Miracle-dz/UniFAR-FTUs huggingface dataset:
Policy-Gradient and Actor-Critic Based State Representation Learning for Safe Driving of Autonomous Vehicles

In this paper, we propose an environment perception framework for autonomous driving using state representation learning (SRL). Unlike existing Q-learning based methods for efficient environment perception and object detection, our proposed method takes the learning loss into account under deterministic as well as stochastic policy gradient. Through a combination of variational autoencoder (VAE), deep deterministic policy gradient (DDPG), and soft actor-critic (SAC), we focus on uninterrupted and reasonably safe autonomous driving without steering off the track for a considerable driving distance. Our proposed technique exhibits learning in autonomous vehicles under complex interactions with the environment, without being explicitly trained on driving datasets. To ensure the effectiveness of the scheme over a sustained period of time, we employ a reward-penalty based system where a negative reward is associated with an unfavourable action and a positive reward is awarded for favourable actions. The results obtained through simulations on DonKey simulator show the effectiveness of our proposed method by examining the variations in policy loss, value loss, reward function, and cumulative reward for ‘VAE+DDPG’ and ‘VAE+SAC’ over the learning process.
Comparison Between Optical Frequency Domain Imaging and Intravascular Ultrasound for Percutaneous Coronary Intervention Guidance in Biolimus A9-Eluting Stent Implantation

Supplemental Digital Content is available in the text. Background: Given the characteristic differences between intravascular ultrasound (IVUS) and optical frequency domain imaging (OFDI), their approach to therapeutic guidance during percutaneous coronary interventions (PCIs) and arterial healing response after stenting may also vary. Methods: MISTIC-1 (The Multimodality Imaging Study in Cardiology cohort 1) is a multicenter, randomized-controlled, noninferiority trial that compared imaging end points between OFDI- and IVUS-guided PCI. Patients with stable coronary artery disease were randomly assigned to either OFDI- or IVUS-guided PCI using a Biolimus A9-eluting stent according to a prespecified protocol for imaging guidance. Stent sizing was based on external elastic lamina in IVUS-guided PCI while lumen up-size in OFDI-guided PCI. Postprocedural OFDI was investigated regardless of randomization, while operators in IVUS-guided PCI arm were blinded to the images. The primary end point was in-segment minimum lumen area assessed using OFDI at 8 months, while the secondary end point was a composite of cardiovascular mortality, target-vessel myocardial infarction, or target-lesion revascularization (device-oriented composite end point). Patients were followed up to 3 years after the index procedure. Results: A total of 109 patients (mean age 70 years, male 78%) with 126 lesions were enrolled. Postprocedural minimum stent area was 6.31±1.89 and 6.72±2.08 mm2 in OFDI and IVUS group, respectively (P=0.26). At the 8-month follow-up, in-segment minimum lumen area was 4.56±1.94 and 4.13±1.86 mm2 in OFDI and IVUS group, respectively (Pnon-inferiority <0.001). Both groups had comparable neointimal healing score (median 0.16 [interquartile range, 0.00–3.14] versus 0.90 [0.00–3.30], respectively; P=0.43). The incidence rate of device-oriented composite end point at 3 years was 7.4% and 7.3% in OFDI and IVUS group, respectively (hazard ratio, 1.05 [95% CI, 0.26–4.18]; P=0.95). Conclusions: OFDI-guided PCI was not inferior to IVUS-guided PCI in terms of in-segment minimum lumen area at 8 months. Although a small sample size was acknowledged, OFDI could be an alternative to IVUS when considering intracoronary imaging-guided PCI in selected populations with coronary artery diseases. Registration: URL: https://www.clinicaltrials. gov. Unique identifier: NCT03292081.
The reaction zone as a defense response in Norway spruce (Picea abies) when infected by the white-rot fungus Heterobasidion parviporum : differentially expressed genes and chemical changes

of the project and results Heterobasidion parviporum (Fr.) is a pathogenic white-rot fungus that causes root and butt rot in Norway spruce (Picea abies (L.) Karsten), and is an extensive problem in Norway and the rest of Europe. Sapwood in 60and 23 year old spruce trees in two separated experiments were treated with wounding or inoculated with H. parviporum or methyl jasmonate mimicking infection from the heartwood and inducing a reaction zone. Chemical and gene expression analysis was conducted on samples from the experimental inductions of chemical reaction zone around the inoculation and wound in the sapwood.
Genome-Wide Characterization and Expression of Two-Component System Genes in Cytokinin-Regulated Gall Formation in Zizania latifolia

The thickening of Zizania latifolia shoots, referred to as gall formation, depends on infection with the fungal endophyte Ustilago esculenta. The swollen and juicy shoots are a popular vegetable in Asia. A key role for cytokinin action in this process was postulated. Here, trans-zeatin stimulated swelling in fungi-infected Z. latifolia. A two-component system (TCS) linked cytokinin binding to receptors with transcriptional regulation in the nucleus and played important roles in diverse biological processes. We characterized 69 TCS genes encoding for 25 histidine kinase/histidine-kinase-like (HK(L)) (21 HKs and 4 HKLs), 8 histidine phosphotransfer proteins (HP) (5 authentic and 3 pseudo), and 36 response regulators (RR; 14 type A, 14 type B, 2 type C, and 6 pseudo) in the genome of Z. latifolia. These TCS genes have a close phylogenetic relationship with their rice counterparts. Nineteen duplicated TCS gene pairs were found and the ratio of nonsynonymous to synonymous mutations indicated that a strong purifying selection acted on these duplicated genes, leading to few mutations during evolution. Finally, ZlCHK1, ZlRRA5, ZIRRA9, ZlRRA10, ZlPRR1, and ZlPHYA expression was associated with gall formation. Among them, ARR5, ARR9, and ZlPHYA are quickly induced by trans-zeatin, suggesting a role for cytokinin signaling in shoot swelling of Z. latifolia.
Exercise Intolerance in Cystic Fibrosis: Importance of Skeletal Muscle.

PURPOSE Exercise intolerance, evaluated by O2 consumption, predicts mortality in Cystic Fibrosis (CF). People with CF exhibit skeletal muscle dysfunctions that may contribute to an imbalance between O2 delivery and utilization. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, increases blood flow and improves O2 consumption, although the exact mechanisms in CF have yet to be elucidated. Thus, we hypothesized that exercise intolerance in CF is limited primarily by an impaired skeletal muscle O2 utilization, and sildenafil improves exercise tolerance in CF by addressing this mismatch between O2 demand and extraction. METHODS Fifteen individuals with mild-to-moderate CF and eighteen healthy controls completed an incremental exercise test and measurements of gaseous exchange, chronotropic response, hemodynamics, and O2 extraction and utilization. People with CF also completed a four-week-treatment with sildenafil with a subsequent follow-up evaluation after treatment. RESULTS Skeletal muscle O2 extraction and utilization during exercise were reduced in people with CF when compared to controls. Exercise capacity in our CF population was minimally limited by hemodynamic or chronotopic responses, while peripheral O2 extraction was more closely associated with exercise capacity. The study also demonstrated that four weeks of sildenafil improved skeletal muscle O2 utilization during exercise to similar values observed in healthy individuals. CONCLUSIONS Individuals with mild to moderate CF exhibit exercise intolerance secondary to a reduction in O2 utilization by the exercising skeletal muscle. The present study demonstrated that four weeks of sildenafil treatment improves the capacity of the skeletal muscle to utilize O2 more efficiently during exercise. Findings from the present study highlight the importance of targeting skeletal muscle O2 utilization to improve exercise tolerance in CF.
Systematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human Pathogens

As drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism’s collateral response to a wide variety of antibiotics. The results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. ABSTRACT As drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism’s collateral response to a wide variety of antibiotics. The results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. However, little is known about the extent of evolutionary conservation of these responses across species. We sought to address this knowledge gap by performing a systematic resistance evolution study of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) under uniform growth conditions using five clinically relevant antibiotics with diverse modes of action. Evolved lineages were analyzed for collateral effects and the molecular mechanisms behind the observed phenotypes. Fourteen universal cross-resistance and two global collateral sensitivity relationships were found among the lineages. Genomic analyses revealed drug-dependent divergent and conserved evolutionary trajectories among the pathogens. Our findings suggest that collateral responses may be preserved across species. These findings may help extend the contribution of previous collateral network studies in the development of treatment strategies to address the problem of antibiotic resistance.
Short telomeres increase the risk of severe COVID-19

Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated β-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.
The tactics of successful attacks in professional association football: large-scale spatiotemporal analysis of dynamic subgroups using position tracking data

ABSTRACT Association football teams can be considered complex dynamical systems of individuals grouped in subgroups (defenders, midfielders and attackers), coordinating their behaviour to achieve a shared goal. As research often focusses on collective behaviour, or on static subgroups, the current study aims to analyse spatiotemporal behaviour of dynamic subgroups in relation to successful attacks. We collected position tracking data of 118 Dutch Eredivisie matches, containing 12424 attacks. Attacks were classified as successful (N = 1237) or non-successful (N = 11187) based on the potential of creating a scoring opportunity. Using unsupervised machine learning, we automatically identified dynamic formations based on position tracking data, and identified dynamic subgroups for every timeframe in a match. We then compared the subgroup centroids to assess the intra- and inter-team spatiotemporal synchronisation during successful and non-successful attacks, using circular statistics. Our results indicated subgroup-level variables provided more information, and were more sensitive to disruption, in comparison to team-level variables. When comparing successful and non-successful attacks, we found decreases (p < .01) in longitudinal inter- and intra-team synchrony of interactions involving the defenders of the attacking team during successful attacks. This study provides the first large-scale dynamic subgroup analysis and reveals additional insights to team-level analyses.
Toxoplasma gondii excreted/secreted proteases disrupt intercellular junction proteins in epithelial cell monolayers to facilitate tachyzoites paracellular migration

Toxoplasma gondii shows high dissemination and migration properties across biological barriers infecting immunologically privileged organs. Toxoplasma uses different routes for dissemination; however, the mechanisms are not fully understood. Herein, we studied the effects of proteases present in excretion/secretion products (ESPs) of Toxoplasma on MDCK cell monolayers. Ultrastructural analysis showed that ESPs of Toxoplasma disrupt the intercellular junctions (IJ) of adjacent cells. The tight junction (TJ) proteins ZO‐1, occludin, and claudin‐1 suffered a progressive decrease in protein levels upon ESPs treatment. In addition, ESPs induced mislocalization of such TJ proteins, along with the adherent junction protein E‐cadherin, and this was prevented by pre‐treating the ESPs with protease inhibitors. Reorganisation of cytoskeleton proteins was also observed. Endocytosis inhibitors, Dyngo®‐4a and Dynasore, impeded the modifications, suggesting that TJ proteins internalisation is triggered by the ESPs proteases hence contributing to the loss of IJ. The observed disruption in TJ proteins went in line with a decrease in the transepithelial electrical resistance of the monolayers, which was significantly blocked by pre‐treating ESPs with metalloprotease and serine protease inhibitors. Moreover, exposure of cell monolayers to ESPs facilitated paracellular migration of tachyzoites. Our results demonstrate that Toxoplasma ESPs contain proteases that can disrupt the IJ of epithelial monolayers and this could facilitate the paracellular route for Toxoplasma tissue dissemination and migration.
Current Knowledge on Snake Dry Bites

Snake ‘dry bites’ are characterized by the absence of venom being injected into the victim during a snakebite incident. The dry bite mechanism and diagnosis are quite complex, and the lack of envenoming symptoms in these cases may be misinterpreted as a miraculous treatment or as proof that the bite from the perpetrating snake species is rather harmless. The circumstances of dry bites and their clinical diagnosis are not well-explored in the literature, which may lead to ambiguity amongst treating personnel about whether antivenom is indicated or not. Here, the epidemiology and recorded history of dry bites are reviewed, and the clinical knowledge on the dry bite phenomenon is presented and discussed. Finally, this review proposes a diagnostic and therapeutic protocol to assist medical care after snake dry bites, aiming to improve patient outcomes.
Competing Substrates for the Bifunctional Diaminopimelic Acid Epimerase/Glutamate Racemase Modulate Peptidoglycan Synthesis in Chlamydia trachomatis

The Chlamydia trachomatis genome encodes multiple bifunctional enzymes, such as DapF, which is capable of both diaminopimelic acid (DAP) epimerase and glutamate racemase activity. Our previous work demonstrated the bifunctional activity of chlamydial DapF in vitro and in a heterologous system (Escherichia coli). In the present study, we employed a substrate competition strategy to demonstrate DapFCt function in vivo in C. trachomatis. ABSTRACT The Chlamydia trachomatis genome encodes multiple bifunctional enzymes, such as DapF, which is capable of both diaminopimelic acid (DAP) epimerase and glutamate racemase activity. Our previous work demonstrated the bifunctional activity of chlamydial DapF in vitro and in a heterologous system (Escherichia coli). In the present study, we employed a substrate competition strategy to demonstrate DapFCt function in vivo in C. trachomatis. We reasoned that, because DapFCt utilizes a shared substrate-binding site for both racemase and epimerase activities, only one activity can occur at a time. Therefore, an excess of one substrate relative to another must determine which activity is favored. We show that the addition of excess l-glutamate or meso-DAP (mDAP) to C. trachomatis resulted in 90% reduction in bacterial titers, compared to untreated controls. Excess l-glutamate reduced in vivo synthesis of mDAP by C. trachomatis to undetectable levels, thus confirming that excess racemase substrate led to inhibition of DapFCt DAP epimerase activity. We previously showed that expression of dapFCt in a murI (racemase) ΔdapF (epimerase) double mutant of E. coli rescues the d-glutamate auxotrophic defect. Addition of excess mDAP inhibited growth of this strain, but overexpression of dapFCt allowed the mutant to overcome growth inhibition. These results confirm that DapFCt is the primary target of these mDAP and l-glutamate treatments. Our findings demonstrate that suppression of either the glutamate racemase or epimerase activity of DapF compromises the growth of C. trachomatis. Thus, a substrate competition strategy can be a useful tool for in vivo validation of an essential bifunctional enzyme.
Secondary metabolites from spice and herbs as potential multitarget inhibitors of SARS-CoV-2 proteins

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the current global pandemic that has caused a death toll of >1.12 million worldwide and number continues to climb in several countries. Currently, there are neither specific antiviral drugs nor vaccines for the treatment and prevention of COVID-19. We screened in silico, a group of natural spice and herbal secondary metabolites (SMs) for their inhibition efficacy against multiple target proteins of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 protein. Docking and simulation results indicated that epicatechin, embelin, hesperidin, cafestol, murrayanine and murrayaquinone-A have higher inhibition efficacy over at least one of the known antiviral drugs such as Hydroxychloroquine, Remdesivir and Ribavirin. Combination of these potentially effective SMs from their respective plant sources was analysed, and its absorption and acute oral toxicity were examined in Wistar rats and classified as category 5 as per the Globally Harmonized System. The identified SMs may be useful in the development of preventive nutraceuticals, food supplements and antiviral drugs. Communicated by Ramaswamy H. Sarma Graphical Abstract
Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio

Objectives Pouchitis is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). Although there have been many investigations of the neutrophil-to-lymphocyte ratio (NLR) in various diseases, its role in predicting the development of pouchitis remains unclear. We aimed to evaluate the clinical utility of the NLR for predicting the development of pouchitis after IPAA in UC patients. Materials and methods UC patients who underwent IPAA at Osaka City University Hospital between May 2006 and March 2019 were included. The incidence of pouchitis was estimated using the Kaplan-Meier method. Potential preoperative, intraoperative, and postoperative predictors for pouchitis, including various demographic and clinical variables, were analyzed. The combined impact of the NLR and other known prognostic factors were investigated using Cox proportional hazard regression with inverse probability of treatment weighting (IPTW). Results Forty-nine patients with UC who underwent IPAA were included. The median follow-up period was 18.3 months (interquartile range: 10.7–47.2 months). Eighteen patients (36.7%) developed pouchitis. The incidence of pouchitis was 19.2%, 32.6%, and 45.9% at 1, 2, and 5 years, respectively. NLR was significantly associated with the development of pouchitis in the univariate Cox regression analysis (hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.01–1.28; P = 0.03). The NLR cutoff value of 2.15 was predictive of the development of pouchitis according to receiver operating characteristic analysis (specificity: 67.7%, sensitivity: 72.2%). The incidence of pouchitis was significantly lower in the low NLR group than that in the high NLR group (P = 0.01, log-rank test). Cox regression analyses using IPTW also identified NLR as a prognostic factor for the development of pouchitis by statistically adjusting for background factors (HR, 3.60; 95% CI, 1.31–9.89; P = 0.01). Conclusions NLR may be a novel and useful indicator for predicting the development of pouchitis after IPAA in UC and should be introduced in clinical practice.
Phospho-proteomic Analysis of Neuroblastoma Tumor Initiating Cell Signaling Pathways: Identification of Src Family and B Cell Receptor Signaling as Novel Drug Targets

Neuroblastoma (NB) is the most common extra-cranial solid tumor in children. Recently discovered neuroblastoma tumor-initiating cells (NB-TICs) have many properties of cancer stem cells and form tumors with as few as 10 cells. To elucidate the signaling pathways driving NBTIC survival and proliferation, we surveyed the phospho-tyrosine containing subset of the NBTIC proteome. Over 300 phosphorylated proteins were identified, including 21 tyrosine kinases of which several belong to the Src kinase family. Using bioinformatics tools, several hematopoietic signaling pathways were identified, including the B cell receptor (BCR) pathway. Further proteomic approaches substantiated molecular hematopoietic features in NB-TICs. Inhibitors of BCR proximal kinases SYK and SFKs were cytotoxic to NB-TICs. Clinically utilized inhibitors of SFKs induce apoptosis in NB-TICs. Targeting hematopoietic survival pathways in NB-TICs from the bone marrow, which have thus far not been predicted to play a role in this neural malignancy, may provide new drug therapies for NB.
First record of the Indian anchovy Stolephorus indicus (van Hasselt, 1823) (Clupeiformes: Engraulidae) in the Mediterranean Sea.

The Indian anchovy Stolephorus indicus (van Hasselt, 1823) was recorded for the first time in the Mediterranean near Tel-Aviv, Israel on 15 May 2015. This Indo-West Pacific species evidently reached the Mediterranean via the Suez Canal from the Red Sea. Several specimens of Stolephorus insularis were also collected, which suggests that species has established a viable population in the Levant.