Miracle-dz/UniFAR-FTUs huggingface dataset:
Insulin Signaling in Type 2 Diabetes

Background: Mechanisms of insulin resistance in type 2 diabetes are not known. Results: A first dynamic mathematical model based on data from human adipocytes yields systems level understanding of insulin resistance. Conclusion: Attenuation of an mTORC1-derived feedback in diabetes explains reduced sensitivity and signal strength throughout the insulin-signaling network. Significance: Findings give a molecular basis for insulin resistance in the signaling network. Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multilevel model, at the whole body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.
Energy Resolution of Plastic Scintillation Detector for Beta Rays

Many experiments on neutrinoless double beta decays have been proposed recently for determining the effective mass of neutrinos. Some of them use a plastic scintillator for measuring the beta-ray energy. Achieving a high energy resolution is critical for neutrinoless double beta decay experiments (e.g., MOON and superNEMO). The motivation of this study is to investigate the energy resolution of a plastic scintillation detector in terms of ldquocomponentsrdquo in the MeV-electron region. It is known that the total energy resolution of a plastic scintillation detector for a monoenergetic spectrum consists of two components: statistical and intrinsic energy resolution. In this paper, these two components were investigated for electrons. Experiments on protons were also performed for the purpose of comparison. Three additional experiments were performed to determine (1) the uniformity of the plastic scintillator materials by scanning a 2.8-MeV proton microbeam, (2) the energy spread of electrons and protons, and (3) the effect of the electron-beam size on the set-up. These additional experiments were performed to ensure that these factors did not affect measurements of the two above-mentioned components.
Cancer-Associated Mutations in the MDM2 Zinc Finger Domain Disrupt Ribosomal Protein Interaction and Attenuate MDM2-Induced p53 Degradation

ABSTRACT The p53-inhibitory function of the oncoprotein MDM2 is regulated by a number of MDM2-binding proteins, including ARF and ribosomal proteins L5, L11, and L23, which bind the central acidic domain of MDM2 and inhibit its E3 ubiquitin ligase activity. Various human cancer-associated MDM2 alterations targeting the central acidic domain have been reported, yet the functional significance of these mutations in tumor development has remained unclear. Here, we show that cancer-associated missense mutations targeting MDM2's central zinc finger disrupt the interaction of MDM2 with L5 and L11. We found that the zinc finger mutant MDM2 is impaired in undergoing nuclear export and proteasomal degradation as well as in promoting p53 degradation, yet retains the function of suppressing p53 transcriptional activity. Unlike the wild-type MDM2, whose p53-suppressive activity can be inhibited by L11, the MDM2 zinc finger mutant escapes L11 inhibition. Hence, the MDM2 central zinc finger plays a critical role in mediating MDM2's interaction with ribosomal proteins and its ability to degrade p53, and these roles are disrupted by human cancer-associated MDM2 mutations.
Study of the relationship between the target tissue necrosis volume and the target tissue size in liver tumours using two-compartment finite element RFA modelling

Abstract Purpose: The aim of this study was to investigate the relationship between the target tissue necrosis volume and the target tissue size during the radiofrequency ablation (RFA) procedure. Materials and methods: The target tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum target tissue necrosis volume for each target tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure. Results: Four different maximum voltages without the roll-off occurrence were found for the four different sizes of target tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The target tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm target tissue. For the target tissue with diameter of 30 mm, the 50 °C isothermal contour (IT50) result showed that the target tissue can be cleanly ablated, but the same result did not show in the Arrhenius damage model result. Furthermore, two optimal RFA protocols with a minimal thermal damage to the healthy tissues were found for the target tissues with diameters of 20 and 25 mm, respectively. Conclusions: The study suggests that target tissues of different sizes should be treated with different RFA protocols. The maximum target tissue volume was achieved with the MVA without the roll-off occurrence for each target tissue size when a constant RF power supply was used.
Sleep characteristics, chronotype and winter depression in 10–20‐year‐olds in northern European Russia

The purpose of this work was to examine the relationships between geographical coordinates and the prevalence of winter depression (SADW), and to compare the sleep characteristics and chronotype of youths with and without SADW. We conducted a cross‐sectional study of self‐reported sleep characteristics, chronotype and winter depression in northern European Russia. Two questionnaires, the Munich Chronotype Questionnaire (MCTQ) and the Seasonal Pattern Assessment Questionnaire (SPAQ), were administered to a total of 3435 adolescents aged 10–20 years (1517 males and 1918 females). The prevalence of SADW in the study population was 8.4% and sub‐SADW 11.8%. Four variables predicted the likelihood of SADW in youths: sex [higher in females: odds ratio (OR): 1.87, P < 0.0001], age (increases with age: OR: 1.09, P < 0.001), latitude (higher in the North: OR: 1.49, P < 0.029) and position in the time zone (higher in the West: OR: 1.61, P < 0.001). Later sleeping and waking, longer sleep latencies, more severe sleep inertia, shorter total sleep times and lower sleep efficiencies were observed in both males and females with SADW. The influence of SADW on sleep characteristics was more pronounced on school days. Significant phase delays of the sleep–wake rhythm and severe social jetlag (the difference between the mid‐point of sleep phase at weekends and on workdays) were observed in females with SADW, but not in males. There are significant differences in sleep characteristics and chronotype between people with SADW and no‐SAD. We demonstrate that both latitude of residence and location within the time zone are significant predictors of SADW in young inhabitants of the North.
A preliminary analysis of long bone measurements of Homo floresiensis: Bone robusticity, body size, proportions and encephalisation

This is the first preliminary analysis of long bone measurements and body size and proportion in Homo floresiensis. In contradiction to the original description (Brown et al. 2004) we have found the bones relatively very robust and that the individual was much taller than it is presented in the original description. A relatively extraordinary large femoral head and relatively short biomechanical neck length is a typical feature of this human fossil. The length of radius is relatively out of range of any known hominine. In summary the fossil find of Homo floresiensis LB1 fossil specimen represents relatively short, but very robust individual with a relatively very small brain comparable to earliest Homo species. The phylogenetic position of Homo floresiensis is not clear because there are not many archaic features typical for Homo erectus on the postcranial skeleton but many specific autapomorphic ones. Some of them are similar to Neanderthals or Upper Paleolithic anatomically modern humans. This specific morphology of long bones contradicts some very archaic features on pelvis or on the skull.
Decision-Making Processes in the Workplace: How Exhaustion, Lack of Resources and Job Demands Impair Them and Affect Performance

The present study aims to connect more the I/O and the decision-making psychological domains, by showing how some common components across jobs interfere with decision-making and affecting performance. Two distinct constructs that can contribute to positive workplace performance have been considered: decision-making competency (DMCy) and decision environment management (DEM). Both factors are presumed to involve self-regulatory mechanisms connected to decision processes by influencing performance in relation to work environment conditions. In the framework of the job demands-resources (JD-R) model, the present study tested how such components as job demands, job resources and exhaustion can moderate decision-making processes and performance, where high resources are advantageous for decision-making processes and performance at work, while the same effect happens with low job demands and/or low exhaustion. In line with the formulated hypotheses, results confirm the relations between both the decision-making competences, performance (i.e., in-role and extra-role) and moderators considered. In particular, employees with low levels of DMCy show to be more sensitive to job demands toward in-role performance, whereas high DEM levels increase the sensitivity of employees toward job resources and exhaustion in relation to extra-role performance. These findings indicate that decision-making processes, as well as work environment conditions, are jointly related to employee functioning.
Observations on Chlamydia trachomatis and other microbes in reactive arthritis

There are problems in attributing causality in inflammatory arthritis. So far as C. trachomatis and sexually acquired reactive arthritis are concerned, there is much in favour of a causal relationship, although there are important caveats which need to be explored before it is possible to say unreservedly that C. trachomatis plays a causative role in reactive arthritis. For example, micro-organisms have never been cultured from synovial effusions in early disease, and only once has substantial benefit of antimicrobial treatment been reported. The claim that ocular strains of C. trachomatis are of over-riding importance in pathogenesis needs confirmation before it can be accepted. No conclusion can be made about the possibility of other small intracellular bacteria in joints having a role in causing disease. However, if it can be shown that eradication of the micro-organism, which may be difficult to prove, coincides with clinical recovery, it would go some way to recognising causality. In spite of the recognised difficulties, antibiotic studies have an important role in identifying aetiology. They need to focus on very early disease and on eradication of intra-articular bacteria. Treatment of established disease is likely to be less informative. Although a combination of antibiotics might have a future in treating established disease, diagnosing and treating non-gonococcal urethritis as soon as possible should be the aim in order to prevent the development of reactive arthritis.
Association between physical activity and depressive symptoms: midlife women in SWAN.

INTRODUCTION The relation of physical activity (PA) and positive mood has been the focus of considerable research, which were primarily cross-sectional. This study was done to evaluate the relation between PA and high depressive symptoms across time and to examine whether being physically active attenuates the risk of depressive symptoms in midlife women. METHODS The present study is a longitudinal observational study on the menopausal transition in a multiethnic population. Ten years of data on 2891 women were analyzed. The participants were women from seven geographic areas nationwide, age 42-52 yr at baseline, still menstruating, and not using exogenous reproductive hormones. PA was measured with the Kaiser Permanente Physical Activity Scale. The main outcome measure, depressive symptoms, was assessed with the Center for Epidemiological Studies Depression Scale (CES-D), with primary outcome of CES-D score of 16 or higher. RESULTS In mixed effect logistic regression models adjusted for covariates, compared with inactivity, PA meeting PA guidelines (approximating public health guidelines) and PA below PA guidelines were each associated with lower risk of high depressive symptoms (CES-D score of 16 or higher) (odds ratio, 0.52; 95% confidence interval, 0.40-0.70; and odds ratio, 0.81; 95% confidence interval, 0.67-0.98, respectively] across 10 yr. Being married, Japanese and Hispanic ethnicity, current smoking, reporting very upsetting life events, using antidepressive medications, having hot flashes, and high body mass index were all positively associated with high depressive symptoms, whereas high social support was negatively associated. CONCLUSIONS Higher PA was associated with lower levels of depressive symptoms persistently over 10 yr, independent of potential confounders. Our findings suggest that reaching moderate-intensity PA levels during midlife may be protective against depressive symptoms.
A review of augmentation therapy for alpha-1 antitrypsin deficiency

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. Specific therapy for lung-affected individuals with AATD is augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT). Augmentation therapy was first approved by the United States Food and Drug Administration (FDA) in 1987 for emphysema associated with severe AATD and today, six augmentation therapy preparations, all of which derive from pooled human plasma, have received FDA approval. Areas covered: This paper reviews augmentation therapy for AATD, including the various available commercial preparations, their processing and biochemical differences, evidence regarding biochemical and clinical efficacy, patterns of clinical use, adverse effect profiles, cost-effectiveness and potential uses in conditions other than emphysema associated with AATD. Novel and emerging strategies for treating AATD are briefly discussed next, including alternative dosing and administration strategies, recombinant preparations, small molecule inhibitors of neutrophil elastase and of AAT polymerization, autophagy-enhancing drugs and gene therapy approaches. Expert opinion: We conclude with a discussion of our approach to managing patients with AATD and use of augmentation therapy.
Learning Feature Embedding with Strong Neural Activations for Fine-Grained Retrieval

Fine-grained object retrieval, which aims at finding objects belonging to the same sub-category as the probe object from a large database, is becoming increasingly popular because of its research and application significance. Recently, convolutional neural network (CNN) based deep learning models have achieved promising retrieval performance, as they can learn both feature representations and discriminative distance metrics jointly. Specifically, a generic method is to extract activations of the fully-connected layer as feature descriptors and simultaneously optimize classification constraints (e.g., softmax loss) and similarity constraints (e.g., triplet loss) to improve the representative capability of the features. However, the typical fully-connected layer activations are more focused on representing global attributes of the corresponding image, thus relatively less sensitive to specific local characteristics. Therefore, the features learned through these approaches in general are not sufficiently capable for retrieving fine-grained objects. To attack this issue, we propose an effective feature embedding by simultaneously encoding original global features and discriminative local features, in which the local features are extracted by exploiting strong neural activations on the last convolutional layer. We present that the novel feature embedding can dramatically enlarge the gap between inter-class variance and intra-class variance, which is the key factor to improve retrieval precision. In addition, we show our architecture can also be applied in person re-identification. Experimental results on multiple challenging benchmarks demonstrate that our method outperforms the current state-of-the-art approaches by large margins.
Murine spinal cord explants: A model for evaluating axonal growth and myelination in vitro

In vitro models of myelinating central nervous system axons have mainly been of two types, organotypic or dissociated. In organotypic cultures, the tissue fragment is thick and usually requires sectioning (physically or optically) before visual examination. In dissociated cultures, tissue is dispersed across the culture surface, making it difficult to measure the extent of myelinated fiber growth. We aimed to develop a method of culturing myelinated CNS fibers in defined medium that could be 1) studied by standard immunofluorescence microscopy (i.e., monolayer type culture), 2) used to measure axonal growth, and 3) used to evaluate the effect of substrate and media components on axonal growth and myelination. We used 120‐μm slices of embryonic murine spinal cord as a focal source of CNS tissue from which myelinated axons could extend in a virtual monolayer. Explants were cultured on both poly‐L‐lysine and astrocytes. The latter were used because they are the scaffold on which axonal growth and myelination occurs during normal development. Outgrowth from the explant and myelination of axons was poor on poly‐L‐lysine but was promoted by an astrocyte bed layer. The best myelin formation occurred in defined media based on DMEM using N2 mix; it was not promoted by Sato mix or Neurobasal medium with B27 supplement. Neuronal survival was poor in serum‐containing medium. This tissue culture model should facilitate the study of factors involved in promoting outgrowth of CNS axons and their myelination. As such it is relevant to studies on myelination and spinal cord repair. © 2006 Wiley‐Liss, Inc.
Changes of Renal Water Diffusion Coefficient After Application of Iodinated Contrast Agents: Effect of Viscosity

Objective:X-ray contrast agents (CA) possess specific physicochemical properties and are excreted renally by glomerular filtration. Thereby, they may affect the diffusion of water molecules within the kidney. The aim of our preclinical study was to investigate potential changes in the apparent diffusion coefficient (ADC) of the kidney after administration of monomeric, low-osmolar, and dimeric, iso-osmolar CA by using diffusion-weighted magnetic resonance imaging (DWI). Material and Methods:First, the relationship between CA viscosity and the ADC of water was assessed by phantom measurements. Subsequently, Han Wistar rats (8 per group) received an intravenous injection of iso-osmolar CA (iodixanol) or low-osmolar CA (iopromide) at a dosage of 4 gI/kg body weight. The control group received saline (0.9% NaCl) at the same volume. The renal ADC was dynamically monitored up to 40 minutes postinjection (p.i.) by DWI using a 1.5-T clinical MR unit. After DWI, the animals were killed and the kidneys were removed for iodine measurements by x-ray fluorescence analysis. Results:The in vitro measurements yielded an inverse relationship between increasing viscosity and decreasing water diffusion. In vivo, a slight increase in ADC was observed immediately after administration of the low-osmolar iopromide (&Dgr;ADC = 80 ± 78 &mgr;m2/s) and saline (&Dgr;ADC = 89 ± 53 &mgr;m2/s), which normalized to the baseline level at 40 minutes p.i. In contrast, a strong decrease in ADC was observed after administration of the iso-osmolar iodixanol. This was most prominent 12 minutes p.i. (&Dgr;ADC = −555 ± 194 &mgr;m2/s) and persisted throughout the investigation. Concomitantly, the kidney iodine concentration 50 minutes p.i. was significantly higher after iodixanol (58.6 ± 5.3 mgI/g kidney) compared with iopromide injection (18.4 ± 4.5 mgI/g kidney). Conclusion:A significant difference in the renal ADC was observed between the low-osmolar CA/saline and the iso-osmolar CA. The in vitro measurements suggest that the substantial decrease in ADC observed after administration of the iso-osmolar CA is based on the high viscosity of the agent during renal passage. This, in turn, may explain the delayed iodine retention after administration of iso-osmolar CA and demonstrates the importance of the physicochemical properties of CA during their renal elimination.
Syndecan-1 Serves as the Major Receptor for Attachment of Hepatitis C Virus to the Surfaces of Hepatocytes

ABSTRACT Our recent studies demonstrated that apolipoprotein E mediates cell attachment of hepatitis C virus (HCV) through interactions with the cell surface heparan sulfate (HS). HS is known to covalently attach to core proteins to form heparan sulfate proteoglycans (HSPGs) on the cell surface. The HSPG core proteins include the membrane-spanning syndecans (SDCs), the lycosylphosphatidylinositol-linked glypicans (GPCs), the basement membrane proteoglycan perlecan (HSPG2), and agrin. In the present study, we have profiled each of the HSPG core proteins in HCV attachment. Substantial evidence derived from our studies demonstrates that SDC1 is the major receptor protein for HCV attachment. The knockdown of SDC1 expression by small interfering RNA (siRNA)-induced gene silence resulted in a significant reduction of HCV attachment to Huh-7.5 cells and stem cell-differentiated human hepatocytes. The silence of SDC2 expression also caused a modest decrease of HCV attachment. In contrast, the siRNA-mediated knockdown of other SDCs, GPCs, HSPG2, and agrin had no effect on HCV attachment. More importantly, ectopic expression of SDC1 was able to completely restore HCV attachment to Huh-7.5 cells in which the endogenous SDC1 expression was silenced by specific siRNAs. Interestingly, mouse SDC1 is also fully functional in mediating HCV attachment when expressed in the SDC1-deficient cells, consistent with recent reports that mouse hepatocytes are also susceptible to HCV infection when expressing other key HCV receptors. Collectively, our findings demonstrate that SDC1 serves as the major receptor protein for HCV attachment to cells, providing another potential target for discovery and development of antiviral drugs against HCV.