Miracle-dz/UniFAR-FTUs huggingface dataset:
Axonal pathology in hPSC-based models of Parkinson’s disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus

Significance Neurological dysfunction in Parkinson’s disease (PD) is highly associated with pathological deposits of aggregated α-synuclein (α-syn) in the brain, and yet an understanding of how early α-syn deposits bring about neuronal dysfunction remains elusive. This study exploits stem cell technology to model PD using two human isogenic stem cell models of the disease. Using these systems, we have identified a mechanism whereby mutant α-syn inhibits the antioxidant response, which, in turn, leads to axonal pathology through loss of expression of microtubule stabilizing proteins. We show that reactivation of this pathway can rescue axonal neuropathology. This is a demonstration of modulation of cytoskeletal elements as a potential therapy against PD, providing a previously unknown link between α-syn mutation and the antioxidant pathway. While mutations in the SNCA gene (α-synuclein [α-syn]) are causal in rare familial forms of Parkinson’s disease (PD), the prevalence of α-syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α-syn accumulation and disease pathogenesis. By employing a combination of human pluripotent stem cells (hPSCs) that harbor the SNCA-A53T mutation contrasted against isogenic controls, we evaluated the consequences of α-syn accumulation in human A9-type dopaminergic (DA) neurons (hNs). We show that the early accumulation of α-syn in SNCA-A53T hNs results in changes in gene expression consistent with the expression profile of the substantia nigra (SN) from PD patients, analyzed post mortem. Differentially expressed genes from both PD patient SN and SNCA-A53T hNs were associated with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2-mediated gene expression and neuritic pathology in SNCA-A53T hNs. We show that SNCA-mutant hNs have deficits in neuritic length and complexity relative to isogenic controls as well as contorted axons with Tau-positive varicosities. Furthermore, we show that mutant α-syn fails to complex with protein kinase C (PKC), which, in turn, results in impaired activation of Nrf2. These neuritic defects result from impaired Nrf2 activity on antioxidant response elements (AREs) localized to a microtubule-associated protein (Map1b) gene enhancer and are rescued by forced expression of Map1b as well as by both Nrf2 overexpression and pharmaceutical activation in PD neurons.
Agreement among equine veterinarians and between equine veterinarians and inertial sensor system during clinical examination of hindlimb lameness in horses.

BACKGROUND Hindlimb lameness evaluation is known to be challenging. Experience is essential for the ability of equine veterinarians to detect lameness. Nevertheless, even an experienced veterinarian is still subject to bias. Objective lameness detecting methods have been established to aid veterinarians. OBJECTIVES 1) to estimate the effect of experience on the inter-observer agreement and the agreement between a body-mounted inertial sensor system (BMISS) and veterinarians on detecting hindlimb lameness, and 2) to estimate the agreement between the BMISS and highly experienced veterinarians on change in lameness after diagnostic analgesia. STUDY DESIGN Cross-sectional study. METHODS Twenty-six horses with hindlimb lameness were evaluated in clinical conditions by clinicians and simultaneously measured by the BMISS. Videos of their lameness examination were recorded and shown to 13 veterinarians from three groups of varying experience for evaluation. The inter-observer agreement and the agreement between veterinarians and the BMISS were calculated. RESULTS Inter-observer agreement from all three groups was recorded as "fair". The strength of agreement between veterinarians and BMISS was "fair" for the highly experienced group, "slight to fair" for the moderately experienced group, and "slight" in the inexperienced group. The BMISS and the highly experienced veterinarians declared a "strong" agreement in assigning an improvement of lameness after diagnostic analgesia. MAIN LIMITATION Lameness evaluation through video viewing might be more challenging for some evaluators than live situations. CONCLUSIONS Given the task of evaluating videos of horses trotting in a straight line, the more experienced veterinarians did not show more reliability than those with less experience. Due to a) the moderate agreement between the BMISS and clinicians (highly experienced and moderately experienced) in the live clinical evaluation in determining hindlimb lameness, and b) the strong association between the BMISS and highly experienced veterinarians in determining improvement of lameness after anaesthesia, therefore the use of the BMISS as a supporting tool for veterinarians is encouraged. This article is protected by copyright. All rights reserved.
Late in-the-bag spontaneous IOL dislocation: risk factors and surgical outcomes.

AIM To evaluate the possible predisposing risk factors for late in-the-bag spontaneous IOL dislocations and to study the early surgical and visual outcomes of repositioning and exchange surgeries. METHODS Medical and surgical records of 39 eyes of 39 patients who underwent IOL repositioning or exchange surgery for dislocation between 2010 and 2018 were reviewed. Possible predisposing risk factors and some characteristics of late in-the-bag spontaneous IOL dislocations; outcomes of IOL repositioning and exchange surgeries, including visual acuity, refractive status before and after surgery and postoperative complications were evaluated. RESULTS The predisposing factors for late in-the-bag spontaneous IOL dislocations were pseudoexfoliation [PEX; 12/39 (30.8%)], previous vitreoretinal surgery [7/39 (17.9%)], axial myopia [3/39 (7.7%)], both PEX and axial myopia [1/39 (2.6%)], both previous vitreoretinal surgery and axial myopia [2/39 (5.1%)] and uveitis [1/39 (2.6%)]. The mean interval between cataract and dislocation surgery was 7.23y, greater in PEX positive group (8.63y). The mean best corrected visual acuity (BCVA) improved significantly after dislocation surgery (P<0.001) and also improved significantly after exchange surgery (P=0.001). The mean value of spherical equivalant decreased significantly after dislocation surgery (P=0.011), whereas corneal astigmatism increased but this difference was not significant after dislocation surgery and exchange surgery (P=0.191, P=0.074, respectively). CONCLUSION The most prevelant risk factors for late in-the-bag spontaneous IOL dislocations are PEX, previous vitreoretinal surgery and axial myopia. In the management of IOL dislocations, exchange surgery with small corneal incision seemed effective with improved BCVA and safety with low postoperative complications.
Predicting Group Contribution Behaviour in a Public Goods Game from Face-to-Face Communication

Experimental economic laboratories run many studies to test theoretical predictions with actual human behaviour, including public goods games. With this experiment, participants in a group have the option to invest money in a public account or to keep it. All the invested money is multiplied and then evenly distributed. This structure incentivizes free riding, resulting in contributions to the public goods declining over time. Face-to-face Communication (FFC) diminishes free riding and thus positively affects contribution behaviour, but the question of how has remained mostly unknown. In this paper, we investigate two communication channels, aiming to explain what promotes cooperation and discourages free riding. Firstly, the facial expressions of the group in the 3-minute FFC videos are automatically analysed to predict the group behaviour towards the end of the game. The proposed automatic facial expressions analysis approach uses a new group activity descriptor and utilises random forest classification. Secondly, the contents of FFC are investigated by categorising strategy-relevant topics and using meta-data. The results show that it is possible to predict whether the group will fully contribute to the end of the games based on facial expression data from three minutes of FFC, but deeper understanding requires a larger dataset. Facial expression analysis and content analysis found that FFC and talking until the very end had a significant, positive effect on the contributions.
A study validating the Italian version of the Level of Sitting Scale in children with cerebral palsy

Objectives: To assess measurement properties of the Italian version of the Level of Sitting Scale when classifying sitting ability of children with cerebral palsy. Design: Methodological study. Setting: Children’s hospital (inpatients and outpatients). Subjects: Children 18 years of age or younger with cerebral palsy. Methods: The original English version of the Level of Sitting Scale was translated and culturally adapted for the Italian culture following international guidelines. Examination of reliability and validity of the Italian Level of Sitting Scale was then undertaken. Inter-rater and one-week test–retest reliability were estimated using both intraclass correlation coefficients (ICCs) with 95% confidence intervals and Bland–Altman plots. Construct validity of the Italian Level of Sitting was evaluated using three approaches examining Pearson’s correlation coefficient (r) and Mann–Whitney U test (P-value < 0.05). Main measures: Italian Level of Sitting Scale and Gross Motor Function Classification System. Results: The Italian Level of Sitting Scale was administered to 109 subjects. Inter-rater reliability and one-week test–retest showed excellent value with ICCs of 0.99 for both. (1) The Pearson correlation coefficient comparing Italian Level of Sitting Scale with Gross Motor Function Classification System was −0.91 and (2) correlation with total amount of adaptive seating components was −0.90. Differences in sitting abilities and use/non-use of wheelchair were found. All reported a statistical significance of P < 0.01. Conclusion: Our findings provide evidence of reliability and validity when using the Italian Level of Sitting Scale to classify seated postural abilities in a sample of Italian children with cerebral palsy.
Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels

The human pan-tissue epigenetic clock is widely used for estimating age across the entire lifespan, but it does not lend itself well to estimating gestational age (GA) based on placental DNAm methylation (DNAm) data. We replicate previous findings demonstrating a strong correlation between GA and genome-wide DNAm changes. Using substantially more DNAm arrays (n=1,102 in the training set) than a previous study, we present three new placental epigenetic clocks: 1) a robust placental clock (RPC) which is unaffected by common pregnancy complications (e.g., gestational diabetes, preeclampsia), and 2) a control placental clock (CPC) constructed using placental samples from pregnancies without known placental pathology, and 3) a refined RPC for uncomplicated term pregnancies. These placental clocks are highly accurate estimators of GA based on placental tissue; e.g., predicted GA based on RPC is highly correlated with actual GA (r>0.95 in test data, median error less than one week). We show that epigenetic clocks derived from cord blood or other tissues do not accurately estimate GA in placental samples. While fundamentally different from Horvath’s pan-tissue epigenetic clock, placental clocks closely track fetal age during development and may have interesting applications.
Non-Invasive Biomarkers for Celiac Disease

Once thought to be uncommon, celiac disease has now become a common disease globally. While avoidance of the gluten-containing diet is the only effective treatment so far, many new targets are being explored for the development of new drugs for its treatment. The endpoints of therapy include not only reversal of symptoms, normalization of immunological abnormalities and healing of mucosa, but also maintenance of remission of the disease by strict adherence of the gluten-free diet (GFD). There is no single gold standard test for the diagnosis of celiac disease and the diagnosis is based on the presence of a combination of characteristics including the presence of a celiac-specific antibody (anti-tissue transglutaminase antibody, anti-endomysial antibody or anti-deamidated gliadin peptide antibody) and demonstration of villous abnormalities. While the demonstration of enteropathy is an important criterion for a definite diagnosis of celiac disease, it requires endoscopic examination which is perceived as an invasive procedure. The capability of prediction of enteropathy by the presence of the high titer of anti-tissue transglutaminase antibody led to an option of making a diagnosis even without obtaining mucosal biopsies. While present day diagnostic tests are great, they, however, have certain limitations. Therefore, there is a need for biomarkers for screening of patients, prediction of enteropathy, and monitoring of patients for adherence of the gluten-free diet. Efforts are now being made to explore various biomarkers which reflect different changes that occur in the intestinal mucosa using modern day tools including transcriptomics, proteomics, and metabolomics. In the present review, we have discussed comprehensively the pros and cons of available biomarkers and also summarized the current status of emerging biomarkers for the screening, diagnosis, and monitoring of celiac disease.
Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons.

Type 2 diabetes (T2D) hampers stroke recovery though largely undetermined mechanisms. Few preclinical studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 months with high-fat diet and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurological recovery by upper-limb grip strength at 1 and 6 weeks after tMCAO. Grey and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantified by immunohistochemistry, at 2 and 6 weeks after tMCAO. Obesity/T2D impaired neurological function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell proliferation and neuroblast formation in striatum and hippocampus at 2 weeks after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 weeks. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 weeks after stroke in both non-diabetic and obese/T2D mice. However, after 6 weeks, this effect selectively persisted in obese/T2D mice. We show in a preclinical setting of clinical relevance that obesity/T2D impairs neurological functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.
SeQuery: an interactive graph database for visualizing the GPCR superfamily

Abstract The rate at which new protein and gene sequences are being discovered has grown explosively in the omics era, which has increasingly complicated the efficient characterization and analysis of their biological properties. In this study, we propose a web-based graphical database tool, SeQuery, for intuitively visualizing proteome/genome networks by integrating the sequential, structural and functional information of sequences. As a demonstration of our tool’s effectiveness, we constructed a graph database of G protein-coupled receptor (GPCR) sequences by integrating data from the UniProt, GPCRdb and RCSB PDB databases. Our tool attempts to achieve two goals: (i) given the sequence of a query protein, correctly and efficiently identify whether the protein is a GPCR, and, if so, define its sequential and functional roles in the GPCR superfamily; and (ii) present a panoramic view of the GPCR superfamily and its network centralities that allows users to explore the superfamily at various resolutions. Such a bottom-up-to-top-down view can provide the users with a comprehensive understanding of the GPCR superfamily through interactive navigation of the graph database. A test of SeQuery with the GPCR2841 dataset shows that it correctly identifies 99 out of 100 queried protein sequences. The developed tool is readily applicable to other biological networks, and we aim to expand SeQuery by including additional biological databases in the near future.
Adult-onset asymmetrical lipomatosis.

To the Editor: An 85-year-old woman presented with extra growth of subcutaneous fat at the left anterior infradiaphragm that expanded circumferentially to the left back over the last 4 years. Two years prior to the current presentation, the left thigh became visibly thicker than the right. Diffuse subtle lipomatosis affecting the ipsilateral face, neck, arms, calf, and foot was noted at that time. Additionally, the patient had hyperlipidemia, gastroesophageal reflux disease, osteoporosis, and scoliosis, all beginning in her late 60s. She reported no alcohol or tobacco use and was taking rosuvastatin, esomeprazole, calcium, vitamin D, and glucosamine. There was no reported family history of asymmetric growth or bony deformities, and her children were healthy. On physical examination, the lipomatosis affected the entire left side, most prominently around the abdomen, back, and thighs. The affected side was nontender and nonpruritic; there was no atrophy of the unaffected side (Figure). Maximum thigh circumference was 55.1 cm on the affected side and 52.6 cm on the unaffected side. There were no differences in power, reflex, or sensation between the 2 sides, and no hyperhidrosis or vascular malformations were present. Laboratory investigations, including complete blood cell count, complete metabolic panel, lipids, and thyroid-stimulating and sex hormone panels all were within reference range. Enzi et al1 reported 2 women who developed asymmetrical lipomatosis between the ages of 13 and 20 years. Acquired asymmetrical lipomatosis should be differentiated from the asymmetrical overgrowth diagnosed in neonates and infants. Proteus syndrome (PS) is a progressive disease involving a combination of overgrowth in a mosaic distribution, connective tissue and epidermal nevi, ovarian cysts, parotid gland tumor, dysregulated adipose tissue, lymphovascular malformation, and certain facial phenotypes.2,3 The average age of onset is 6 to 18 months, and Adult-Onset Asymmetrical Lipomatosis
Excess Membrane Cholesterol is an Early Contributing Reversible Aspect of Skeletal Muscle Insulin Resistance in C57BL/6NJ Mice Fed a Western-Style High-Fat Diet.

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter GLUT4 regulation occurs early after high-fat feeding. We fed six-week old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for one week. This HF-feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet, or two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3- and 6-days during the one-week HF-feeding intervention, completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.
Execution model and optimizing compilation for execution migration

Although systems with hardware support for fine-grained execution migration are becoming a reality, no concrete execution model or compiler exist for these machines. This limits the complexity of software that can be written for these machines, and therefore also the scope of studies for which these machines can be used. In this thesis, we define a productive programming model for an execution migration platform by exposing migration as a set of interfaces usable with the C programming language via a custom optimizing compiler. We employ hardware-software co-design to describe a stack core architecture with support for partial context migration in order to simplify the compiler problem and improve compiler efficiency. We also consider instruction encoding in abstract terms to establish a baseline comparison of encoded instruction density to an ideal upper bound. The stack-based execution migration platform offers a new and unexplored cost model, which leads us to reevaluate the trade-offs associated with compilation for these architectures, and to explore novel algorithms, or novel applications of existing optimizations. Throughout this work, we attempt to gain a deep understanding of the costs and benefits of execution migration by aggressive design space exploration. We use the insight gained to better inform the the problem of compiling to this unorthodox architecture, and design the compiler, a library of optimized parallel primitives, and a set of compiler optimization passes to best reflect and utilize the underlying hardware. Thesis Supervisor: Srinivas Devadas Title: Professor