Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel INS mutation in a family with maturity‐onset diabetes of the young: Variable insulin secretion and putative mechanisms

Insulin gene (INS) mutations cause a rare form of maturity‐onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least 14 confirmed causative genes. Here, we describe a family with MODY due to a novel INS mutation, detected using massively parallel sequencing (MPS). The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes affecting both her two siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin, and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5%‐30%). Sanger sequencing of HNF4A, HNF1A, and HNF1B in the proband was negative. Targeted MPS using a custom‐designed amplicon panel sequenced on an Illumina MiSeq detected a heterozygous INS mutation c.277G>A (p.Glu93Lys). Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested disruption of a critical hydrogen bond between insulin and the insulin receptor; however, the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency. This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations.
Technologies and Trends to Improve Power Electronic Packaging

In the realm of power modules a strong trend toward high temperature and high reliability applications can be observed, which entails new technological challenges, especially for the assembly and packaging of power semiconductors. Because of the well known failure mechanisms of established lead-free standard soldering and heavy aluminum wire bonding technologies, such as fatigue and creep of die attach material and wire bonds at thermal cycling, academic and industrial research focuses on more reliable interconnection technologies. A priority is the research of alternative top and bottom side chip interconnection materials or technologies to improve the temperature cycling capability of power chips that are typically assembled on ceramic substrates. The scientific focus is on Ag sintering as die attach and/or heavy ribbon bonding, for example with Al or bi-metal (Al-Cu). Another focus is the material behavior of ribbon bonds in combination with bonding machine improvements (higher bonding parameters, cutt.
Anomaly Detection for Industrial Big Data

As the Industrial Internet of Things (IIoT) grows, systems are increasingly being monitored by arrays of sensors returning time-series data at ever-increasing 'volume, velocity and variety' (i.e. Industrial Big Data). An obvious use for these data is real-time systems condition monitoring and prognostic time to failure analysis (remaining useful life, RUL). (e.g. See white papers by Senseye.io, and output of the NASA Prognostics Center of Excellence (PCoE). ) However, as noted by Agrawal and Choudhary 'Our ability to collect "big data" has greatly surpassed our capability to analyze it, underscoring the emergence of the fourth paradigm of science, which is data-driven discovery. ' In order to fully utilize the potential of Industrial Big Data we need data-driven techniques that operate at scales that process models cannot. Here we present a prototype technique for data-driven anomaly detection to operate at industrial scale. The method generalizes to application with almost any multivariate dataset based on independent ordinations of repeated (bootstrapped) partitions of the dataset and inspection of the joint distribution of ordinal distances.
Oxidant/Antioxidant Imbalance in Alzheimer's Disease: Therapeutic and Diagnostic Prospects

Alzheimer's disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society. Compelling evidence demonstrates that molecular change characteristics for AD, such as oxidative stress and amyloid β (Aβ) oligomerization, precede by decades the onset of clinical dementia and that the disease represents a biological and clinical continuum of stages, from asymptomatic to severely impaired. Nevertheless, the sequence of the early molecular alterations and the interplay between them are incompletely understood. This review presents current knowledge about the oxidative stress-induced impairments and compromised oxidative stress defense mechanisms in AD brain and the cross-talk between various pathophysiological insults, with the focus on excessive reactive oxygen species (ROS) generation and Aβ overproduction at the early stages of the disease. Prospects for AD therapies targeting oxidant/antioxidant imbalance are being discussed, as well as for the development of novel oxidative stress-related, blood-based biomarkers for early, noninvasive AD diagnostics.
[Face protective patches do not reduce facial pressure ulcers in a simulated model of non-invasive ventilation].

Noninvasive ventilation (NIV) frequently involves the development of facial pressure ulcers (FPU). Its prevention considers the empirical use of protective patches between skin and mask, in order to reduce the pressure exerted by it. OBJECTIVES To evaluate the effect of protective patches on the pressure exerted by the facial mask, and its impact on the programmed ventilatory parameters. METHOD Bilevel NIV simulated model using full face mask in phantom with a physiological airway (ALS PRO +) in supine position. Forehead, chin and cheekbones pressure were measured using 3 types of standard protective patches versus a control group using pressure sensors (Interlinks Electronics®). The values obtained with the protective patches-mask model were evaluated in the programmed variables maximum inspiratory flow (MIF)), expired tidal volume (Vte) and positive inspiratory pressure (IPAP), with Trilogy 100 ventilator, Respironics®. The programming and recording of the variables was carried out in 8 opportunities in each group by independent operators. RESULTS There was no decrease in facial pressure with any of the protective patches compared to the control group. Moltopren increased facial pressure at all support points (p < 0.001), increased leakage, it decreased MIF, Vte and IPAP (p < 0.001). Hydrocolloid patches increased facial pressure only in the left cheekbone, increased leakage and decreased MIF. Polyurethane patches did not produce changes in facial pressure or ventilatory variables. CONCLUSION The use of protective patches of moltopren, hydrocolloid and polyurethane transparent did not contribute to the decrease of the facial pressure. A deleterious effect of the moltopren and hydrocolloid patches was observed on the administration of ventilatory variables, concluding that the non-use of the protective patches allowed a better administration of the programmed parameters.
Bacterial Symbionts in Lepidoptera: Their Diversity, Transmission, and Impact on the Host

The insect’s microbiota is well acknowledged as a “hidden” player influencing essential insect traits. The gut microbiome of butterflies and moths (Lepidoptera) has been shown to be highly variable between and within species, resulting in a controversy on the functional relevance of gut microbes in this insect order. Here, we aim to (i) review current knowledge on the composition of gut microbial communities across Lepidoptera and (ii) elucidate the drivers of the variability in the lepidopteran gut microbiome and provide an overview on (iii) routes of transfer and (iv) the putative functions of microbes in Lepidoptera. To find out whether Lepidopterans possess a core gut microbiome, we compared studies of the microbiome from 30 lepidopteran species. Gut bacteria of the Enterobacteriaceae, Bacillaceae, and Pseudomonadaceae families were the most widespread across species, with Pseudomonas, Bacillus, Staphylococcus, Enterobacter, and Enterococcus being the most common genera. Several studies indicate that habitat, food plant, and age of the host insect can greatly impact the gut microbiome, which contributes to digestion, detoxification, or defense against natural enemies. We mainly focus on the gut microbiome, but we also include some examples of intracellular endosymbionts. These symbionts are present across a broad range of insect taxa and are known to exert different effects on their host, mostly including nutrition and reproductive manipulation. Only two intracellular bacteria genera (Wolbachia and Spiroplasma) have been reported to colonize reproductive tissues of Lepidoptera, affecting their host’s reproduction. We explore routes of transmission of both gut microbiota and intracellular symbionts and have found that these microbes may be horizontally transmitted through the host plant, but also vertically via the egg stage. More detailed knowledge about the functions and plasticity of the microbiome in Lepidoptera may provide novel leads for the control of lepidopteran pest species.
Why Fuzzy Decision Trees are Good Rankers

Several fuzzy extensions of decision tree induction, which is an established machine-learning method, have already been proposed in the literature. So far, however, fuzzy decision trees have almost exclusively been used for the performance task of classification. In this paper, we show that a fuzzy extension of decision trees is arguably more useful for another performance task, namely ranking. Roughly, the goal of ranking is to order a set of instances from most likely positive to most likely negative. The motivation for applying fuzzy decision trees to this problem originates from recent investigations of the ranking performance of conventional decision trees. These investigations will be continued and complemented in this paper. Our results reveal some properties that seem to be crucial for a good ranking performance-properties that are better and more naturally offered by fuzzy than by conventional decision trees. Most notably, a fuzzy decision tree produces scores in terms of membership degrees on a fine-granular scale. Using these membership degrees as a ranking criterion, a key problem of conventional decision trees is solved in an elegant way, namely the question of how to break ties between instances in the same leaf or, more generally, between equally scored instances.
DNA binding by the MATα2 transcription factor controls its access to alternative ubiquitin-modification pathways

Like many transcription factors, the yeast protein MATalpha2 (α2) undergoes rapid proteolysis via the ubiquitin-proteasome system (UPS). At least two ubiquitylation pathways regulate α2 degradation: one pathway utilizes the ubiquitin ligase (E3) Doa10 and the other the heterodimeric E3 Slx5/Slx8. Doa10 is a transmembrane protein of the endoplasmic reticulum/inner nuclear membrane, whereas Slx5/Slx8 localizes to the nucleus and binds DNA nonspecifically. While a single protein can often be ubiquitylated by multiple pathways, the reasons for this “division of labor” are not well understood. Here we show that α2 mutants with impaired DNA binding become inaccessible to the Slx5/Slx8 pathway but are still rapidly degraded through efficient shunting to the Doa10 pathway. These results are consistent with the distinct localization of these E3s. We also characterized a novel class of DNA binding-defective α2 variants whose degradation is strongly impaired. Our genetic data suggest that this is due to a gain-of-function interaction that limits their access to Doa10. Together, these results suggest multiple ubiquitin-ligation mechanisms may have evolved to promote rapid destruction of a transcription factor that resides in distinct cellular subcompartments under different conditions. Moreover, gain-of-function mutations, which also occur with oncogenic forms of human transcription factors such as p53, may derail this fail-safe system.
An Appropriate Modulation of Lymphoproliferative Response and Cytokine Release as Possible Contributors to Longevity

The decrease in the proliferative response of lymphocytes is one of the most evident among the age-related changes of the immune system. This has been linked to a higher risk of mortality in both humans and experimental animals. However, long-lived individuals, in spite of optimally maintaining most of the functions of the immune system, also seem to show an impaired proliferative response. Thus, it was hypothesized that these individuals may have distinct evolution times in this proliferation and a different modulatory capacity through their cytokine release profiles. An individualized longitudinal study was performed on female ICR-CD1 mice, starting at the adult age (40 weeks old), analyzing the proliferation of peritoneal leukocytes at different ages in both basal conditions and in the presence of the mitogen Concanavalin A, for 4, 24 and 48 h of culture. The cytokine secretions (IL-2, IL-17, IL-1β, IL-6, TNF-α and IL-10) in the same cultures were also studied. Long-lived mice show a high proliferative capacity after short incubation times and, despite experiencing a functional decline when they are old, are able to compensate this decrease with an appropriate modulation of the lymphoproliferative response and cytokine release. This could explain their elevated resistance to infections and high longevity.
An analysis of the economic and patient outcome impact of an integrated COPD service in east London

Exacerbations of COPD carry a huge burden of morbidity and a significant economic impact. It has been shown that home care may be useful for exacerbations of COPD. This article presents a review of an integrated COPD service in east London. Hospital Episode Statistics, Public Health Mortality Files and clinical data were used to analyze differences in health care usage and COPD patient outcomes, including COPD assessment test (CAT) scores for a subsample, before and after the introduction of the integrated service. There was a significant (30%) reduction in the number of hospital bed days for COPD patients (P<0.05), alongside a significant increase in patients with only a short stay (0–1 days) in hospital (P<0.0001). There was a significant increase in the number of patients dying outside of hospital (a proxy for quality of end-of-life care) following introduction of the service (P=0.00015). Patients also reported a clinically significant improvement in CAT scores. A locally developed economic model shows that the economic benefits of the service (via impact on place of death and reduction in length of hospital stay) were almost equal to the cost of the service. The increase in proportion of short-stay admissions and the reduction in bed days suggest an impact of the service on early supported discharge and that this along with an improvement in patient clinical outcomes and in quality of end-of-life care shows that an exemplar integrated COPD service can provide benefits that equate to a nearly cost-neutral service.
Margin Based Semi-Supervised Elastic Embedding for Face Image Analysis

This paper introduces a graph-based semi-supervised elastic embedding method as well as its kernelized version for face image embedding and classification. The proposed frameworks combines Flexible Manifold Embedding and non-linear graph based embedding for semi-supervised learning. In both proposed methods, the nonlinear manifold and the mapping (linear transform for the linear method and the kernel multipliers for the kernelized method) are simultaneously estimated, which overcomes the shortcomings of a cascaded estimation. Unlike many state-of-the art non-linear embedding approaches which suffer from the out-of-sample problem, our proposed methods have a direct out-of-sample extension to novel samples. We conduct experiments for tackling the face recognition and image-based face orientation problems on four public databases. These experiments show improvement over the state-of-the-art algorithms that are based on label propagation or graph-based semi-supervised embedding.
Interpreting Deep Classifier by Visual Distillation of Dark Knowledge

Interpreting black box classifiers, such as deep networks, allows an analyst to validate a classifier before it is deployed in a high-stakes setting. A natural idea is to visualize the deep network's representations, so as to "see what the network sees". In this paper, we demonstrate that standard dimension reduction methods in this setting can yield uninformative or even misleading visualizations. Instead, we present DarkSight, which visually summarizes the predictions of a classifier in a way inspired by notion of dark knowledge. DarkSight embeds the data points into a low-dimensional space such that it is easy to compress the deep classifier into a simpler one, essentially combining model compression and dimension reduction. We compare DarkSight against t-SNE both qualitatively and quantitatively, demonstrating that DarkSight visualizations are more informative. Our method additionally yields a new confidence measure based on dark knowledge by quantifying how unusual a given vector of predictions is.
Denitrification in Soil Aggregate Analogues-Effect of Aggregate Size and Oxygen Diffusion

Soil-borne nitrous oxide (N$_2$O) emissions have a high spatial and temporal variability which is commonly attributed to the occurrence of hotspots and hot moments for microbial activity in aggregated soil. Yet there is only limited information about the biophysical processes that regulate the production and consumption of N$_2$O on microscopic scales in undisturbed soil. In this study, we introduce an experimental framework relying on simplified porous media that circumvents some of the complexities occuring in natural soils while fully accounting for physical constraints believed to control microbial activity in general and denitrification in particular. We used this framework to explore the impact of aggregate size and external oxygen concentration on the kinetics of O$_2$ consumption, as well as CO$_2$ and N$_2$O production. Model aggregates of different sizes (3.5 vs. 7\,mm diameter) composed of porous, sintered glass were saturated with a defined growth medium containing roughly 10$^9$ cells ml$^{-1}$ of the facultative anaerobic, \textsl{nosZ}-deficient denitrifier \textsl{Agrobacterium tumefaciens} with N$_2$O as final denitrification product and incubated at five different oxygen levels (0-13\,vol-$\%$). We demonstrate that the onset of denitrification depends on the amount of external oxygen and the size of aggregates. Smaller aggregates were better supplied with oxygen due to a larger surface-to-volume ratio, which resulted in faster growth and an earlier onset of denitrification. In larger aggregates, the onset of denitrification was more gradual, but with comparably higher N$_2$O production rates once the anoxic aggregate centers were fully developed. The normalized electron flow from the reduced carbon substrate to N-oxyanions (e$^{-}_{\rm denit}$/e$^{-}_{\rm total}$ ratio) could be solely described as a function of initial oxygen concentration in the headspace with a simple, hyperbolic model, for which the two empirical parameters changed with aggregate size in a consistent way. These findings confirm the important role of soil structure on N$_2$O emissions from denitrification by shaping the spatial patterns of microbial activity and anoxia in aggregated soil. Our dataset may serve as a benchmark for constraining or validating spatially explicit, biophysical models of denitrification in aggregated soil.
Competence and commitment of Caenorhabditis elegans vulval precursor cells.

Multipotent Caenorhabditis elegans vulval precursor cells (VPCs) choose among three fates (1 degrees, 2 degrees, and 3 degrees ) in response to two intercellular signals: the EGF family growth factor LIN-3 induces 1 degrees fates at high levels and 2 degrees fates at low levels; and a signal via the receptor LIN-12 induces 2 degrees fates. If the level of LIN-3 signal is reduced by a lin-3 hypomorphic mutation, the daughters of the VPC closest to the anchor cell (AC), P6.p, are induced by the AC. By expressing LIN-3 as a function of time in LIN-3-deficient animals, we find that both VPCs and the daughters of VPCs are competent to respond to LIN-3, and VPC daughters lose competence after fusing with the hypodermis. We also demonstrate that the daughters of VPCs specified to be 2 degrees can respond to LIN-3, indicating that 2 degrees VPCs are not irreversibly committed. We propose that maintenance of VPC competence after the first cell cycle and the prioritization of the 1 degrees fate help ensure that P6.p will become 1 degrees. This mechanism of competence regulation might have been maintained from ancestral nematode species that used induction both before and after VPC division and serves to maximize the probability that a functional vulva is formed.
Placental expression of sFlt-1 and PlGF in early preeclampsia vs. early IUGR vs. age-matched healthy pregnancies

ABSTRACT Objective: To investigate whether differences between early preeclampsia and early fetal growth restriction can be explained by differential placental expression patterns of sFlt-1, Flt-1, and PlGF. Methods: Placental tissues and maternal blood samples from six cases of preeclampsia, seven IUGR, and six age-matched controls were studied for mRNA and protein levels as well as protein localization and expression intensity. Results: Neither placental PlGF mRNA and protein expression nor placental villous trophoblast expression intensity of PlGF was altered by placental dysfunction. Conclusion: High sFlt-1 concentrations may account for diminished maternal serum PlGF levels.
Echolocating bats rely on audiovocal feedback to adapt sonar signal design

Significance Echolocating animals are well known for their capability to extract rich information about the environment from echo returns. However, past research has not determined whether audiovocal feedback contributes to sonar call design. Audiovocal feedback is the process whereby an animal listens to the sounds it is producing and is used by both nonecholocating animals and humans to control their ongoing vocalizations. Here, we show that echolocating bats rely on audiovocal feedback, instead of echo feedback, to adapt their sonar call design in response to acoustic jamming signals. Our findings demonstrate that bats, like birds and humans, not only use audiovocal feedback to fine-tune the features of their calls, but also do so on a rapid timescale. Many species of bat emit acoustic signals and use information carried by echoes reflecting from nearby objects to navigate and forage. It is widely documented that echolocating bats adjust the features of sonar calls in response to echo feedback; however, it remains unknown whether audiovocal feedback contributes to sonar call design. Audiovocal feedback refers to the monitoring of one’s own vocalizations during call production and has been intensively studied in nonecholocating animals. Audiovocal feedback not only is a necessary component of vocal learning but also guides the control of the spectro-temporal structure of vocalizations. Here, we show that audiovocal feedback is directly involved in the echolocating bat’s control of sonar call features. As big brown bats tracked targets from a stationary position, we played acoustic jamming signals, simulating calls of another bat, timed to selectively perturb audiovocal feedback or echo feedback. We found that the bats exhibited the largest call-frequency adjustments when the jamming signals occurred during vocal production. By contrast, bats did not show sonar call-frequency adjustments when the jamming signals coincided with the arrival of target echoes. Furthermore, bats rapidly adapted sonar call design in the first vocalization following the jamming signal, revealing a response latency in the range of 66 to 94 ms. Thus, bats, like songbirds and humans, rely on audiovocal feedback to structure sonar signal design.