Miracle-dz/UniFAR-FTUs huggingface dataset:
Wakefulness Is Promoted during Day Time by PDFR Signalling to Dopaminergic Neurons in Drosophila melanogaster

Visual Abstract Circadian clocks modulate timing of sleep/wake cycles in animals; however, the underlying mechanisms remain poorly understood. In Drosophila melanogaster, large ventral lateral neurons (l-LNv) are known to promote wakefulness through the action of the neuropeptide pigment dispersing factor (PDF), but the downstream targets of PDF signalling remain elusive. In a screen using downregulation or overexpression (OEX) of the gene encoding PDF receptor (pdfr), we found that a subset of dopaminergic neurons responds to PDF to promote wakefulness during the day. Moreover, we found that small LNv (s-LNv) and dopaminergic neurons form synaptic contacts, and PDFR signalling inhibited dopaminergic neurons specifically during day time. We propose that these dopaminergic neurons that respond to PDFR signalling are sleep-promoting and that during the day when PDF levels are high, they are inhibited, thereby promoting wakefulness. Thus, we identify a novel circadian clock pathway that mediates wake promotion specifically during day time.
Update on α1-antitrypsin deficiency

α1-Antitrypsin deficiency (AATD) is an inherited metabolic disorder in which mutations in the coding sequence of the SERPINA1 gene prevent secretion of α1-antitrypsin (α1-AT) and cause predisposition to pulmonary and liver diseases. The heterogeneity of clinical manifestations in AATD is related to the complexity of biological function of α1-AT. The role of smoking is crucial in the natural history of lung damage progression in severe AATD individuals, even if it also partly explains the heterogeneity in lung disease. Lung damage progression in AATD can also be related to body mass index, exacerbation rate, sex, environmental exposure and specific mutations of SERPINA1. Recent randomised controlled trials, together with previous observational work, have provided compelling evidence for the importance of early detection and intervention in order to enable patients to receive appropriate treatment and preserve functional lung tissue. Early detection and intervention in cases of α1-antitrypsin deficiency are essential to enable appropriate treatment and preserve functional lung tissue http://ow.ly/Mr3P30jUEyn
Video-to-Video Synthesis

We study the problem of video-to-video synthesis, whose goal is to learn a mapping function from an input source video (e.g., a sequence of semantic segmentation masks) to an output photorealistic video that precisely depicts the content of the source video. While its image counterpart, the image-to-image synthesis problem, is a popular topic, the video-to-video synthesis problem is less explored in the literature. Without understanding temporal dynamics, directly applying existing image synthesis approaches to an input video often results in temporally incoherent videos of low visual quality. In this paper, we propose a novel video-to-video synthesis approach under the generative adversarial learning framework. Through carefully-designed generator and discriminator architectures, coupled with a spatio-temporal adversarial objective, we achieve high-resolution, photorealistic, temporally coherent video results on a diverse set of input formats including segmentation masks, sketches, and poses. Experiments on multiple benchmarks show the advantage of our method compared to strong baselines. In particular, our model is capable of synthesizing 2K resolution videos of street scenes up to 30 seconds long, which significantly advances the state-of-the-art of video synthesis. Finally, we apply our approach to future video prediction, outperforming several state-of-the-art competing systems.
Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease

Parkinson’s disease (PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons. The cell bodies of these neurons are present in the substantia nigra, with the nerve terminals being in the striatum. Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these. Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway. Characteristic of neuroinflammation is the activation of brain glial cells, principally microglia and astrocytes that release various soluble factors. Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons. Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD. All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and, when measured, preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals. Some of these agents were shown to exert an anti-inflammatory action, decrease oxidative stress, and reduce lipid peroxidation products. Activation of microglia and astrocytes was also decreased, as well as infiltration of T cells into the substantia nigra. Pretreatment with fingolimod, tanshinoine I, dimethyl fumarate, thalidomide, or cocaine- and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals. Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk, including genetic factors.
In Defense of Single-column Networks for Crowd Counting

Crowd counting usually addressed by density estimation becomes an increasingly important topic in computer vision due to its widespread applications in video surveillance, urban planning, and intelligence gathering. However, it is essentially a challenging task because of the greatly varied sizes of objects, coupled with severe occlusions and vague appearance of extremely small individuals. Existing methods heavily rely on multi-column learning architectures to extract multi-scale features, which however suffer from heavy computational cost, especially undesired for crowd counting. In this paper, we propose the single-column counting network (SCNet) for efficient crowd counting without relying on multi-column networks. SCNet consists of residual fusion modules (RFMs) for multi-scale feature extraction, a pyramid pooling module (PPM) for information fusion, and a sub-pixel convolutional module (SPCM) followed by a bilinear upsampling layer for resolution recovery. Those proposed modules enable our SCNet to fully capture multi-scale features in a compact single-column architecture and estimate high-resolution density map in an efficient way. In addition, we provide a principled paradigm for density map generation and data augmentation for training, which shows further improved performance. Extensive experiments on three benchmark datasets show that our SCNet delivers new state-of-the-art performance and surpasses previous methods by large margins, which demonstrates the great effectiveness of SCNet as a single-column network for crowd counting.
Visual-Interactive Semi-Supervised Labeling of Human Motion Capture Data

The characterization and abstraction of large multivariate time series data often poses challenges with respect to effectiveness or efﬁciency. Using the example of human motion capture data challenges exist in creating compact solutions that still re-ﬂect semantics and kinematics in a meaningful way. We present a visual-interactive approach for the semi-supervised labeling of human motion capture data. Users are enabled to assign labels to the data which can subsequently be used to represent the multivariate time series as sequences of motion classes. The approach combines multiple views supporting the user in the visual-interactive labeling process. Visual guidance concepts further ease the labeling process by propagating the results of supportive algorithmic models. The abstraction of motion capture data to sequences of event intervals allows overview and detail-on-demand visualizations even for large and heterogeneous data collections. The guided selection of candidate data for the extension and improvement of the labeling closes the feedback loop of the semi-supervised workﬂow. We demonstrate the effectiveness and the efﬁciency of the approach in two usage scenarios, taking visual-interactive learning and human motion synthesis as examples.
Carcinoid syndrome: update on the pathophysiology and treatment

Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.
Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice

Significance Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by severe cognitive decline. The connection between neuroinflammation and the progressive loss of neurons is well known; however, the fact that most patients with AD suffer from concomitant seizure disorders is underappreciated. We have previously shown that the NLRP3 inflammasome, a major source of the proinflammatory cytokines IL1β and IL18, drives the pathology of AD in APP/PS1 mice. Here we report that surprisingly, IL18-deficient APP/PS1 mice develop a lethal seizure disorder due to an increase in neuronal network transmission. While targeting the NLRP3 inflammasome might be one potential method of halting AD progression, it should be recognized that specific cytokine inhibition in the brain may result in unintended deleterious consequences. Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.
Intensive care nurse conceptions of well‐being: a prototype analysis

BACKGROUND Accurately conceptualizing intensive care nurse work well-being is fundamental for successful engagement with workplace well-being interventions. Little is currently known about intensive care nurse work well-being. AIMS The study aimed to identify intensive care nurses' conceptions of work well-being and ascertain whether the term 'work well-being' is prototypically organized. METHODS Three linked studies conceptualize intensive care nurse well-being. For study one, participants listed key features of work well-being as free-text responses. Study two measured whether there was prototypical organization of these responses. Study three sought to confirm the prototypical organization of the term 'work well-being' through narrative ratings. RESULTS A total of 82 New Zealand intensive care nurses were randomly allocated to the three studies; 65 participated. In study one (n = 23), the most frequently endorsed elements included: workload (n = 14), job satisfaction (n = 13) and support (n = 13). In study two (n = 25), the highest rated elements included: feeling valued, respect, support, work-life balance and workplace culture. Elements of support, work-life balance and workload were in the top five most frequently endorsed elements and were also rated in the top 12 most central. Overall, the ratings of centrality and number of endorsements were positively correlated (r = 0.35, P < 0.05). In study three (n = 17), nine participants selected the same rating across both narratives with no differentiation on the 11-point scale and were excluded from analysis. The mean score for the central narrative was 7.88 and for the peripheral narrative was 7.38. Confirmatory analyses did not reach statistical significance. CONCLUSIONS Unique conceptions of work well-being were identified. Workload and work-life balance were central characteristics. Feeling valued and experiencing respect and support were considered most important. RELEVANCE TO CLINICAL PRACTICE Intensive care nurse conceptions of work well-being are fundamental for future measures of work well-being and future interventional studies and initiatives.
Genetics and Expression Profile of the Tubulin Gene Superfamily in Breast Cancer Subtypes and Its Relation to Taxane Resistance

Taxanes are a class of chemotherapeutic agents that inhibit cell division by disrupting the mitotic spindle through the stabilization of microtubules. Most breast cancer (BC) tumors show resistance against taxanes partially due to alterations in tubulin genes. In this project we investigated tubulin isoforms in BC to explore any correlation between tubulin alterations and taxane resistance. Genetic alteration and expression profiling of 28 tubulin isoforms in 6714 BC tumor samples from 4205 BC cases were analyzed. Protein-protein, drug-protein and alterations neighbor genes in tubulin pathways were examined in the tumor samples. To study correlation between promoter activity and expression of the tubulin isoforms in BC, we analyzed the ChIP-seq enrichment of active promoter histone mark H3K4me3 and mRNA expression profile of MCF-7, ZR-75-30, SKBR-3 and MDA-MB-231 cell lines. Potential correlation between tubulin alterations and taxane resistance, were investigated by studying the expression profile of taxane-sensitive and resistant BC tumors also the MDA-MB-231 cells acquired resistance to paclitaxel. All genomic data were obtained from public databases. Results showed that TUBD1 and TUBB3 were the most frequently amplified and deleted tubulin genes in the BC tumors respectively. The interaction analysis showed physical interactions of α-, β- and γ-tubulin isoforms with each other. The most of FDA-approved tubulin inhibitor drugs including taxanes target only β-tubulins. The analysis also revealed sex tubulin-interacting neighbor proteins including ENCCT3, NEK2, PFDN2, PTP4A3, SDCCAG8 and TBCE which were altered in at least 20% of the tumors. Three of them are tubulin-specific chaperons responsible for tubulin protein folding. Expression of tubulin genes in BC cell lines were correlated with H3K4me3 enrichment on their promoter chromatin. Analyzing expression profile of BC tumors and tumor-adjacent normal breast tissues showed upregulation of TUBA1A, TUBA1C, TUBB and TUBB3 and downregulation of TUBB2A, TUBB2B, TUBB6, TUBB7P pseudogene, and TUBGCP2 in the tumor tissues compared to the normal breast tissues. Analyzing taxane-sensitive versus taxane-resistant tumors revealed that expression of TUBB3 and TUBB6 was significantly downregulated in the taxane-resistant tumors. Our results suggest that downregulation of tumor βIII- and βV-tubulins is correlated with taxane resistance in BC. Based on our results, we conclude that aberrant protein folding of tubulins due to mutation and/or dysfunction of tubulin-specific chaperons may be potential mechanisms of taxane resistance. Thus, we propose studying the molecular pathology of tubulin mutations and folding in BC and their impacts on taxane resistance.
Modeling Buffer-Related Charge Trapping Effect by Using Threshold Voltage Shifts in AlGaN/GaN HEMTs

In this paper, buffer-related charge tapping effect is modeled as threshold voltage shifts for the first time in AlGaN/ GaN HEMTs. The threshold voltage shifts are described by a threshold voltage model, which does not contain any fitting parameters and is also continuously differentiable. The threshold voltage model can be easily implemented into a compact large-signal model. The large-signal model with trapping effects can accurately predict the dynamic I-V behavior, S-parameters up to 14 GHz, and large-signal output characteristics.
Complex Care Needs in Multiple Chronic Conditions: Population Prevalence and Characterization in Primary Care. A Study Protocol

Background: Chronicity, and particularly complex care needs for people with chronic diseases is one of the main challenges of health systems. Objective: To determine the population prevalence of people with chronic diseases and complex care needs and to characterize these needs considering features of health and social complexity in Primary Care. Design: Cross-sectional population-based study. Scope: Patients who have one or more chronic health conditions from three Primary Care urban centres of a reference population of 43.647 inhabitants older than 14 years old. Methodology: Data will be obtained from the review of electronical medical records. Complexity will be defined by: 1) the independent clinical judgment of primary care physicians and nurses and 2) the aid of three complexity domains (clinical and social). Patients with advanced chronic disease and limited life prognosis will be also described. Conclusions: This research protocol intends to describe and analyse complex care needs from a primary care professional perspective in order to improve knowledge of complexity beyond multimorbidity and previous consumption of health resources. Knowing about health and social complexity with a more robust empirical basis could help for a better integration of social and health policies and a more proactive and differentiated care approach in this most vulnerable population.
Optimal infusion rate in antimicrobial therapy explosion of evidence in the last five years

Background Sporadic studies in antimicrobial therapy have evaluated the effects of infusion rates on therapeutic and economic outcomes, and new findings may challenge the regular infusion regimen. Methods Focusing on studies comparing the outcomes of different infusion regimens, the relevant literature was identified by searching PubMed, Web of Science, and Scopus from January 1, 2013 to March 1, 2018. Papers were finally chosen using a PRISMA flowchart. Results Antimicrobials with the superiority of prolonged infusion to standard infusion in terms of efficacy and safety include meropenem, doripenem, imipenem, cefepime, ceftazidime, piperacillin/tazobactam, linezolid, and vancomycin. The strategy of concomitantly reducing total daily dose and prolonging infusion time may cause treatment failure (eg, imipenem). Extended infusion of piperacillin/tazobactam has pharmacoeconomic advantage over standard infusion. Prolonged infusion of voriconazole is inferior to standard infusion because of lower efficacy caused by pharmacokinetic changes. Comparable outcomes following standard infusion and continuous infusion were observed with norvancomycin and nafcillin. Factors determining whether prolonged infusion has a benefit over standard infusion include MIC of bacterial pathogens, bacterial density, diagnosis, disease severity, total daily dose, and renal function. Conclusion To maximally preserve the effectiveness of current antimicrobials, effective interventions should be implemented to enhance the application of optimal infusion strategies. For reducing nephrotoxicity, prolonged infusion of meropenem is better than conventional infusion in neonates with Gram-negative late-onset sepsis, and continuous infusion of vancomycin is superior to intermittent infusion. For increasing efficacy, prolonged or continuous infusion of time-dependent antimicrobials (eg, meropenem, doripenem, imipenem, cefepime, ceftazidime, piperacillin/tazobactam, linezolid, and vancomycin) is an optimal choice. Nevertheless, such advantages may only be demonstrated in special clinical circumstances and special populations (eg, patients with a sequential organ failure assessment (SOFA) score≥9, respiratory tract infections, urinary or intra-abdominal infections, or infections caused by less susceptible pathogens would benefit from prolonged infusion of piperacillin/tazobactam).
Model Change Detection With the MDL Principle

We are concerned with the issue of detecting model changes in probability distributions. We specifically consider the strategies based on the minimum description length (MDL) principle. We theoretically analyze their basic performance from the two aspects: data compression and hypothesis testing. From the view of data compression, we derive a new bound on the minimax regret for model changes. Here, the mini–max regret is defined as the minimum of the worst-case code-length relative to the least normalized maximum likelihood code-length over all model changes. From the view of hypothesis testing, we reduce the model change detection into a simple hypothesis testing problem. We thereby derive upper bounds on error probabilities for the MDL-based model change test. The error probabilities are valid for finite sample size and are related to the information-theoretic complexity as well as the discrepancy measure of the hypotheses to be tested.