Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypothermia elongates the contraction-relaxation cycle in explanted human failing heart decreasing the time for ventricular filling during diastole.

Targeted temperature management is part of the standardized treatment for patients in cardiac arrest. Hypothermia decreases cerebral oxygen consumption and induces bradycardia; thus, increasing the heart rate may be considered to maintain cardiac output. We hypothesized that increasing heart rate during hypothermia would impair diastolic function. Human left ventricular trabeculae obtained from explanted hearts of patients with terminal heart failure were stimulated at 0.5 Hz, and contraction-relaxation cycles were recorded. Maximal developed force (Fmax), maximal rate of development of force [(dF/d t)max], time to peak force (TPF), time to 80% relaxation (TR80), and relaxation time (RT = TR80 - TPF) were measured at 37, 33, 31, and 29°C. At these temperatures, stimulation frequency was increased from 0.5 to 1.0 and to 1.5 Hz. At 1.5 Hz, concentration-response curves for the β-adrenergic receptor (β-AR) agonist isoproterenol were performed. Fmax, TPF, and RT increased when temperature was lowered, whereas (dF/d t)max decreased. At all temperatures, increasing stimulation frequency increased Fmax and (dF/d t)max, whereas TPF and RT decreased. At 31 and 29°C, resting tension increased at 1.5 Hz, which was ameliorated by β-AR stimulation. At all temperatures, maximal β-AR stimulation increased Fmax, (dF/d t)max, and maximal systolic force, whereas resting tension decreased progressively with lowering temperature. β-AR stimulation reduced TPF and RT to the same extent at all temperatures, despite the more elongated contraction-relaxation cycle at lower temperatures. Diastolic dysfunction during hypothermia results from an elongation of the contraction-relaxation cycle, which decreases the time for ventricular filling. Hypothermic bradycardia protects the heart from diastolic dysfunction and increasing the heart rate during hypothermia should be avoided. NEW & NOTEWORTHY Decreasing temperature increases the duration of the contraction-relaxation cycle in the human ventricular myocardium, significantly reducing the time for ventricular filling during diastole. During hypothermia, increasing heart rate further reduces the time for ventricular filling and in some situations increases resting tension further impairing diastolic function. Modest β-adrenergic receptor stimulation can ameliorate these potentially detrimental changes during diastole while improving contractile force generation during targeted temperature management.
Beta-Blocker Propranolol Modulates Decision Urgency During Sequential Information Gathering

Arbitrating between timely choice and extended information gathering is critical for effective decision making. Aberrant information gathering behavior is thought to be a feature of psychiatric disorders such as schizophrenia and obsessive-compulsive disorder, but we know little about the underlying neurocognitive control mechanisms. In a double-blind, placebo-controlled drug study involving 60 healthy human subjects (30 female), we examined the effects of noradrenaline and dopamine antagonism on information gathering during performance of an information sampling task. We show that modulating noradrenaline function with 40 mg of the β-blocker propranolol leads to decreased information gathering behavior. Modulating dopamine function via a single dose of 400 mg of amisulpride revealed some effects that were intermediate between those of propranolol and placebo. Using a Bayesian computational model, we show that sampling behavior is best explained by inclusion of a nonlinear urgency signal that promotes commitment to an early decision. Noradrenaline blockade promotes the expression of this decision-related urgency signal during information gathering. We discuss the findings with respect to psychopathological conditions that are linked to aberrant information gathering. SIGNIFICANCE STATEMENT Knowing when to stop gathering information and commit to a choice option is nontrivial. This is an important element in arbitrating between information gain and energy conservation. In this double-blind, placebo-controlled drug study, we investigated the role of catecholamines noradrenaline and dopamine on sequential information gathering. We found that blockade of noradrenaline led to a decrease in information gathering. Dopamine blockade showed an intermediate, but nonsignificant, effect. Using a Bayesian computational model, we show that this noradrenaline effect is driven by increased decision urgency, a signal that reflects an escalating subjective cost of sampling. The observation that noradrenaline modulates decision urgency suggests new avenues for treating patients that show information gathering deficits.
Noninvasive wave intensity analysis predicts functional worsening in children with pulmonary arterial hypertension.

The purpose of the present study was to characterize pulmonary vascular stiffness using wave intensity analysis (WIA) in children with pulmonary arterial hypertension (PAH), compare the WIA indexes with catheterization- and MRI-derived hemodynamics, and assess the prognostic ability of WIA-derived biomarkers to predict the functional worsening. WIA was performed in children with PAH ( n = 40) and healthy control subjects ( n = 15) from phase-contrast MRI-derived flow and area waveforms in the main pulmonary artery (MPA). From comprehensive WIA spectra, we collected and compared with healthy control subjects forward compression waves (FCW), backward compression waves (BCW), forward decompression waves (FDW), and wave propagation speed ( c-MPA). There was no difference in the magnitude of FCW between PAH and control groups (88 vs. 108 mm5·s-1·ml-1, P = 0.239). The magnitude of BCW was increased in patients with PAH (32 vs. 5 mm5·s-1·ml-1, P < 0.001). There was no difference in magnitude of indexed FDW (32 vs. 28 mm5·s-1·ml-1, P = 0.856). c-MPA was increased in patients with PAH (3.2 vs. 1.6 m/s, P < 0.001). BCW and FCW correlated with mean pulmonary arterial pressure, right ventricular volumes, and ejection fraction. Elevated indexed BCW [heart rate (HR) = 2.91, confidence interval (CI): 1.18-7.55, P = 0.019], reduced indexed FDW (HR = 0.34, CI: 0.11-0.90, P = 0.030), and increased c-MPA (HR = 3.67, CI: 1.47-10.20, P = 0.004) were strongly associated with functional worsening of disease severity. Our results suggest that noninvasively derived biomarkers of pulmonary vascular resistance and stiffness may be helpful for determining prognosis and monitoring disease progression in children with PAH. NEW & NOTEWORTHY Wave intensity analysis (WIA) studies are lacking in children with pulmonary arterial hypertension (PAH) partially because WIA, which is necessary to assess vascular stiffness, requires an invasive pressure-derived waveform along with simultaneous flow measurements. We analyzed vascular stiffness using WIA in children with PAH who underwent phase-contrast MRI and observed significant differences in WIA indexes between patients with PAH and control subjects. Furthermore, WIA indexes were predictive of functional worsening and were associated with standard catheterization measures.
Evolution in clinical presentation of inflammatory bowel disease over time at diagnosis: a multicenter cohort study

Introduction Delayed diagnosis of inflammatory bowel disease (IBD) has become a major issue, particularly in terms of the presence of nonspecific and heterogeneous clinical signs. This study aimed to identify changes over time in the epidemiological characteristics and clinical presentation of IBD in a French cohort. Patients and methods Sociodemographic data from patients at three French hospitals (age, sex, country of origin, smoking habits) and characteristics of IBD [diagnostic delay, phenotype, location, first symptoms, first test suggesting diagnosis (endoscopy, imaging examination)] were collected in a computerized database (Focus_MICI). Four diagnostic time periods were assessed: <2000, 2000–2004, 2005–2009, and >2009. Results Among the 926 patients analyzed, 638 (<2000, n=181; 2000–2004, n=104; 2005–2009, n=147; >2009, n=206) had Crohn’s disease (CD) and 288 (<2000, n=54; 2000–2004, n=39; 2005–2009, n=80; >2009, n=115) had ulcerative colitis (UC). For CD, statistically significant differences over time were observed for (a) the first revealing disease symptom [more frequent abdominal pain vs. chronic diarrhea (P<0.001)], (b) first investigation suggestive of diagnosis [more frequent computed tomography vs. colonoscopy (P<0.001)], and (c) CD behavior [more frequent inflammatory vs. stricturing/penetrating forms (P<0.001)]. No significant differences over time were observed for UC variables. Conclusion In this large multicenter cohort study clinical diagnostic presentation of CD has changed over time. By contrast, there were no changes in the UC clinical presentation.
Large-Scale, High-Resolution Comparison of the Core Visual Object Recognition Behavior of Humans, Monkeys, and State-of-the-Art Deep Artificial Neural Networks

Primates, including humans, can typically recognize objects in visual images at a glance despite naturally occurring identity-preserving image transformations (e.g., changes in viewpoint). A primary neuroscience goal is to uncover neuron-level mechanistic models that quantitatively explain this behavior by predicting primate performance for each and every image. Here, we applied this stringent behavioral prediction test to the leading mechanistic models of primate vision (specifically, deep, convolutional, artificial neural networks; ANNs) by directly comparing their behavioral signatures against those of humans and rhesus macaque monkeys. Using high-throughput data collection systems for human and monkey psychophysics, we collected more than one million behavioral trials from 1472 anonymous humans and five male macaque monkeys for 2400 images over 276 binary object discrimination tasks. Consistent with previous work, we observed that state-of-the-art deep, feedforward convolutional ANNs trained for visual categorization (termed DCNNIC models) accurately predicted primate patterns of object-level confusion. However, when we examined behavioral performance for individual images within each object discrimination task, we found that all tested DCNNIC models were significantly nonpredictive of primate performance and that this prediction failure was not accounted for by simple image attributes nor rescued by simple model modifications. These results show that current DCNNIC models cannot account for the image-level behavioral patterns of primates and that new ANN models are needed to more precisely capture the neural mechanisms underlying primate object vision. To this end, large-scale, high-resolution primate behavioral benchmarks such as those obtained here could serve as direct guides for discovering such models. SIGNIFICANCE STATEMENT Recently, specific feedforward deep convolutional artificial neural networks (ANNs) models have dramatically advanced our quantitative understanding of the neural mechanisms underlying primate core object recognition. In this work, we tested the limits of those ANNs by systematically comparing the behavioral responses of these models with the behavioral responses of humans and monkeys at the resolution of individual images. Using these high-resolution metrics, we found that all tested ANN models significantly diverged from primate behavior. Going forward, these high-resolution, large-scale primate behavioral benchmarks could serve as direct guides for discovering better ANN models of the primate visual system.
Neospora caninum Dense Granule Protein 7 Regulates the Pathogenesis of Neosporosis by Modulating Host Immune Response

Neospora caninum invades and replicates in a broad range of host species and cells within those hosts. The effector proteins exported by Neospora induce its pathogenesis by modulating the host immunity. We show that most of the transcriptomic effects in N. caninum-infected cells depend upon the activity of NcGRA7. A deficiency in NcGRA7 reduced the virulence of the parasite in mice. This study demonstrates the importance of NcGRA7 in the pathogenesis of neosporosis. ABSTRACT Neospora caninum is a protozoan parasite closely related to Toxoplasma gondii. Neosporosis caused by N. caninum is considered one of the main causes of abortion in cattle and nervous-system dysfunction in dogs, and identification of the virulence factors of this parasite is important for the development of control measures. Here, we used a luciferase reporter assay to screen the dense granule proteins genes of N. caninum, and we found that NcGRA6, NcGRA7, and NcGRA14 are involved in the activation of the NF-κB, calcium/calcineurin, and cAMP/PKA signals. To analyze the functions of these proteins and Neospora cyclophilin, we successfully knocked out their genes in the Nc1 strain using plasmids containing the CRISPR/Cas9 components. Among the deficient lines, the NcGRA7-deficient parasites showed reduced virulence in mice. An RNA sequencing analysis of infected macrophage cultures showed that NcGRA7 mainly regulates the host cytokine and chemokine production. The levels of gamma interferon in the ascites fluid, CXCL10 expression in the peritoneal cells, and CCL2 expression in the spleen were lower 5 days after infection with the NcGRA7-deficient parasite than after infection with the parental strain. The parasite burden and the degree of necrosis in the brains of mice infected with the NcGRA7-deficient parasite were also lower than in those of the parental strain. Collectively, our data suggest that both the NcGRA7-dependent activation of the inflammatory response and the parasite burden are important in Neospora virulence. IMPORTANCE Neospora caninum invades and replicates in a broad range of host species and cells within those hosts. The effector proteins exported by Neospora induce its pathogenesis by modulating the host immunity. We show that most of the transcriptomic effects in N. caninum-infected cells depend upon the activity of NcGRA7. A deficiency in NcGRA7 reduced the virulence of the parasite in mice. This study demonstrates the importance of NcGRA7 in the pathogenesis of neosporosis.
On Sharing Intentions, and Personal and Interdependent Privacy Considerations for Genetic Data: A Vignette Study

Genetics and genetic data have been the subject of recent scholarly work, with significant attention paid towards understanding consent practices for the acquisition and usage of genetic data as well as genetic data security. Attitudes and perceptions concerning the trustworthiness of governmental institutions receiving test-taker data have been explored, with varied findings, but no robust models or deterministic relationships have been established that account for these differences. These results also do not explore in detail the perceptions regarding other types of organizations (e.g., private corporations). Further, considerations of privacy interdependence arising from blood relative relationships have been absent from the conversation regarding the sharing of genetic data. This paper reports the results from a factorial vignette survey study in which we investigate how variables of ethnicity, age, genetic markers, and association of data with the individual's name affect the likelihood of sharing data with different types of organizations. We also investigate elements of personal and interdependent privacy concerns. We document the significant role these factors have in the decision to share or not share genetic data. We support our findings with a series of regression analyses.
Extractive Document Summarization Based on Hierarchical GRU

Neural network has provided an efficient approach for extractive document summarization, which means selecting sentences from the text to form the summary. However, there are two shortcomings about the conventional methods: they directly extract summary from the whole document which contains huge redundancy, and they neglect relations between abstraction and the document. The paper proposes TSERNN, a two-stage structure, the first of which is a key-sentence extraction, followed by the Recurrent Neural Network-based model to handle the extractive summarization of documents. In the extraction phase, it conceives a hybrid sentence similarity measure by combining sentence vector and Levenshtein distance, and integrates it into graph model to extract key sentences. In the second phase, it constructs GRU as basic blocks, and put the representation of entire document based on LDA as a feature to support summarization. Finally, the model is tested on CNN/Daily Mail corpus, and experimental results verify the accuracy and validity of the proposed method.
Triptolide inhibits Wnt signaling in NSCLC through upregulation of multiple Wnt inhibitory factors via epigenetic modifications to Histone H3

In the last decade, it has become clear that epigenetic changes act together with genetic mutations to promote virtually every stage of tumorigenesis and cancer progression. This knowledge has triggered searches for “epigenetic drugs” that can be developed into new cancer therapies. Here we report that triptolide reduced lung cancer incidence from 70% to 10% in a Fen1 E160D transgenic mouse model and effectively inhibited cancer growth and metastasis in A549 and H460 mouse xenografts. We found that triptolide induced lung cancer cell apoptosis that was associated with global epigenetic changes to histone 3 (H3). These global epigenetic changes in H3 are correlated with an increase in protein expression of five Wnt inhibitory factors that include WIF1, FRZB, SFRP1, ENY2, and DKK1. Triptolide had no effect on DNA methylation status at any of the CpG islands located in the promoter regions of all five Wnt inhibitory factors. Wnt expression is implicated in promoting the development and progression of many lung cancers. Because of this, the potential to target Wnt signaling with drugs that induce epigenetic modifications provides a new avenue for developing novel therapies for patients with these tumor types.
SNRP-27, the C. elegans homolog of the tri-snRNP 27K protein, has a role in 5′ splice site positioning in the spliceosome

The tri-snRNP 27K protein is a component of the human U4/U6-U5 tri-snRNP and contains an N-terminal phosphorylated RS domain. In a forward genetic screen in C. elegans, we previously identified a dominant mutation, M141T, in the highly-conserved C-terminal region of this protein. The mutant allele promotes changes in cryptic 5′ splice site choice. To better understand the function of this poorly characterized splicing factor, we performed high-throughput mRNA sequencing analysis on worms containing this dominant mutation. Comparison of alternative splice site usage between the mutant and wild-type strains led to the identification of 26 native genes whose splicing changes in the presence of the snrp-27 mutation. The changes in splicing are specific to alternative 5′ splice sites. Analysis of new alleles suggests that snrp-27 is an essential gene for worm viability. We performed a novel directed-mutation experiment in which we used the CRISPR-cas9 system to randomly generate mutations specifically at M141 of SNRP-27. We identified eight amino acid substitutions at this position that are viable, and three that are homozygous lethal. All viable substitutions at M141 led to varying degrees of changes in alternative 5′ splicing of native targets. We hypothesize a role for this SR-related factor in maintaining the position of the 5′ splice site as U1snRNA trades interactions at the 5′ end of the intron with U6snRNA and PRP8 as the catalytic site is assembled.
Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD‐J (Flow‐Mediated Dilation Japan) Study A

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. Clinical Trial Registration URL: http://www.umin. ac.jp. Unique identifier: UMIN000012950.
The analysis of the applicability of the decimation and the group addition property to M-NLFSR

The possibility of using decimation to the sequence generated by NLFSR is considered in this paper. The possibility of searching of sequence with maximal period by dint of the decimation is considered. The possibility of calculating the correlation for NLFSR based on the principle of group addition is considered. This correlation is used for calculating of the sequences with the predetermined shift.
Refined structure of BeM9 reveals arginine hand, an overlooked structural motif in scorpion toxins affecting sodium channels

Sodium channel alpha‐toxins from scorpion venom (α‐NaTx) inhibit the inactivation of voltage‐gated sodium channels. We used solution NMR to investigate the structure of BeM9 toxin from Mesobuthus eupeus scorpion, a prototype α‐NaTx classified as an “α‐like” toxin due to its wide spectrum of activity on insect and mammalian channels. We identified a new motif that we named “arginine hand,” whereby arginine side chain forms several hydrogen bonds with main chain atoms. The arginine hand was found in the “specificity module,” a part of the molecule that dictates toxin selectivity; and just single arginine‐to‐lysine point mutation drastically changed BeM9 selectivity profile.
Modeling and Simulation of a Lower Extremity Powered Exoskeleton

Lower extremity powered exoskeletons (LEPEs) allow people with spinal cord injury (SCI) to stand and walk. However, the majority of LEPEs walk slowly and users can become fatigued from overuse of forearm crutches, suggesting LEPE design can be enhanced. Virtual prototyping is a cost-effective way of improving design; therefore, this research developed and validated two models that simulate walking with the Bionik Laboratories’ ARKE exoskeleton attached to a human musculoskeletal model. The first model was driven by kinematic data from 30 able-bodied participants walking at realistic slow walking speeds (0.2–0.8 m/s) and accurately predicted ground reaction forces (GRF) for all speeds. The second model added upper limb crutches and was driven by 3-D-marker data from five SCI participants walking with ARKE. Vertical GRF had the strongest correlations (>0.90) and root-mean-square error (RMSE) and mediolateral center of pressure trajectory had the weakest (<0.35), for both models. Strong correlations and small RMSE between predicted and measured GRFs support the use of these models for optimizing LEPE joint mechanics and improving LEPE design.