticity. eEF2K is regulated by multiple mechanisms including Ca2+‐ions and the mTORC1 signaling pathway, both of which play key roles in neurological processes such as learning and memory. In such settings, the localized control of protein synthesis is of crucial importance. In this work, we sought to investigate how the localization of eEF2K is controlled and the impact of this on protein synthesis in neuronal cells. In this study, we used both SH‐SY5Y neuroblastoma cells and mouse cortical neurons, and pharmacologically and/or genetic approaches to modify eEF2K function. We show that eEF2K activity and localization can be regulated by its binding partner Homer1b/c, a scaffolding protein known for its participation in calcium‐regulated signaling pathways. Furthermore, our results indicate that this interaction is regulated by the mTORC1 pathway, through a known phosphorylation site in eEF2K (S396), and that it affects rates of localized protein synthesis at synapses depending on the presence or absence of this scaffolding protein.
Indigenous microbial communities in Albertan sediments are capable of anaerobic benzene biodegradation under methanogenic, sulfate‐reducing, nitrate‐reducing, and iron‐reducing redox conditions

Alberta is a major center for oil and gas production, and correspondingly harbors hundreds of unresolved contamination sites by environmental hazards such as benzene (C6H6). Due to its cost‐effectiveness, bioremediation has become a promising strategy for C6H6 removal. Contamination sites typically take on an anaerobic context, which complicates the energetics of contamination sites and is a subject that is scarcely broached in studies of Albertan sediments. This study examines the innate potential for indigenous microbial communities in Albertan sediments to remove C6H6 in a multitude of reduced conditions. Community profiles of these sediments were analyzed by 16S rRNA gene amplicon sequencing, and removal rates and reaction stoichiometries were observed by gas chromatography and ion chromatography. Organisms belonging to known primary degrader taxa were identified, including Geobacter (iron‐reducing), and Peptococcaceae (nitrate‐reducing). Furthermore, benzene removal patterns of the cultures were similar to those observed in previously reported microcosms, with lag times between 70 and 168 days and removal rates between 3.27 and 12.70 µM/day. Such information could support a more comprehensive survey of Albertan sediment consortia, which may eventually be utilized in informing future remediation efforts in the province.
Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

Modern health care requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping, and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long‐lasting therapies. Escalating healthcare costs together with questions about the efficacy of the current management of allergic diseases require further development of a biomarker‐driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen immunotherapy with a special emphasis on specific IgE, the microbiome and the epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.