Miracle-dz/UniFAR-FTUs huggingface dataset:
A Fundamental Role of Myh9 for Neutrophil Migration in Innate Immunity

Neutrophils are the first leukocytes to arrive at sites of injury during the acute inflammatory response. To maintain the polarized morphology during migration, nonmuscle myosins class II are essential, but studies using genetic models to investigate the role of Myh9 for neutrophil migration were missing. In this study, we analyzed the functional role of Myh9 on neutrophil trafficking using genetic downregulation of Myh9 in Vav-iCre+/Myh9wt/fl mice because the complete knockout of Myh9 in the hematopoietic system was lethal. Migration velocity and Euclidean distance were significantly diminished during mechanotactic migration of Vav-iCre+/Myh9wt/fl neutrophils compared with Vav-iCre−/Myh9wt/fl control neutrophils. Similar results were obtained for transmigration and migration in confined three-dimensional environments. Stimulated emission depletion nanoscopy revealed that a certain threshold of Myh9 was required to maintain proper F-actin dynamics in the front of the migrating cell. In laser-induced skin injury and in acute peritonitis, reduced Myh9 expression in the hematopoietic system resulted in significantly diminished neutrophil extravasation. Investigation of bone marrow chimeric mice in the peritonitis model revealed that the migration defect was cell intrinsic. Expression of Myh9-EGFP rescued the Myh9-related defects in two-dimensional and three-dimensional migration of Hoxb8-SCF cell–derived neutrophils generated from fetal liver cells with a Myh9 knockdown. Live cell imaging provided evidence that Myh9 was localized in branching lamellipodia and in the uropod where it may enable fast neutrophil migration. In summary, the severe migration defects indicate an essential and fundamental role of Myh9 for neutrophil trafficking in innate immunity.
Spoilage potential of psychrotrophic bacteria isolated from raw milk and the thermo-stability of their enzymes

The storage and transportation of raw milk at low temperatures promote the growth of psychrotrophic bacteria and the production of thermo-stable enzymes, which pose great threats to the quality and shelf-life of dairy products. Though many studies have been carried out on the spoilage potential of psychrotrophic bacteria and the thermo-stabilities of the enzymes they produce, further detailed studies are needed to devise an effective strategy to avoid dairy spoilage. The purpose of this study was to explore the spoilage potential of psychrotrophic bacteria from Chinese raw milk samples at both room temperature (28 °C) and refrigerated temperature (7 °C). Species of Yersinia, Pseudomonas, Serratia, and Chryseobacterium showed high proteolytic activity. The highest proteolytic activity was shown by Yersinia intermedia followed by Pseudomonas fluorescens (d). Lipolytic activity was high in isolates of Acinetobacter, and the highest in Acinetobacter guillouiae. Certain isolates showed positive β-galactosidase and phospholipase activity. Strains belonging to the same species sometimes showed markedly different phenotypic characteristics. Proteases and lipases produced by psychrotrophic bacteria retained activity after heat treatment at 70, 80, or 90 °C, and proteases appeared to be more heat-stable than lipases. For these reasons, thermo-stable spoilage enzymes produced by a high number of psychrotrophic bacterial isolates from raw milk are of major concern to the dairy industry. The results of this study provide valuable data about the spoilage potential of bacterial strains in raw milk and the thermal resistance of the enzymes they produce.
Development, Psychometric Assessment, and Predictive Validity of the Postpartum Childcare Stress Checklist

Background Childcare stress has been shown to predict postpartum depression; however, there is little research exploring and validating the dimensions of childcare stress instruments such that preventive interventions can be created. Objectives The aim of this study was to develop and psychometrically test an instrument to measure parental perceptions of postpartum childcare stress. Methods Using research based on postpartum stress and childcare stress, the Postpartum Childcare Stress Checklist (PCSC) was developed, and content validity was judged by experts. The PCSC was psychometrically assessed in a cohort of 541 women in a health region near Vancouver, Canada, who were followed to 8 weeks postpartum in 2002. The psychometric assessment analyses comprised internal consistency, exploratory factory analysis, concurrent validity, and predictive validity. Results The 19-item PCSC had good internal consistency (Kuder–Richardson Formula 20 coefficient: 0.81). Exploratory factor analysis revealed the following dimensions: (a) relationship with the partner, (b) caring for the infant, (c) maternal social interactions, and (d) establishing a new routine. Predictive validity analyses showed that PCSC total and subscale scores at 4 weeks were positively correlated with depressive symptomatology, anxiety, and perceived stress and negatively correlated with global and partner support at 8 weeks postpartum. Discussion The PCSC is a measure of childcare stress with excellent reliability and validity. Upon further testing, it may be used to identify women and couples in need of greater support, individualize postpartum care, and evaluate the effectiveness of preventive interventions.
Effects of behavioural activation on the neural circuit related to intrinsic motivation

Background Behavioural activation is an efficient treatment for depression and can improve intrinsic motivation. Previous studies have revealed that the frontostriatal circuit is involved in intrinsic motivation; however, there are no data on how behavioural activation affects the frontostriatal circuit. Aims We aimed to investigate behavioural activation-related changes in the frontostriatal circuit. Method Fifty-nine individuals with subthreshold depression were randomly assigned to either the intervention or non-intervention group. The intervention group received five weekly behavioural activation sessions. The participants underwent functional magnetic resonance imaging scanning on two separate occasions while performing a stopwatch task based on intrinsic motivation. We investigated changes in neural activity and functional connectivity after behavioural activation. Results After behavioural activation, the intervention group had increased activation and connectivity in the frontostriatal region compared with the non-intervention group. The increased activation in the right middle frontal gyrus was correlated with an improvement of subjective sensitivity to environmental rewards. Conclusions Behavioural activation-related changes to the frontostriatal circuit advance our understanding of psychotherapy-induced improvements in the neural basis of intrinsic motivation. Declaration of interest None.
Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS)

Abstract Objective: The monitoring and evaluation of sintering-induced tablet strength of a polyethylene oxide (PEO) based placebo tables was accomplished using infrared spectroscopy (NIRS). Significance: Evaluation of high molecular weight PEO-based tablet matrices for abuse deterrent formulation applications is an analytical challenge. NIRS is one tool that can provide physical and chemical evaluation of this polymer and tablet system. In addition, the use of NIRS as a process analytical tool (PAT) to monitor oven sintering of pharmaceutical tablets has not been recorded in the literature. The multiplicative scattering correction (MSC) algorithm was also successfully applied as a new and fast way to calculate NIRS spectral slopes and intercepts to build models against tablet tensile strength with respect to sinter time. Methods: Both spectral slope regression (SSR) and spectral intercept regression (SIR) models were compared to commonly used partial least squares analysis (PLS) to evaluate placebo PEO based pharmaceutical tablets comprised of PEO at 70, 50, 30% w/w that were compressed at two solid fraction (SF) levels. Results: All three regression techniques, PLS, SSR, SIR, were evaluated for robustness and reliability and physical relevancy to the system studied. The methods were ranked in utility with SSR being the best method followed by SIR then PLS. Conclusions: The MSC algorithm was presented to quickly calculate spectral slopes and intercepts for use in SSR and SIR analysis. SSR models were successfully applied and assessed as the optimal modeling technique to monitor sintering of PEO-based matrix tablets.
Ecosystem engineering by foxes is mediated by the landscape context—A case study from steppic burial mounds

Abstract In intensively used landscapes, remnant grassland fragments are often restricted to places unsuitable for agricultural cultivation. Such refuges are the ancient burial mounds called “kurgans,” which are typical landscape elements of the Eurasian steppe and forest steppe zone. Due to their hill‐like shape, loose soil structure and undisturbed status kurgans provide proper habitats for burrowing mammals. Accordingly, grassland vegetation on kurgans is often exposed to bioturbation, which can influence the habitat structure and plant species pool. In our study, we explored the effect of fox burrows and landscape context on the habitat properties and vegetation composition of small landscape elements, using kurgans as model habitats. We surveyed the vegetation of fox burrows and that of the surrounding grassland on five kurgans situated in cleared landscapes surrounded by arable lands and five kurgans in complex landscapes surrounded by grazed grasslands. We recorded the percentage cover of vascular plants, the amount of litter, and soil moisture content in twelve 0.5 m × 0.5 m plots per kurgan, in a total of 120 plots. We found that foxes considerably transformed habitat conditions and created microhabitats by changing the soil nutrient availability and reducing total vegetation cover and litter. Several grassland specialist species, mostly grasses (Agropyron cristatum, Elymus hispidus, and Stipa capillata) established in the newly created microhabitats, although the cover of noxious species was also considerable. We found that landscape context influenced the sort of species which could establish on kurgans by affecting the available species pool and soil moisture. Our results revealed that foxes act as ecosystem engineers on kurgans by transforming abiotic and biotic conditions by burrowing. Their engineering activity maintains disturbance‐dependent components of dry grasslands and increases local environmental heterogeneity.
Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole using a bottom-up approach is challenging, not only due to complex saturable pharmacokinetics (PK) and the presence of three metabolites exhibiting CYP3A4 inhibition, but also because of discrepancies in reported in vitro data. The overall objective of this study is to provide a comprehensive mechanistic PBPK model for itraconazole in order to increase the confidence in its drug-drug interaction (DDI) predictions. To achieve this, key in vitro and in vivo data for itraconazole and its major metabolites were generated. These data were crucial to developing a novel bottom-up PBPK model in Simcyp (Simcyp Ltd., Certara, Sheffield, United Kingdom) for itraconazole and two of its major metabolites: hydroxy-itraconazole (OH-ITZ) and keto-itraconazole (keto-ITZ). Performance of the model was validated using prespecified acceptance criteria against different dosing regimens, formulations for 29 PK, and DDI studies with midazolam and other CYP3A4 substrates. The main outcome is an accurate PBPK model that simultaneously predicts the PK profiles of itraconazole, OH-ITZ, and keto-ITZ. In addition, itraconazole DDIs with midazolam and other CYP3A4 substrates were successfully predicted within a 2-fold error. Prediction precision and bias of DDI expressed as geometric mean fold error were for the area under the concentration-time curve and peak concentration, 1.06 and 0.96, respectively. To conclude, in this paper a comprehensive data set for itraconazole and its metabolites is provided that enables bottom-up mechanism-based PBPK modeling. The presented model is applicable for studying the contribution from the metabolites and allows improved assessments of itraconazole DDI.
Fluctuating thermal environments and time‐dependent effects on fruit fly egg‐hatching performance

Abstract Organismal performance in a changing environment is dependent on temporal patterns and duration of exposure to thermal variability. We experimentally assessed the time‐dependent effects of thermal variability (i.e., patterns of thermal exposure) on the hatching performance of Drosophila melanogaster. Flies were collected in central Chile and maintained for four generations in laboratory conditions. Fourth generation eggs were acclimated to different thermal fluctuation cycles until hatching occurred. Our results show that the frequency of extreme thermal events has a significant effect on hatching success. Eggs exposed to 24 hr cycles of thermal fluctuation had a higher proportion of eggs that hatched than those acclimated to shorter (6 and 12 hr) and longer cycles (48 hr). Furthermore, eggs subjected to frequent thermal fluctuations hatched earlier than those acclimated to less frequent thermal fluctuations. Overall, we show that, egg‐to‐adult viability is dependent on the pattern of thermal fluctuations experienced during ontogeny; thus, the pattern of thermal fluctuation experienced by flies has a significant and until now unappreciated impact on fitness.
The Importance of Context When Recommending TV Content: Dataset and Algorithms

Home entertainment systems feature in a variety of usage scenarios with one or more simultaneous users, for whom the complexity of choosing media to consume has increased rapidly over the last decade. Users’ decision processes are complex and highly influenced by contextual settings, but data supporting the development and evaluation of context-aware recommender systems are scarce. In this paper we present a dataset of self-reported TV consumption enriched with contextual information of viewing situations. We show how choice of genre associates with, among others, the number of present users and users’ attention levels. Furthermore, we evaluate the performance of predicting chosen genres given different configurations of contextual information, and compare the results to contextless predictions. The results suggest that including contextual features in the prediction cause notable improvements, and both temporal and social context show significant contributions.
Pulmonary Manifestations and Progression of Lung Disease in Juvenile-onset Mixed Connective Tissue Disease

Objective. To assess the occurrence and extent of interstitial lung disease (ILD) in patients with juvenile mixed connective tissue disease (JMCTD), compare pulmonary function in patients and matched controls, study associations between ILD and disease-related variables, and examine progression of pulmonary manifestations over time. Methods. A cohort of 52 patients with JMCTD were examined in a cross-sectional study after a mean 16.2 (SD 10.3) years of disease duration with high-resolution computed tomography (HRCT) and pulmonary function tests (PFT) comprising spirometry, DLCO, and total lung capacity (TLC). Matched controls were examined with PFT. Previous HRCT and PFT were available in 37 and 38 patients (mean 8.8 and 10.3 yrs before study inclusion), respectively. Results. Compared to controls, patients with JMCTD had lower forced vital capacity (FVC), DLCO, and TLC (p < 0.01). The most frequent abnormal PFT was DLCO in 67% of patients versus 17% of controls (p < 0.001). Fourteen patients (27%) had ILD on HRCT. Most had ILD in < 10% of their lungs. ILD was associated with low values for FVC and TLC, but not with DLCO. HRCT findings did not progress significantly over time, but FVC declined (p < 0.01). Conclusion. Compared to controls, patients with JMCTD had impaired pulmonary function. ILD was present in 27% of patients after a mean 16 years of disease duration, mostly as mild disease, and did not progress. ILD seems to be less common in juvenile-onset than in adult-onset MCTD, and ILD in JMCTD seems mostly mild and stable over time.
Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well‐known for its contribution to multi‐drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC‐cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib‐treated ccRCC‐cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC‐cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer‐specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression‐free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR‐212‐3p and miR‐132‐3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3′UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR‐212‐3p and miR‐132‐3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.
Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

Pathogens that infect the gastrointestinal and respiratory tracts are subjected to intense pressure due to the environmental conditions of the surroundings. This pressure has led to the development of mechanisms of bacterial tolerance or persistence which enable microorganisms to survive in these locations. SUMMARY Pathogens that infect the gastrointestinal and respiratory tracts are subjected to intense pressure due to the environmental conditions of the surroundings. This pressure has led to the development of mechanisms of bacterial tolerance or persistence which enable microorganisms to survive in these locations. In this review, we analyze the general stress response (RpoS mediated), reactive oxygen species (ROS) tolerance, energy metabolism, drug efflux pumps, SOS response, quorum sensing (QS) bacterial communication, (p)ppGpp signaling, and toxin-antitoxin (TA) systems of pathogens, such as Escherichia coli, Salmonella spp. , Vibrio spp. , Helicobacter spp. , Campylobacter jejuni, Enterococcus spp. , Shigella spp. , Yersinia spp. , and Clostridium difficile, all of which inhabit the gastrointestinal tract. The following respiratory tract pathogens are also considered: Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cenocepacia, and Mycobacterium tuberculosis. Knowledge of the molecular mechanisms regulating the bacterial tolerance and persistence phenotypes is essential in the fight against multiresistant pathogens, as it will enable the identification of new targets for developing innovative anti-infective treatments.
An efficient control flow validation method using redundant computing capacity of dual-processor architecture

Microprocessors in safety-critical system are extremely vulnerable to hacker attacks and circuit crosstalk, as they can modify binaries and lead programs to run along the wrong control flow paths. It is a significant challenge to design a run-time validation method with few hardware modification. In this paper, an efficient control flow validation method named DCM (Dual-Processor Control Flow Validation Method) is proposed basing on dual-processor architecture. Since a burst of memory-access-intensive instructions could block pipeline and cause lots of waiting clocks, the DCM assigns the idle pipeline cycles of the blocked processor to the other processor to validate control flow at run time. An extra lightweight monitor unit in each processor is needed and a special dual-processor communication protocol is also designed to schedule the redundant computing capacity between two processors to do validation tasks better. To further improve the efficiency, we also design a software-based self-validation algorithm to help reduce validation times. The combination of both hardware method and software method can speed up the validation procedure and protect the control flow paths with different emphasis. The cycle-accurate simulator GEM5 is used to simulate two ARMv7-A processors with out-of-order pipeline. Experiment shows the performance overhead of DCM is less than 22% on average across the SPEC 2006 benchmarks.
EagleEye: Attack-Agnostic Defense against Adversarial Inputs (Technical Report)

Deep neural networks (DNNs) are inherently vulnerable to adversarial inputs: such maliciously crafted samples trigger DNNs to misbehave, leading to detrimental consequences for DNN-powered systems. The fundamental challenges of mitigating adversarial inputs stem from their adaptive and variable nature. Existing solutions attempt to improve DNN resilience against specific attacks; yet, such static defenses can often be circumvented by adaptively engineered inputs or by new attack variants. Here, we present EagleEye, an attack-agnostic adversarial tampering analysis engine for DNN-powered systems. Our design exploits the {\em minimality principle} underlying many attacks: to maximize the attack's evasiveness, the adversary often seeks the minimum possible distortion to convert genuine inputs to adversarial ones. We show that this practice entails the distinct distributional properties of adversarial inputs in the input space. By leveraging such properties in a principled manner, EagleEye effectively discriminates adversarial inputs and even uncovers their correct classification outputs. Through extensive empirical evaluation using a range of benchmark datasets and DNN models, we validate EagleEye's efficacy. We further investigate the adversary's possible countermeasures, which implies a difficult dilemma for her: to evade EagleEye's detection, excessive distortion is necessary, thereby significantly reducing the attack's evasiveness regarding other detection mechanisms.