Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Scanning Calorimetry — A Method for Assessing the Thermal Stability and Conformation of Protein Antigen

Differential scanning calorimetry (DSC) is an analytical technique that measures the molar heat capacity of samples as a function of temperature. In the case of protein samples, DSC profiles provide information about thermal stability, and to some extent serves as a structural “fingerprint” that can be used to assess structural conformation. It is performed using a differential scanning calorimeter that measures the thermal transition temperature (melting temperature; Tm) and the energy required to disrupt the interactions stabilizing the tertiary structure (enthalpy; ∆H) of proteins. Comparisons are made between formulations as well as production lots, and differences in derived values indicate differences in thermal stability and structural conformation. Data illustrating the use of DSC in an industrial setting for stability studies as well as monitoring key manufacturing steps are provided as proof of the effectiveness of this protocol. In comparison to other methods for assessing the thermal stability of protein conformations, DSC is cost-effective, requires few sample preparation steps, and also provides a complete thermodynamic profile of the protein unfolding process.
Impact of an emergency department electronic sepsis surveillance system on patient mortality and length of stay

Objective The purpose of this study was to determine whether an electronic health record-based sepsis alert system could improve quality of care and clinical outcomes for patients with sepsis. Materials and Methods We performed a patient-level interrupted time series study of emergency department patients with severe sepsis or septic shock between January 2013 and April 2015. The intervention, introduced in February 2014, was a system of interruptive sepsis alerts triggered by abnormal vital signs or laboratory results. Primary outcomes were length of stay (LOS) and in-hospital mortality; other outcomes included time to first lactate and blood cultures prior to antibiotics. We also assessed sensitivity, positive predictive value (PPV), and clinician response to the alerts. Results Mean LOS for patients with sepsis decreased from 10.1 to 8.6 days (P < .001) following alert introduction. In adjusted time series analysis, the intervention was associated with a decreased LOS of 16% (95% CI, 5%-25%; P = .007, with significance of α = 0.006) and no change thereafter (0%; 95% CI, -2%, 2%). The sepsis alert system had no effect on mortality or other clinical or process measures. The intervention had a sensitivity of 80.4% and a PPV of 14.6%. Discussion Alerting based on simple laboratory and vital sign criteria was insufficient to improve sepsis outcomes. Alert fatigue due to the low PPV is likely the primary contributor to these results. Conclusion A more sophisticated algorithm for sepsis identification is needed to improve outcomes.
Robust and Real-Time Traffic Lights Recognition in Complex Urban Environments

The traffic lights play an indispensable role in urban road safety and researches on intelligent vehicles become more popular recently. In this paper an automatic system for robust and real-time detection and recognition of traffic lights for intelligent vehicles based on vehicle-mounted camera is proposed. The method applying image processing and pattern recognition theory mainly works in three stages. First, the candidate regions of traffic lights are extracted using the color threshold segmentation method. Secondly, noise removal and two types of filtering which take account of shape information are applied to the candidate regions. Thirdly, template matching using normalized cross correlation techniques is adopted to validate the traffic lights candidate. Experimental results show that the proposed algorithm works effectively and robustly for traffic lights recognition in complex urban environments.
Inhibitory Selection Mechanisms in Clinically Healthy Older and Younger Adults

Objective Declines in working memory are a ubiquitous finding within the cognitive-aging literature. A unitary inhibitory selection mechanism that serves to guide attention toward task-relevant information and resolve interference from task-irrelevant information has been proposed to underlie such deficits. However, inhibition can occur at multiple time points in the memory-processing stream. Here, we tested whether the time point at which inhibition occurs in the memory-processing stream affects age-related memory decline. Method Clinically healthy younger (n = 23) and older (n = 22) adults performed two similar item-recognition working memory tasks. In one task, participants received an instruction cue telling them which words to attend to followed by a memory set, promoting perceptual inhibition at the time of encoding. In the other task, participants received the instruction cue after they received the memory set, fostering inhibition of items already in memory. Results We found that older and younger adults differed in their ability to inhibit items both during encoding and when items had to be inhibited in memory but that these age differences were exaggerated when irrelevant information had to be inhibited from memory. These results provide insights into the mechanisms that support cognitive changes to memory processes in healthy aging.
Salvador has an extended SARAH domain that mediates binding to Hippo kinase

The Hippo pathway controls cell proliferation and differentiation through the precisely tuned activity of a core kinase cassette. The activity of Hippo kinase is modulated by interactions between its C-terminal coiled-coil, termed the SARAH domain, and the SARAH domains of either dRassF or Salvador. Here, we wanted to understand the molecular basis of SARAH domain–mediated interactions and their influence on Hippo kinase activity. We focused on Salvador, a positive effector of Hippo activity and the least well-characterized SARAH domain–containing protein. We determined the crystal structure of a complex between Salvador and Hippo SARAH domains from Drosophila. This structure provided insight into the organization of the Salvador SARAH domain including a folded N-terminal extension that expands the binding interface with Hippo SARAH domain. We also found that this extension improves the solubility of the Salvador SARAH domain, enhances binding to Hippo, and is unique to Salvador. We therefore suggest expanding the definition of the Salvador SARAH domain to include this extended region. The heterodimeric assembly observed in the crystal was confirmed by cross-linked MS and provided a structural basis for the mutually exclusive interactions of Hippo with either dRassF or Salvador. Of note, Salvador influenced the kinase activity of Mst2, the mammalian Hippo homolog. In co-transfected HEK293T cells, human Salvador increased the levels of Mst2 autophosphorylation and Mst2-mediated phosphorylation of select substrates, whereas Salvador SARAH domain inhibited Mst2 autophosphorylation in vitro. These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway.
Rs13293512 polymorphism located in the promoter region of let‐7 is associated with increased risk of radiation enteritis in colorectal cancer

RE (Radiation enteritis) has been characterized by the inflammation reaction, and in this study, we aim to explore inflammatory cytokines and underlying mechanism involved in the pathogenesis of RE. Luciferase assay was performed to explore whether polymorphism affected the expression of let‐7, and also validated let‐7 directly regulated f IL‐6 expression. Then Elisa was performed to study the mechanism of rs13293512 polymorphism associated with enteritis occurrence. And Western‐blot and real‐time PCR were performed to verify the relationship between let‐7 and IL‐6. 380 colorectal cancer patients were recruited, and all participants were genotyped. We found that occurrence probability of enteritis patients carried CC genotype (32%) was much higher than that in TT and TC groups (15%). In addition, we showed that the presence of the minor (C) allele of the polymorphism in the promoter region of let‐7 substantially reduced the transcription activity of let‐7, furthermore, we validated that let‐7 directly regulated IL‐6 expression by using luciferase reporter system. Moreover, IL‐6 was highly expressed in peripheral blood and colonic mucosa samples genotyped as CC compared to those in TT and TC groups, furthermore, IL‐6 was highly expressed in peripheral blood and colonic mucosa samples from participants with enteritis than without enteritis, whereas let‐7 was highly expressed in peripheral blood and colonic mucosa samples genotyped as TT and TC compared to those in CC groups. Let‐7 polymorphism (rs13293512) was associated with risk of RE in the colorectal cancer patients who received radiotherapy.
Absorption, metabolism, and excretion of [14C]evogliptin tartrate in male rats and dogs

ABSTRACT The objective of this study was to determine the absorption, excretion, and metabolism of a novel, oral antihyperglycemic drug, evogliptin, in male rats and dogs. Plasma, urine, feces, and expired air samples were collected after a single oral dose administration of [14C]evogliptin, samples were analyzed by measuring overall radioactivity levels using high-performance liquid chromatography (HPLC), and radioactivity levels were measured by utilizing LC-tandem mass spectrometry (LC-MS/MS). The total amounts of radioactivity excreted in urine, feces, and expired air up to 168 h after administration of [14C]evogliptin tartrate to rats (30 mg evogliptin/kg) and dogs (10 mg evogliptin/kg) were 96.7% and 96.8% of initial doses administered, respectively. The extent of urinary and fecal excretion in the rat up to 168 h constituted 29.7% and 66.5% of the given dose, respectively; and in dog was 43.3% and 53.5%, respectively. A total of 23 possible metabolites were detected with radiochromatograms of plasma, urinary, and fecal samples, but only the structures of 12 metabolites were identified via LC-MS/MS analysis. Evogliptin was the major component. Regarding the total radiochromatographic peak areas, peaks 9 (evogliptin acid) and 11 (hydroxyevogliptin) were the major metabolites in rats, and peaks 8 [4(S)-hydroxyevogliptin glucuronide], 15 [4(S)-hydroxyevogliptin], and 17 [4(R)-hydroxyevogliptin] were the predominant metabolites in dogs. Data demonstrated that evogliptin was the major component excreted in urine and feces of rats and dogs, but the metabolite profiles varied between species.
Adaptive response criteria in road hazard detection among older drivers

ABSTRACT Objectives: The majority of existing investigations on attention, aging, and driving have focused on the negative impacts of age-related declines in attention on hazard detection and driver performance. However, driving skills and behavioral compensation may accommodate for the negative effects that age-related attentional decline places on driving performance. In this study, we examined an important question that had been largely neglected in the literature linking attention, aging, and driving: can top-down factors such as behavioral compensation, specifically adaptive response criteria, accommodate the negative impacts from age-related attention declines on hazard detection during driving? Methods: In the experiment, we used the Drive Aware Task, a task combining the driving context with well-controlled laboratory procedures measuring attention. We compared younger (n = 16, age 21–30) and older (n = 21, age 65–79) drivers on their attentional processing of hazards in driving scenes, indexed by percentage of correct responses and reaction time of hazard detection, as well as sensitivity and response criteria using signal detection analysis. Results: Older drivers, in general, were less accurate and slower on the task than younger drivers. However, results from this experiment revealed that older, but not younger, drivers adapted their response criteria when the traffic condition changed in the driving scenes. When there was more traffic in the driving scene, older drivers became more liberal in their responses, meaning that they were more likely to report that a driving hazard was detected. Conclusions: Older drivers adopt compensatory strategies for hazard detection during driving. Our findings showed that, in the driving context, even at an older age our attentional functions are still adaptive according to environmental conditions. This leads to considerations on potential training methods to promote adaptive strategies that may help older drivers maintain performance in road hazard detection.
Neuroimaging of ischemia and infarction

SummarySince the introduction of thrombolytic therapy as the foundation of acute stroke treatment, neuroimaging has rapidly advanced to empower therapeutic decision making. Diffusion-weighted imaging is the most sensitive and accurate method for stroke detection, and, allied with perfusion-weighted imaging, provides information on the functional status of the ischemic brain. It can also help to identify a response to thrombolytic and neuroprotective therapies. Additionally, multimodal magnetic resonance imaging, including magnetic resonance angiography, offers information on stroke mechanism and pathophysiology that can guide long-term medical management. Multimodal computed tomography is a comprehensive, cost-effective, and safe stroke imaging modality that can be easily implemented in the emergency ward and that offers fast and reliable information with respect to the arterial and functional status of the ischemic brain. Accessibility, contraindications, cost, speed, and individual patient-determined features influence which is the best imaging modality to guide acute stroke management.
Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Bone marrow fibrosis is the continuous replacement of blood‐forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis‐driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis‐causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet‐derived growth factor (PDGF) receptor‐α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell‐to‐myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non‐malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Sequence Modeling with Hierarchical Deep Generative Models with Dual Memory

Deep Generative Models (DGMs) are able to extract high-level representations from massive unlabeled data and are explainable from a probabilistic perspective. Such characteristics favor sequence modeling tasks. However, it still remains a huge challenge to model sequences with DGMs. Unlike real-valued data that can be directly fed into models, sequence data consist of discrete elements and require being transformed into certain representations first. This leads to the following two challenges. First, high-level features are sensitive to small variations of inputs as well as the way of representing data. Second, the models are more likely to lose long-term information during multiple transformations. In this paper, we propose a Hierarchical Deep Generative Model With Dual Memory to address the two challenges. Furthermore, we provide a method to efficiently perform inference and learning on the model. The proposed model extends basic DGMs with an improved hierarchically organized multi-layer architecture. Besides, our model incorporates memories along dual directions, respectively denoted as broad memory and deep memory. The model is trained end-to-end by optimizing a variational lower bound on data log-likelihood using the improved stochastic variational method. We perform experiments on several tasks with various datasets and obtain excellent results. The results of language modeling show our method significantly outperforms state-of-the-art results in terms of generative performance. Extended experiments including document modeling and sentiment analysis, prove the high-effectiveness of dual memory mechanism and latent representations. Text random generation provides a straightforward perception for advantages of our model.
Psychosocial work factors and low back pain in taxi drivers

INTRODUCTION Taxi drivers are at high risk for low back pain (LBP). AIM Identify the association between psychosocial-work factors (Job strain, Iso-strain, effort-reward imbalance [ERI], unfairness, and mental exertion) and LBP in taxi drivers. METHODS A cross-sectional study was done with 129 taxi drivers. RESULTS Approximately 63% reported LBP in the prior 12 months. Chi square or t-test analyses identified the associations between demographic, work, health, and psychosocial work factors, and self-report of LBP in the prior 12 months. Depression, perceived physical exertion, dispatcher and manager support, unfair treatment at work, and unfair treatment due to nationality were significantly associated with LBP in bivariate analyses. Multivariate logistic regression was done to identify the predictors of LBP. High dispatcher support remained the sole significant predictor for lower prevalence of LBP (OR = 0.66, P = 0.017). CONCLUSION Greater understanding of psychosocial work factors may aid in developing interventions to prevent LBP in taxi drivers.
Comments on ‘Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers’ by M. J. Pencina, R. B. D'Agostino, Sr. and E. W. Steyerberg

The continuous version of the net reclassification improvement (NRI), as presented and advocated in the paper by Pencina et al. [1], is an appealing addition to the bevy of measures used to compare the fit of two risk prediction models. Some advantages are that it does not depend on categories that can be arbitrary, uses all of the continuous data, and can be more directly compared across studies. How it performs relative to other measures, specifically to reclassification using categories, however, should be explored further. We used data from the Women’s Health Study (WHS) to examine the values of the NRI for predicting cardiovascular disease using the continuous version or various category definitions to see how the values may change in practical situations. TheWHS is a nationwide cohort ofwomen aged 45 and older followed for an average of 10 years for the development of cardiovascular and other diseases. The cohort, predictive models developed from it, and the measures of reclassification and other measures of fit have been described elsewhere [2, 3]. We now add the results for the continuousNRI, and compare this with the original measures using categories. The continuous NRI (also denoted as NRI(>0)) is equivalent to assuming infinite categories and compares the probability that the risk estimate for model 2 is higher than that for model 1 among cases versus controls. It can be thought of as a two-by-two table of cases status by an indicator of whether the risk estimate from model 2 is higher than that for model 1 [4]. Note that the variance for the continuous NRI should either use the formula for binomial proportions, namely
Implicit parameter estimation for conditional Gaussian Bayesian networks

AbstractThe Bayesian estimation of the conditional Gaussian parameter needs to define several a priori parameters. The proposed approach is free from this definition of priors. We use the Implicit estimation method for learning from observations without a prior knowledge. We illustrate the interest of such an estimation method by giving first the Bayesian Expectation A Posteriori estimator for conditional Gaussian parameters. Then, we describe the Implicit estimators for the same parameters. Moreover, an experimental study is proposed in order to compare both approaches.
Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome. Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation. Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell–mediated increase of intratumoral IDO1. Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell–mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell–mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650–60. ©2017 AACR.