Miracle-dz/UniFAR-FTUs huggingface dataset:
δ-Catenin Is Genetically and Biologically Associated with Cortical Cataract and Future Alzheimer-Related Structural and Functional Brain Changes

Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, ρ = 0.24, P<10−4). A genome-wide association study using 187,657 single nucleotide polymorphisms (SNPs) for the bivariate outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6×10−7). These SNPs were also significantly associated with bivariate outcomes of CC and scores on several highly heritable neuropsychological tests (5.7×10−9≤P<3.7×10−6). Statistical interaction was demonstrated between rs17183619 and APP SNP rs2096488 on CC (P = 0.0015) and CC-THV (P = 0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-β1–42 in neuronal cell culture. Immunohistopathological analysis of lens tissue obtained from two autopsy-confirmed AD subjects and two non-AD controls revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in delta catenin may underlie both cortical lens opacities in mid-life and subsequent MRI and cognitive changes that presage the development of AD.
High-resolution structure of a Shigella type III secretion needle by solid-state NMR and cryo-electron microscopy

We introduce a general hybrid approach for determining the structures of supramolecular assemblies. Cryo-electron microscopy (cryo-EM) data define the overall envelope of the assembly and rigid-body orientation of the subunits while solid-state NMR (ssNMR) chemical shifts and distance constraints define the local secondary structure, protein fold and inter-subunit interactions. Finally, Rosetta structure calculations provide a general framework to integrate the different sources of structural information. Combining a 7.7-Å cryo-EM density map and 996 ssNMR distance constraints, the structure of the Type-III Secretion System (T3SS) needle of Shigella flexneri is determined to a precision of 0.4 Å. The calculated structures are cross-validated using an independent dataset of 691 ssNMR constraints and STEM measurements. The hybrid model resolves the conformation of the non-conserved N-terminus, that occupies a protrusion in the cryo-EM density, and reveals conserved pore residues forming a continuous pattern of electrostatic interactions, thereby suggesting a mechanism for effector protein translocation.
Improving accuracy in indoor localization system using fingerprinting technique

Indoor localization system is an important topic in the wireless navigation system. Many technologies, such as Wi-Fi, Bluetooth, and ZigBee, have been developed for the indoor localization system; however, these systems still demonstrate poor accuracy and performance. The indoor localization system using Wi-Fi signals is the best option for indoor localization because most of the buildings are covered by Wi-Fi access points. In this paper, we proposed a clustering algorithm to improve the system accuracy for indoor environment and reduce computational time. Fingerprinting technique was used to evaluate the performance of the proposed algorithm. Results show that the clustering algorithm achieves an average distance error of 2.4 m compared with the non-clustering algorithm, which has an average distance error of 3.4 m. In particular, the clustering algorithm improves the system accuracy by 41% compared with the conventional algorithm. Moreover, the clustering algorithm reduces the computational time of the system that requires computing the prediction of mobile user location.
Health, Wellbeing, and Academic Achievement among Urban College Students

The post-secondary educational environment is full of demands—both academically and outside of the direct college setting—and as a result, stress is a prevailing concern for college students. Chronic, high levels of stress have been linked to a number of negative health outcomes, such as anxiety and depression, and academic outcomes, such as lower academic achievement. Using a diverse sample of undergraduate and masters students [n=84; mean (SD) age = 22.89 (5.99) years] from an urban, public college, the current study measured students’ experiences of stress (Perceived Stress Scale) and the adaptive and maladaptive strategies they utilized to cope with stress, including mindfulness (Mindful Attention Awareness Scale), physical activity (International Physical Activity Questionnaire – Short Form), and substance use (Rutgers Collegiate Substance Abuse Screening Test). This study then assessed whether these experiences differed for students who were achieving highly (as measured by semester-end GPA) and whether stress predicted anxiety (Beck Anxiety Inventory) and depression (Beck Depression Inventory-II). Participants completed three surveys at the beginning, middle, and end of the academic semester. Participants experienced chronic, high levels of stress and a substantial minority experienced moderate to severe levels of anxiety and depression. Experiences of stress did not differ as a function of academic achievement. Few students expressed problem substance use and most engaged in moderate to high levels of physical activity. There is preliminary evidence to suggest that changes in stress and mindfulness were predictive of changes in anxiety and depression. These results suggest that promoting mindfulness and physical activity as interventions in college settings may be beneficial to buffer the effects of stress on anxiety and depression. Future studies delineating the sources of stress and their relation to coping strategies may help to better identify those most likely to benefit from these strategies. Furthermore, HEALTH, WELLBEING, & ACADEMIC ACHIEVEMENT viii assessing concurrent coping strategies specifically associated with academics would help to further clarify the role of mindfulness and physical activity as adaptive coping mechanisms.
The Role of Perceived Cost toward on Continuance Intention of Mobile TV: Focused on Chinese users

This study highlight the role of perceived cost on user's continuance intention to use mobile TV service in china. We proposed research model based on the expectation-confirmation model(ECM) and reclaim 243 questionnaires from experienced users in china. Above all, the analysis results support significant relationship perceived variables, satisfaction, and continuance intention of mobile TV. First, while expectation confirmation has positive influence on perceived playfulness and satisfaction, the effect on perceived usefulness is not significant. Second, perceived cost can significantly predict perceived usefulness and satisfaction, however, we found no evidence of a statistically significant influence on perceived playfulness. Third, perceived usefulness and perceived playfulness have a positive influence on satisfaction, and perceived usefulness, satisfaction, and perceived playfulness have a positive influence on continuance intention. This results provide implications from both theoretical and managerial perspectives and the limitations have been discussed for future research.
Deep brain stimulation relieves refractory hypertension

Increased activity of the sympathoadrenal system plays a major role in the pathogenesis of essential hypertension and end organ damage.1,2 Recent effective antihypertensive strategies have manipulated autonomic nervous control mechanisms including renal nerve ablation.1 Here, we present the first patient in whom refractory hypertension was controlled chronically with deep brain stimulation (DBS) of the ventrolateral periaqueductal gray (PAG)/periventricular gray (PVG) as a primary response and not secondary to associated pathologic changes. ### Level of evidence. This study provides Class IV evidence that chronic electrical stimulation of the PAG/PVG may provide effective treatment for controlling blood pressure in patients with drug-resistant hypertension. ### Case report. A 55-year-old man developed left-sided weakness, and an ischemic stroke affecting the internal capsule was diagnosed (figure e-1A on the Neurology ® Web site at www.neurology.org). At hospital admission, hypertension and hypercholesterolemia were diagnosed. In the peristroke period, blood pressure readings ranged from 265/96 to 153/89 mm Hg, and antihypertensive medication was prescribed: atenolol (50 mg), diltiazem (240 mg), perindopril (4 mg), and indapamide (1.25 mg). Aspirin (75 mg) and simvastatin (40 mg) were also prescribed. This medication regimen maintained his blood pressure at 145/69 mm Hg. Four months later, subsequent to multiple dose increases in the quadruple therapy, his blood pressure ranged from 153/87 to 134/72 mm Hg. Unfortunately, although his hemiplegia resolved, he developed a severe left-sided hemibody central pain syndrome that proved refractory to treatment over the following 3 years, leading to referral for DBS to treat his pain. With use of established protocols3 and a MRI-guided stereotactic technique, the PAG/PVG region was …
Targeted O‐glycoproteomics explored increased sialylation and identified MUC16 as a poor prognosis biomarker in advanced‐stage bladder tumours

Bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation on the cell surface, which may be explored for improving disease management. In a search for prognosis biomarkers and novel therapeutic targets we have screened, using immunohistochemistry, a series of bladder tumours with differing clinicopathology for short‐chain O‐glycans commonly found in glycoproteins of human solid tumours. These included the Tn and T antigens and their sialylated counterparts sialyl‐Tn(STn) and sialyl‐T(ST), which are generally associated with poor prognosis. We have also explored the nature of T antigen sialylation, namely the sialyl‐3‐T(S3T) and sialyl‐6‐T(S6T) sialoforms, based on combinations of enzymatic treatments. We observed a predominance of sialoglycans over neutral glycoforms (Tn and T antigens) in bladder tumours. In particular, the STn antigen was associated with high‐grade disease and muscle invasion, in accordance with our previous observations. The S3T and S6T antigens were detected for the first time in bladder tumours, but not in healthy urothelia, highlighting their cancer‐specific nature. These glycans were also overexpressed in advanced lesions, especially in cases showing muscle invasion. Glycoproteomic analyses of advanced bladder tumours based on enzymatic treatments, Vicia villosa lectin‐affinity chromatography enrichment and nanoLC‐ESI‐MS/MS analysis resulted in the identification of several key cancer‐associated glycoproteins (MUC16, CD44, integrins) carrying altered glycosylation. Of particular interest were MUC16 STn+‐glycoforms, characteristic of ovarian cancers, which were found in a subset of advanced‐stage bladder tumours facing the worst prognosis. In summary, significant alterations in the O‐glycome and O‐glycoproteome of bladder tumours hold promise for the development of novel noninvasive diagnostic tools and targeted therapeutics. Furthermore, abnormal MUC16 glycoforms hold potential as surrogate biomarkers of poor prognosis and unique molecular signatures for designing highly specific targeted therapeutics.
Does the 1H-NMR plasma metabolome reflect the host-tumor interactions in human breast cancer?

Breast cancer (BC) is the most common diagnosed cancer and the leading cause of cancer death in women worldwide. There is an obvious need for a better understanding of BC biology. Alterations in the serum metabolome of BC patients have been identified but their clinical significance remains elusive. We evaluated by 1H-Nuclear Magnetic Resonance (1H-NMR) spectroscopy, filtered plasma metabolome of 50 early (EBC) and 15 metastatic BC (MBC) patients. Using Principal Component Analysis, Partial Least-Squares Discriminant Analysis and Hierarchical Clustering we show that plasma levels of glucose, lactate, pyruvate, alanine, leucine, isoleucine, glutamate, glutamine, valine, lysine, glycine, threonine, tyrosine, phenylalanine, acetate, acetoacetate, β-hydroxy-butyrate, urea, creatine and creatinine are modulated across patients clusters. In particular lactate levels are inversely correlated with the tumor size in the EBC cohort (Pearson correlation r = −0.309; p = 0.044). We suggest that, in BC patients, tumor cells could induce modulation of the whole patient's metabolism even at early stages. If confirmed in a lager study these observations could be of clinical importance.
Metabotropic Glutamate Receptor 2 and 3 Gene Expression in The Human Prefrontal Cortex and Mesencephalon in Schizophrenia

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.
Admixture mapping of ankle–arm index: identification of a candidate locus associated with peripheral arterial disease

Background Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle–arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD. Methods The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus. Results The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95% CI 1.29 to 2.76). Conclusion This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans.
Genetic Effects in Drosophila on the Potency of Diverse General Anesthetics: A Distinctive Pattern of Altered Sensitivity

Mutations that influence the sensitivity of an organism to a volatile general anesthetic can be divided into two classes. In one, sensitivity to all other volatile agents is affected to a similar degree. Although this class may contain mutations of interest for understanding anesthesia, it is also likely to contain mutations that merely alter general health. In the second class, mutations confer non-uniform effects on potency (NEP), i.e., larger effects for some volatile anesthetics than for others. Members of this class are of special interest for studies of arousal and its pharmacological suppression because they not only avoid the pitfall of effects on global health, but also imply the existence of drug targets that are preferentially affected by particular agents. In this work, we provide the first systematic investigation of the relative frequency and diversity of NEP mutations in Drosophila. As a first step, we isolated and characterized a set of P element insertion mutations that confer altered sensitivity of the fruit fly to the clinical anesthetic halothane. Then we tested the members of this collection for their effect on the sensitivity of flies to five other volatile agents. Not only do we find that most of the mutations show non-uniform effects, they also share a characteristic arrangement of altered potencies (halothane > >desflurane ≥ enflurane~isoflurane~methoxyflurane > sevoflurane). From this result, although we do not know how direct or indirect are the effects of the mutations, we infer the existence of a biologically relevant target for anesthetic action that has a distinct preference for halothane over other agents. Intriguingly, P element insertions that co-map with several NEP loci have been shown to alter the fly's response to cocaine and ethanol, suggesting that common genetic elements are involved in the response to all three drugs.
Criteria for validating mouse models of psychiatric diseases

Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing the validity of a mouse model of a human brain dysfunction. We address the common question raised by molecular geneticists and clinical researchers in psychiatry, “what is a ‘good enough’ mouse model”11 Published 2008 Wiley‐Liss, Inc.
A PCP characterization of NP with optimal amortized query complexity

For every ε > 0 and integers k and q (with k ≤ q ≤ k + k/4), we present a PCP characterization of NP where the verifier queries q bits (of which only k are free bits), accepts a correct proof with probability ≥ 1 − ε and accepts a “proof” of a wrong statement with probability ≤ 2. In particular, for every δ > 0 we have a PCP characterization of NP where the verifier has, simultaneously, 1 + δ amortized query complexity and δ amortized free bit complexity. Both results are tight, unless P = NP . The optimal amortized query complexity of our verifier implies essentially tight nonapproximability results for constraint satisfaction problems. Specifically, we can show that k-CSP, the problem of finding an assignment satisfying the maximum number of given constraints (where each constraint involves at most k variables) is NP-hard to approximate to within a factor 2 √ . The problem can be approximated to within a factor 2, and was known to be NP-hard to approximate to within a factor about 2. We can also prove some new separation results between different PCP model. A PCP characterization of NP with optimal amortized free bit complexity implies that for every δ > 0 it is hard to approximate the maximum clique problem to within a n factor. Such a characterization had already been proved by H̊astad [H̊as96], in a celebrated recent breakthrough. Our construction gives an alternative, simpler, proof of this result. Our techniques also give a tight analysis of linearity testing algorithms with low amortized query complexity. As in the case of PCP, we show that it is possible to have a linearity testing algorithm that makes q queries and has error bounded from above by 2 √ . We also prove a lower bound showing that, for a certain, fairly general, class of testing algorithms, our analysis is tight even in the lower order term. That is, we show that the error of a q-query testing algorithm in this class has to be at least 2 √ . ∗ asamor@ias.edu. Institute for Advanced Study and DIMACS † luca@cs.columbia. edu. Columbia University. Work partly done at DIMACS.
Protective role of metformin against chronic experimental pulmonary arterial hypertension

Background: Our previous study has indicated that activation of AMPK inhibits the proliferation of rat pulmonary artery smooth muscle cells (PASMCs) in vitro through inhibiting the expression of S phase kinase-associated protein 2 (Skp2), which in turn up-regulates the p27 expression. In the present study, we intended to determine whether similar mechanisms have been involved in rat PAH model. Methods: Rat pulmonary arterial hypertension (PAH) model was established by intraperitoneal injection of monocrotaline (MCT). Metformin was administered to activate AMPK. Parameters including the right ventricle systolic pressure (RVSP), the right ventricular hypertrophy (RVH) and the percentage of medial wall thickness were used to evaluate the development of PAH. Immunoblotting was used to determine the phosphorylation and expression of AMPK, and expression of Skp2 and p27. Results: Metformin significantly decreased the RVSP and inhibited the RVH in MCT-induced rat PAH model, and partially inhibited the pulmonary vascular remodeling. These effects were coupled with the decrease of Skp2 and increase of p27 expressions as well as the activation of AMPK. Conclusions: Metformin benefits PAH by inhibiting proliferation of PASMCs and reducing pulmonary vascular remodeling. The present study suggests that metformin might have potential value in clinical treatment of PAH.
β‐catenin signalling in mesenchymal islet‐derived precursor cells

Abstract. Objectives: Previously, we characterized human islet‐derived precursor cells (hIPCs) as mesenchymal stem cells that migrate out from islets in vitro and can differentiate into functional islet‐like structures following proliferative expansion. Here, we investigate the role of β‐catenin signalling in derivation and proliferation of hIPCs. Materials and methods: Localization of β‐catenin was performed using confocal microscopy. Expression levels of β‐catenin target genes were measured by quantitative real‐time polymerase chain reaction. Loss‐of‐function studies were performed using specific short interfering RNAs. Results: Immunostaining of islet outgrowths revealed translocation of β‐catenin from plasma membranes in intact islets to the nucleus in cells migrating out. There were no nuclear β‐catenin‐positive cells in intact islets whereas between 35% and 70% of cells in established hIPC cultures exhibited nuclear β‐catenin. Transcripts for β‐catenin target genes were increased in hIPCs compared to those in islets. β‐Catenin translocated to the cell membrane when hIPCs formed epithelial cell clusters. In proliferating hIPCs, there was a strong correlation between markers of proliferation and nuclear β‐catenin. Treatment of hIPCs with the glycogen synthase kinase‐3β inhibitor (2′Z,3′E)‐6‐Bromoindirubin‐3′‐oxime increased intracellular β‐catenin but reduced nuclear β‐catenin, and was associated with reduced cell proliferation. Finally, knockdown of β‐catenin decreased β‐catenin target gene expression and hIPC proliferation. Conclusions: These results support a functional role for β‐catenin during proliferation of hIPCs and suggest that activated β‐catenin signalling may also be important during hIPC derivation from islets.