Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10−4, permutation p = 1.0×10−3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10−7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.
Abstract SELF-HEALING CIRCUITS USING STATISTICAL ELEMENT SELECTION by

SELF-HEALING CIRCUITS USING STATISTICAL ELEMENT SELECTION by Gokce Keskin Doctor of Philosophy in Electrical and Computer Engineering Carnegie Mellon University Professor Lawrence T. Pileggi, Chair Process variations in advanced CMOS process nodes limit the benefits of scaling for analog designs. In the presence of increasing random intra-die variations, mismatch becomes a significant design challenge in circuits such as comparators. In this dissertation, the statistical element selection (SES) methodology that was first proposed in [1] is analyzed in detail and extended to accommodate a broader spectrum of circuits and systems. SES relies on choosing a subset of selectable circuit elements (e.g., input transistors in a comparator) to achieve the desired specification (e.g., offset). Silicon results from a 65nm bulk CMOS test chip demonstrate that it can achieve an order of magnitude better matching than both redundancy and simple scaling given the same core circuit area. To demonstrate its efficacy, we applied SES to enable a novel flash ADC topology in 45nm SOI CMOS that operated at 1GS/s and achieved 4.6bits of ENOB with a figure of merit of 160fJ/step. SES is also applied to an array of microelectromechanical resonators to improve the expected yield of RF MEMS filters.
Utilization and in-hospital complications of cardiac resynchronization therapy: trends in the United States from 2003 to 2013

Aims Cardiac resynchronization therapy (CRT) device implantation has been shown to reduce morbidity and mortality in selected patients with heart failure. We sought to investigate the utilization and in-hospital complications of cardiac resynchronization therapy defibrillator (CRT-D) and pacemaker (CRT-P) implantations in the United States from 2003 to 2013. Methods and results Patients receiving CRT-D or CRT-P were identified in the National Inpatient Sample database (NIS), using the International Classification of Diseases-Ninth Revision-Clinical Modification procedure codes. Annual implantation rates, patient demographics, co-morbidities, in-hospital complications, and length of stay were analysed. From 2003 to 2013, an estimated total of 439 010 (95% CI: 406 723-471 296) inpatient CRT implantations were performed in the U.S. The median age of patients was 72 and 71% were male. Overall, 6.1% had at least one complication. During the study period, comorbidity index and overall complication rate increased (P = 0.002 and P = 0.01, respectively). Mortality and length of stay showed no significant trend. Predictors of complications included: age 65 and older, female sex (OR: 1.19; 95% CI: 1.12-1.27), Deyo-Charlson Comorbidity Index, and elective admission (OR: 0.61; 95% CI: 0.57-0.66). Conclusion From 2003 to 2013, the severity of comorbid conditions increased and a rising trend was observed in the rate of periprocedural complications among patients undergoing CRT in the United States. In-hospital mortality and length of stay showed no uniform trend.
Treatment of Hepatitis C in Children: A Systematic Review

Background Current guidelines recommend children be treated for hepatitis C virus (HCV) using the same principles applied in adults. There are however few published studies which assess the efficacy and safety of HCV therapy in children. Methodology/Principal Findings A systematic review of the literature was completed for studies of any design that evaluated HCV therapy in children. The primary outcome was sustained virologic response (SVR), with sub-group analysis of response rates by genotype. There were 4 randomized controlled trials (RCTs) and 31 non-randomized studies, all involving interferon, pegylated interferon (PEG-IFN), or combinations of these drugs with ribavirin. The SVR rate could not be directly compared as the populations and interventions differed across studies. Genotype was not reported or differed substantially from study to study. The overall SVR rate for PEG-IFN and ribavirin ranged from 30 to 100% which is comparable to the rate in adults. Similar to adults, the SVR rates were significantly higher in children with genotype 2 or 3 compared to genotype 1. Adverse effects were primarily flu-like symptoms and neutropenia. There were insufficient data to assess the applicability of the week 12 stop rule (stopping therapy at week 12 if there is less than a 2 log drop in HCV RNA) or the efficacy of shortening therapy to 24 weeks in children with genotype 2 and 3. Conclusions/Significance Current guidelines for the treatment of HCV in children are based on limited data. Further research is needed to define the optimal therapy for HCV in children.
Proteolytic processing of palmitoylated Hedgehog peptides specifies the 3-4 intervein region of the Drosophila wing

Cell fate determination during development often requires morphogen transport from producing to distant responding cells. Hedgehog (Hh) morphogens present a challenge to this concept, as all Hhs are synthesized as terminally lipidated molecules that form insoluble clusters at the surface of producing cells. While several proposed Hh transport modes tie directly into these unusual properties, the crucial step of Hh relay from producing cells to receptors on remote responding cells remains unresolved. Using wing development in Drosophila melanogaster as a model, we show that Hh relay and direct patterning of the 3–4 intervein region strictly depend on proteolytic removal of lipidated N-terminal membrane anchors. Site-directed modification of the N-terminal Hh processing site selectively eliminated the entire 3–4 intervein region, and additional targeted removal of N-palmitate restored its formation. Hence, palmitoylated membrane anchors restrict morphogen spread until site-specific processing switches membrane-bound Hh into bioactive forms with specific patterning functions.
A human prefrontal-subthalamic circuit for cognitive control

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson's disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson's disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.awx300media15660002226001.
Ursolic Acid Hydrazide Based Organometallic Complexes: Synthesis, Characterization, Antibacterial, Antioxidant, and Docking Studies

In thecurrent research work,eleven metal complexes were synthesized from the hydrazide derivative of ursolic acid. Metal complexes of tin, antimony and iron were synthesized and characterized by FT-IR and NMR spectroscopy. The antibacterial and antioxidant activities were performed for these complexes, which revealed that the metal complexes synthesized are more potent than their parent compounds. We observed that antioxidant activity showed by triphenyltin complex was significant and least activity have been shown by antimony trichloride complex. The synthesized metal complexes were then evaluated against two Gram-negative and two Gram-positive bacterial strains. Triphenyl tin complex emerged as potent antibacterial agent with MIC value of 8 μg/ml each against Shigellaspp, Salmonella typhi and Staphylococcus aureus. While, the MIC value against Streptococcus pneumoniae is 4 μg/ml. Computational docking studies were carried out on molecular targets to interpret the results of antioxidant and antibacterial activities. Based on the results, it may be inferred that the metal complexes of ursolic acid are more active as compared to the parent drug and may be proved for some other pharmacological potential by further analysis.
Grasp Detection from Human ECoG during Natural Reach-to-Grasp Movements

Various movement parameters of grasping movements, like velocity or type of the grasp, have been successfully decoded from neural activity. However, the question of movement event detection from brain activity, that is, decoding the time at which an event occurred (e.g. movement onset), has been addressed less often. Yet, this may be a topic of key importance, as a brain-machine interface (BMI) that controls a grasping prosthesis could be realized by detecting the time of grasp, together with an optional decoding of which type of grasp to apply. We, therefore, studied the detection of time of grasps from human ECoG recordings during a sequence of natural and continuous reach-to-grasp movements. Using signals recorded from the motor cortex, a detector based on regularized linear discriminant analysis was able to retrieve the time-point of grasp with high reliability and only few false detections. Best performance was achieved using a combination of signal components from time and frequency domains. Sensitivity, measured by the amount of correct detections, and specificity, represented by the amount of false detections, depended strongly on the imposed restrictions on temporal precision of detection and on the delay between event detection and the time the event occurred. Including neural data from after the event into the decoding analysis, slightly increased accuracy, however, reasonable performance could also be obtained when grasping events were detected 125 ms in advance. In summary, our results provide a good basis for using detection of grasping movements from ECoG to control a grasping prosthesis.
Incompleteness Shocks ∗

This paper studies the effects of shocks to the degree of market completeness. We present a dynamic stochastic economy where agents can trade in complete markets in normal times, but where financial markets can stochastically become incomplete. When this happens, agents cannot trade in state contingent assets and cannot re-hedge their risks. Our model formalizes a new type of purely financial shock, which we call an incompleteness shock. Even if we allow our agents to hedge the incompleteness shock itself, we find that these shocks are sufficient to trigger a recession with misallocation of capital, lower aggregate output, and consumption. Our results imply that financial market disruptions will unavoidably generate a recession, even if they are perfectly anticipated and agents can freely reallocate resources ex-ante. JEL numbers: E44, E32, G12
The Discriminative Effect of Ownership Structure on Stock Returns in Taiwan during Bear Markets

A number of papers have found evidences that better corporate governance leads to better operating per formance or firm value. But the relation between corporate governanc e and stock prices or returns is not concluded yet. Previous consensus regarding stock returns is that the retur ns are unpredictable and prices are characterized b y a random walk. But the earlier consensus has been replaced by a vi ew that returns are predictable, particularly at lo nger time horizons. Under consideration of control variables or conditi ons, some literature finds that ownership structure has a powerful effect on stock prices or returns. The interest of this paper is to investigate the discriminative effect of ownership structure on stock returns in Taiwan during bull an d bear periods. The results suggest that the discri minative effect of ownership structure on stock returns not only depen ds on control rights but also on market status. The hypothesis is
Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1&agr; and Causes Mitochondrial Dysfunction in Diabetic Embryopathy

Endoplasmic reticulum (ER) stress has been implicated in the development of maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP homologous protein (CHOP) plays an important role in the pro-apoptotic execution pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced neuroepithelium cell apoptosis in diabetic embryopathy is still unclear. Deletion of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and neuroepithelium cell apoptosis. Further analysis demonstrated that CHOP repressed the expression of peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α), an essential regulator for mitochondrial biogenesis and function. Both CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed PGC-1α expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1α by high glucose. In response to the ER stress inducer tunicamycin, PGC-1α expression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid blocked high glucose-suppressed PGC-1α expression. Moreover, maternal diabetes in vivo and high glucose in vitro promoted the interaction between CHOP and the PGC-1α transcriptional regulator CCAAT/enhancer binding protein-β (C/EBPβ), and reduced C/EBPβ binding to the PGC-1α promoter leading to markedly decrease in PGC-1α expression. Together, our findings support the hypothesis that maternal diabetes-induced ER stress increases CHOP expression which represses PGC-1α through suppressing the C/EBPβ transcriptional activity, subsequently induces mitochondrial dysfunction and ultimately results in NTDs.
On the Race of Worms and Patches: Modeling the Spread of Information in Wireless Sensor Networks

Sensor networks are a branch of distributed ad hoc networks with a broad range of applications in surveillance and environment monitoring. In these networks, message exchanges are carried out in a multi-hop manner. Due to resource constraints, security professionals often use lightweight protocols, which do not provide adequate security. Even in the absence of constraints, designing a foolproof set of protocols and codes is almost impossible. This leaves the door open to the worms that take advantage of the vulnerabilities to propagate via exploiting the multi-hop message exchange mechanism. This issue has drawn the attention of security researchers recently. In this paper, we investigate the propagation pattern of information in wireless sensor networks based on an extended theory of epidemiology. We develop a geographical susceptible-infective model for this purpose and analytically derive the dynamics of information propagation. Compared with the previous models, ours is more realistic and is distinguished by two key factors that had been neglected before: 1) the proposed model does not purely rely on epidemic theory but rather binds it with geometrical and spatial constraints of real-world sensor networks and 2) it extends to also model the spread dynamics of conflicting information (e.g., a worm and its patch). We do extensive simulations to show the accuracy of our model and compare it with the previous ones. The findings show the common intuition that the infection source is the best location to start patching from, which is not necessarily right. We show that this depends on many factors, including the time it takes for the patch to be developed, worm/patch characteristics as well as the shape of the network.
Effects of Screw Configuration on the Preload Force of Implant-Abutment Screws.

PURPOSE The aim of this study was to investigate the effects of tightening torque, screw head angle, and thread number on the preload force of abutment screws. MATERIALS AND METHODS The test specimens consisted of three self-manufactured components (ie, a thread sleeve serving as an implant analog, an abutment analog, and an abutment screw). The abutment screws were fabricated with metric M1.6 external threads. The thread number varied between one and seven threads. The screw head angles were produced in eight varying angles (30 to 180 degrees). A sensor unit simultaneously measured the preload force of the screw and the torsion moment inside the screw shank. The tightening of the screw with the torque wrench was performed in five steps (15 to 35 Ncm). The torque wrench was calibrated before each step. RESULTS Only the tightening torque and screw head angle affected the resulting preload force of the implant-abutment connection. The thread number had no effect. There was an approximately linear correlation between tightening torque and preload force. CONCLUSION The tightening torque and screw head angle were the only study parameters that affected the resulting preload force of the abutment screw. The results obtained from this experiment are valid only for a single torque condition. Further investigations are needed that analyze other parameters that affect preload force. Once these parameters are known, it will add value for a strong, but detachable connection between the implant and abutment. Short implants and flat-to-flat connections especially will benefit significantly from this knowledge.
Aliskiren combined with losartan in type 2 diabetes and nephropathy.

BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. METHODS We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. RESULTS The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. CONCLUSIONS Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).
Non-Hemagglutinating Flaviviruses: Molecular Mechanisms for the Emergence of New Strains via Adaptation to European Ticks

Tick-borne encephalitis virus (TBEV) causes human epidemics across Eurasia. Clinical manifestations range from inapparent infections and fevers to fatal encephalitis but the factors that determine disease severity are currently undefined. TBEV is characteristically a hemagglutinating (HA) virus; the ability to agglutinate erythrocytes tentatively reflects virion receptor/fusion activity. However, for the past few years many atypical HA-deficient strains have been isolated from patients and also from the natural European host tick, Ixodes persulcatus. By analysing the sequences of HA-deficient strains we have identified 3 unique amino acid substitutions (D67G, E122G or D277A) in the envelope protein, each of which increases the net charge and hydrophobicity of the virion surface. Therefore, we genetically engineered virus mutants each containing one of these 3 substitutions; they all exhibited HA-deficiency. Unexpectedly, each genetically modified non-HA virus demonstrated increased TBEV reproduction in feeding Ixodes ricinus, not the recognised tick host for these strains. Moreover, virus transmission efficiency between infected and uninfected ticks co-feeding on mice was also intensified by each substitution. Retrospectively, the mutation D67G was identified in viruses isolated from patients with encephalitis. We propose that the emergence of atypical Siberian HA-deficient TBEV strains in Europe is linked to their molecular adaptation to local ticks. This process appears to be driven by the selection of single mutations that change the virion surface thus enhancing receptor/fusion function essential for TBEV entry into the unfamiliar tick species. As the consequence of this adaptive mutagenesis, some of these mutations also appear to enhance the ability of TBEV to cross the human blood-brain barrier, a likely explanation for fatal encephalitis. Future research will reveal if these emerging Siberian TBEV strains continue to disperse westwards across Europe by adaptation to the indigenous tick species and if they are associated with severe forms of TBE.