Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Response to High Glucose in Skin Fibroblasts of Monozygotic Twins Discordant for Type 1 Diabetes.

CONTEXT Most epigenetic studies in diabetes compare normal cells in "high glucose" (HG) to cells in "normal glucose" (NG) and cells returned from HG to NG. Here we challenge this approach. OBJECTIVE The objective was to determine whether there were differences in gene expression in skin fibroblasts of monozygotic twins (MZT) discordant for type 1 diabetes (T1D). DESIGN Skin fibroblasts were grown in NG (5.5 mmol/L) and HG (25 mmol/L) for multiple passages. SETTING This study was conducted at the University of Minnesota. PATIENTS Patients were nine MZT pairs discordant for T1D. MAIN OUTCOME MEASURE(S) Gene expression was assessed by mRNA-Seq, using the Illumina HiSeq 2000 instrument. Pathway analysis tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS A total of 3308 genes were differentially expressed between NG and HG in T1D MZT vs 889 in non-T1D twins. DNA replication, proteasome, cell cycle, base excision repair, homologous recombination, pyrimidine metabolism, and spliceosome pathways had overrepresented genes with increased expression in T1D twins with P values ranging from 7.21 × 10(-10) to 1.39 × 10(-4). In a companion article, we demonstrate that these pathway changes are related to diabetic nephropathy risk. There were no pathways statistically significant differently expressed in nondiabetic twins in HG vs NG. CONCLUSIONS In vivo exposure to diabetes alters cells in a manner that markedly changes their in vitro responses to HG. These results highlight the importance of using cells directly derived from diabetic patients for studies examining the effects of HG in diabetes.
Active Devices Based on Organic Semiconductors for Wearable Applications

Plastic electronics is an enabling technology for obtaining active (transistor based) electronic circuits on flexible and/or nonplanar surfaces. For these reasons, it appears as a perfect candidate to promote future developments of wearable electronics toward the concept of fabrics and garments made by functional (in this case, active electronic) yarns. In this paper, a panoramic view of recent achievements and future perspectives is given.
The Effect of HIV Infection Risk Beliefs on Risky Sexual Behaviors : Scared Straight or Scared to Death ?

Economists typically assume that risk compensation is uniformly self-protective – that people become more careful as the health risks of their actions increase. However, risk-seeking, or fatalistic, responses can also be rational: increased risks can lead people to take fewer precautions. I extend the typical model of risk compensation to show that fatalism is a rational response to sufficiently high risks if people do not have perfect control over all possible exposures, and if the condition in question is irreversible. This result holds even for people who do not understand how to add up probabilities. I test this model’s implications by randomizing the provision of information on HIV transmission risks to people in Malawi, a country with a severe HIV epidemic where there is qualitative evidence of fatalistic responses to the virus. Average risk responses are self-protective and statistically significant, but small in magnitude: the mean risk elasticity of sexual behavior is roughly -0.6. To test the model of rational fatalism, I develop a method of decomposing 2SLS estimates of the risk elasticity of sexual behavior by baseline risk beliefs. Consistent with the predictions of my theoretical framework, I find that this elasticity varies sharply by baseline risk beliefs: the risk elasticity varies from -2.3 for the lowest initial beliefs to 2.9 for the highest initial beliefs. 13.8% of the population has a positive elasticity, suggesting they are fatalistic. ∗University of Michigan Department of Economics and Population Studies Center. Email jtkerwin@umich.edu. I am grateful to Rebecca Thornton, Jeff Smith, John DiNardo, David Lam, Matias Cattaneo, Bob Willis, Mel Stephens, John Bound, Miles Kimball, Susan Watkins, Pinar Keskin, Daniel Bennett, Nate Young, Sanyu Mojola, Ophira Vishkin, Evan Herrnstadt, Joe Golden, Audrey Dorélien, Laura Derksen, Eric Chyn, Olga Malkova, Justin Ladner, and seminar participants at the University of Michigan, PAA, MIEDC, ABCDE, and NEUDC for their valuable feedback. This project would not have been possible without the excellent fieldwork supervision efforts of Anderson Moyo, Synab Njerenga, and Christopher Nyirenda. Data collection on this project was supported by internal UM grants from the Center for Global Health, the Population Studies Center, the Weinberg International Travel Fund, the Center for Education of Women, and the Michigan Institute for Teaching and Research in Economics as well as the Russell Sage Foundation’s Small Grants in Behavioral Economics program. I acknowledge fellowship support from the Population Studies Center and the Rackham Graduate School. All errors and omissions are my own.
Clinical gene analysis and manipulation: overview and applications in pathology

Accepted for publication 23 September 1994 The science of molecular cell biology has advanced dramatically over the last century and in the last decade this has had important implications for medical research particularly for oncology, microbiology, immunology, and inherited genetic diseases. Globally, the oncological sciences have the most resources devoted to them including specialist scientific journals, research funding, national institutions, and number of scientists. The increasing use of molecular cell biological techniques has lead to considerable diversity in methodological practice and interpretation of genetic analysis. It is particularly important, therefore, that the calibre of clinical scientific endeavour keeps pace with the scope and potential of new developments in basic science. Furthermore, the rapid and exponential increase in knowledge and potential clinical applications of the new molecular techniques requires that clinical scientists are abreast of
Protein Kinase C-mediated Interphase Lamin B Phosphorylation and Solubilization*

Disassembly of the sperm nuclear envelope at fertilization is one of the earliest events in the development of the male pronucleus. We report that nuclear lamina disassembly in interphase sea urchin egg cytosol is a result of lamin B phosphorylation mediated by protein kinase C (PKC). Lamin B of permeabilized sea urchin sperm nuclei incubated in fertilized egg G1 phase cytosolic extract is phosphorylated within 1 min of incubation and solubilized prior to sperm chromatin decondensation. Phosphorylation is Ca2+-dependent. It is reversibly inhibited by the PKC-specific inhibitor chelerythrine, a PKC pseudosubstrate inhibitor peptide, and a PKC substrate peptide, but not by inhibitors of PKA, p34 cdc2 or calmodulin kinase II. Phosphorylation is inhibited by immunodepletion of cytosolic PKC and restored by addition of purified rat brain PKC. Sperm lamin B is a substrate for rat brain PKC in vitro, resulting in lamin B solubilization. Two-dimensional phosphopeptide maps of lamin B phosphorylated by the cytosolic kinase and by purified rat PKC are virtually identical. These data suggest that PKC is the major kinase required for interphase disassembly of the sperm lamina.
Surface labeling of sialic acid residues in BHK cells and viral transformants.

Conditions were found for the direct radioactive labeling of glycoproteins on the membranes of baby hamster kidney fibroblasts and their Rous sarcoma virus transformants with negligible loss of viability. Sialic acid residues were specifically detected by oxidation of the cells with periodate followed by reduction with sodium borotritide. Highly specific incorporation of radioactivity was demonstrated into surface membranes isolated as whole structures from these cells. Comparison was made with a known method which labeled galactose residues utilizing galactose oxidase. It was suggested that, when surface labeling procedures are used which are not extremely gentle to the cells, cell fractionation should be performed. Gel electrophoresis in sodium dodecyl sulfate enabled comparisons to be made of the sialic acid-containing glycoproteins in the surface membranes from the transformed cells and their normal counterpart, and a number of conclusions were drawn on the exposure of different glycosylated macromolecules to the external environment. These included: ( a ) differences were observed in the molecular weights and number of species of the prominent sialic acid-containing glycoproteins; ( b ) labeling of isolated membranes showed additional glycoproteins above M.W. 150,000; ( c ) the method of oxidation prior to labeling yielded different externally oriented glycoproteins in the normal cells, although the transformants showed no difference; and ( d ) a number of other differences depended on the method of cell harvest prior to labeling. Transformed cells appeared to adhere more strongly to the plastic surface of the culture flasks and required longer treatments with a variety of reagents than did their normal counterparts to ensure their complete dislodgement.
Comparison Pregnancy Outcomes Between Minimal Stimulation Protocol and Conventional GnRH Antagonist Protocols in Poor Ovarian Responders

Objective: To compare the pregnancy outcomes achieved by in vitro fertilization (IVF) between minimal stimulation and conventional antagonist protocols in poor ovarian responders (PORs). Materials and methods: In this randomized controlled trial, 77 PORs undergoing IVF were selected and divided into two groups. First group was the minimal stimulation group (n = 42) receiving 100 mg/day clomiphene citrate on day 2of the cycle for 5 day that was followed by150IU/day human menopausal gonadotropin (hMG) on day 5 of the cycle. Second group was the conventional group (n = 35) receiving at least 300 IU/daygonadotropin on day 2 of the cycle. Gonadotropin-releasing hormone (GnRH) antagonist protocol was applied for both groups according to flexible protocol. Number of retrieved oocytes and chemical pregnancy rate were the main outcomes. Results: There was no difference in number ofretrieved oocyte and pregnancy rate (2.79 ± 1.96 vs. 2.20 ± 1.71 and 5.6% vs. 4.1%; p > 0.05) between both groups. The gonadotropin dose used in the minimal stimulation group was lower than conventional group (1046 ± 596 vs. 2806 ± 583). Conclusion: Minimal stimulation protocol with lower gonadotropin used is likely to be considered as a patient- friendly and cost-effective substitute for PORs.
Analysis of rhythms of EEG signals using orthogonal polynomial approximation

We present a new method for analysis of the rhythms of the electroencephalogram (EEG) signal. The method is based on the multi-resolution analysis using the orthogonal polynomial approximation (OPA). It is demonstrated that the proposed analysis technique employing the OPA gives similar performance as the popular method based on the wavelet packet decomposition. However, the proposed technique is simpler in principle and can be implemented as a one-step process. Some advantages of the proposed technique manifest in reduced computational complexity and feasibility of real-time implementation.
Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Purpose: Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity. Experimental Design: We analyzed archived tumor tissue of 5 patients with renal cell carcinoma, who previously achieved durable disease control with rapalogs (median duration, 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultradeep sequencing was used to identify alterations across 230 target genes. Whole-exome sequence analysis was added to investigate genes beyond this original target list. Results: Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1 and MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In 1 patient, concurrent genomic events occurred in two separate pathway components across different tumor regions. Conclusions: Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents. Clin Cancer Res; 20(7); 1955–64. ©2014 AACR.
Assembly of α4β2 Nicotinic Acetylcholine Receptors Assessed with Functional Fluorescently Labeled Subunits: Effects of Localization, Trafficking, and Nicotine-Induced Upregulation in Clonal Mammalian Cells and in Cultured Midbrain Neurons

Fura-2 recording of Ca2+ influx was used to show that incubation in 1 μm nicotine (2-6 d) upregulates several pharmacological components of acetylcholine (ACh) responses in ventral midbrain cultures, including a MLA-resistant, DHβE-sensitive component that presumably corresponds to α4β2 receptors. To study changes in α4β2 receptor levels and assembly during this upregulation, we incorporated yellow and cyan fluorescent proteins (YFPs and CFPs) into the α4 or β2 M3-M4 intracellular loops, and these subunits were coexpressed in human embryonic kidney (HEK) 293T cells and cultured ventral midbrain neurons. The fluorescent receptors resembled wild-type receptors in maximal responses to ACh, dose-response relations, ACh-induced Ca2+ influx, and somatic and dendritic distribution. Transfected midbrain neurons that were exposed to nicotine (1 d) displayed greater levels of fluorescent α4 and β2 nicotinic ACh receptor (nAChR) subunits. As expected from the hetero-multimeric nature of α4β2 receptors, coexpression of the α4-YFP and β2-CFP subunits resulted in robust fluorescence resonance energy transfer (FRET), with a FRET efficiency of 22%. In midbrain neurons, dendritic α4β2 nAChRs displayed greater FRET than receptors inside the soma, and in HEK293T cells, a similar increase was noted for receptors that were translocated to the surface during PKC stimulation. When cultured transfected midbrain neurons were incubated in 1 μm nicotine, there was increased FRET in the cell body, denoting increased assembly of α4β2 receptors. Thus, changes in α4β2 receptor assembly play a role in the regulation of α4β2 levels and responses in both clonal cell lines and midbrain neurons, and the regulation may result from Ca2+-stimulated pathways.
Study of the phorbol ester effect on Alzheimer amyloid precursor processing: Sequence requirements and involvement of a Cholera toxin sensitive protein

Phorbol esters (PDBu) stimulate α‐secretase cleavage and secretion of the Alzheimer amyloid precursor protein (APP). To determine whether any cytoplasmic residues or sequence motifs mediate the PDBu effect on APP processing, this region of APP was altered by point mutations or deletions. To differentiate the mutated APP from the endogenous APP, the APP751 ectodomain between amino acids 1 and 647 was replaced by a human secreted alkaline phosphatase derivative (SEAP). The resultant fusion protein (SEAP‐APP751) was cleaved by α‐secretase at the same site as full‐length APP, and its secretion was stimulated by PDBu at a level similar to APP751. However, PDBu‐stimulated secretion of the SEAP‐APP751 fusion protein reached its maximum level after 30 min of treatment, while secretion of APP751 reached its maximum after 60 min, suggesting that the APP ectodomain affects the kinetics of APP secretion.
Finding the centre: corrections for asymmetry in high-throughput sequencing datasets

High throughput sequencing is a technology that allows for the generation of millions of reads of genomic data regarding a study of interest, and data from high throughput sequencing platforms are usually count compositions. Subsequent analysis of such data can yield information on tran- scription profiles, microbial diversity, or even relative cellular abundance in culture. Because of the high cost of acquisition, the data are usually sparse, and always contain far fewer observations than variables. However, an under-appreciated pathology of these data are their often unbalanced nature: i.e, there is often systematic variation between groups simply due to presence or absence of features, and this variation is important to the biological interpretation of the data. A simple example would be comparing transcriptomes of yeast cells with and without a gene knockout. This causes samples in the comparison groups to exhibit widely varying centres. This work extends a previously described log-ratio transformation method that allows for variable comparisons between samples in a Bayesian compositional context. We demonstrate the pathology in modelled and real unbalanced experimental designs to show how this dramatically causes both false negative and false positive inference. We then introduce several approaches to demonstrate how the pathologies can be addressed. An extreme example is presented where only the use of a predefined basis is appropriate. The transformations are implemented as an extension to a general compositional data analysis tool known as ALDEx2 which is available on Bioconductor.
Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing.

BACKGROUND The long-QT syndrome is associated with sudden cardiac death. Combination of beta-blocker and pacing therapy has been proposed for treatment of drug-resistant patients. The purpose of this study was to summarize our long-term experience with combined therapy in patients with long-QT syndrome. METHODS AND RESULTS A total of 37 patients with idiopathic long-QT syndrome were treated with combined therapy consisting of continuous cardiac pacing and maximally tolerated beta-blocker therapy and followed up for 6.3+/-4. 6 years (mean+/-SD). The group consisted of 32 female and 5 male patients with a mean age of 31.6 years. The mean paced rate was 82+/-7 bpm (range, 60 to 100 bpm). On follow-up, recurrent symptoms caused by pacemaker malfunction were documented in 3 patients. Four patients died during the follow-up period: 2 adolescents stopped beta-blocker therapy, 1 patient died suddenly while treated with combined therapy, and 1 patient died of unrelated causes. In addition, 3 patients had resuscitated cardiac arrest while on combined therapy, and 1 patient had repeated, appropriate implantable cardioverter-defibrillator discharges on follow-up. CONCLUSIONS Because 28 of 37 patients remain without symptoms with beta-blocker therapy and continuous pacing, combined therapy appears to provide reasonable, long-term control for this high-risk group. However, the incidence of sudden death and aborted sudden death (24% in all patients and 17% in compliant patients) strongly suggests the use of a "back-up" defibrillator, particularly in noncompliant adolescent patients. Implantable cardioverter-defibrillator therapy, however, may be associated with recurrent shocks in susceptible patients.
Molecular Mechanisms Regulating Macrophage Response to Hypoxia

Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ.
Improving GP classifier generalization using a cluster separation metric

Genetic Programming offers freedom in the definition of the cost function that is unparalleled among supervised learning algorithms. However, this freedom goes largely unexploited in previous work. Here, we revisit the design of fitness functions for genetic programming by explicitly considering the contribution of the wrapper and cost function. Within the context of supervised learning, as applied to classification problems, a clustering methodology is introduced using cost functions which encourage maximization of separation between in and out of class exemplars. Through a series of empirical investigations of the nature of these functions, we demonstrate that classifier performance is much more dependable than previously the case under the genetic programming paradigm.
Generating Connectives

We present an implemented procedure to select an appropriate connective to link two propositions, which is part of a large text generation system. Each connective is defined as a set of constraints between features of the propositions it connects. Our focus has been to identify pragmatic features that can be produced by a deep generator to provide a simple representation of connectives. Using these features, we can account for a variety of connective usages, and we can distinguish between similar connectives. We describe how a surface generator can produce complex sentences when given these features in input. The selection procedure is implemented as part of a large functional unification grammar.