Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiovascular care of patients with stroke and high risk of stroke: The need for interdisciplinary action: A consensus report from the European Society of Cardiology Cardiovascular Round Table

Comprehensive stroke care is an interdisciplinary challenge. Close collaboration of cardiologists and stroke physicians is critical to ensure optimum utilisation of short- and long-term care and preventive measures in patients with stroke. Risk factor management is an important strategy that requires cardiologic involvement for primary and secondary stroke prevention. Treatment of stroke generally is led by stroke physicians, yet cardiologists need to be integrated care providers in stroke units to address all cardiovascular aspects of acute stroke care, including arrhythmia management, blood pressure control, elevated levels of cardiac troponins, valvular disease/endocarditis, and the general management of cardiovascular comorbidities. Despite substantial progress in stroke research and clinical care has been achieved, relevant gaps in clinical evidence remain and cause uncertainties in best practice for treatment and prevention of stroke. The Cardiovascular Round Table of the European Society of Cardiology together with the European Society of Cardiology Council on Stroke in cooperation with the European Stroke Organisation and partners from related scientific societies, regulatory authorities and industry conveyed a two-day workshop to discuss current and emerging concepts and apparent gaps in stroke care, including risk factor management, acute diagnostics, treatments and complications, and operational/logistic issues for health care systems and integrated networks. Joint initiatives of cardiologists and stroke physicians are needed in research and clinical care to target unresolved interdisciplinary problems and to promote the best possible outcomes for patients with stroke.
Estimation of high‐dimensional propensity scores with multiple exposure levels

Little information is available on the performance of high‐dimensional propensity scores (HDPS) in settings with more than two exposure levels. Our objective was to adapt the HDPS algorithm to allow for the inclusion of multilevel treatments and compare estimates obtained via this approach with those obtained via pairwise comparisons in a case study using real‐world data.
Fluid Overload in Pediatric Severe Traumatic Brain Injury*

Objective: Pediatric traumatic brain injury is a major public health problem in the United States. Hypertonic saline therapy is a well-established treatment in patients with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) who have intracranial hypertension. In children, fluid overload is associated with increased mortality, ventilator duration, and length of PICU stay, even when controlling for severity of illness. This study reports prevalence of fluid overload in pediatric patients with severe traumatic brain injury treated with 3% hypertonic saline and effect on clinical outcomes. Design: Single-center retrospective chart review. Setting: PICUs at two tertiary children’s hospitals. Patients: One hundred thirty-eight patients with traumatic brain injury with postresuscitation Glasgow Coma Scale less than or equal to 8 who received hypertonic saline from September 1, 2010, to February 28, 2016, and intracranial pressure monitoring and survived at least 24 hours from admission. Interventions: None. Measurements and Main Results: We used fluid balance percentage greater than or equal to 10% as our definition of fluid overload. Ninety-one percent of patients less than 1 year old had fluid overload on day 10 of admission compared with 47% of patients greater than 1 year. Fluid overloaded patients did not have increased mortality, acute kidney injury, PICU length of stay, or ventilator days. Hypertonic saline was not the cause of fluid overload in these patients. Conclusions: Patients with severe traumatic brain injury do have high rates of fluid overload. However, fluid overload did not contribute to mortality, longer days on the ventilator, increased risk of acute kidney injury, or increased PICU length of stay.
Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD‐1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system and explored gene signature‐based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap‐based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex‐dependent actin polymerization and inhibited the vinculin‐mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A, ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene‐editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild‐type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.
Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia.

OBJECTIVE Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival. METHODS Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009-2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients. RESULTS There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19-0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67-4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72-17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors. CONCLUSION Tumor EBV positivity is a favorable prognostic factor in gastric cancer.
Manganese Is Required for the Rapid Recovery of DNA Synthesis following Oxidative Challenge in Escherichia coli

Iron and manganese play important roles in how cell’s cope with oxygen stress. However, how these metals affect the ability of cells to replicate after oxidative challenges is not known. Here, we show that replication in Escherichia coli is inhibited following a challenge with hydrogen peroxide and requires manganese for the rapid recovery of DNA synthesis. The manganese-dependent recovery of DNA synthesis occurs independently of lesion repair and modestly improves survival, but it also increases the mutation rate in cells. The results imply that replication in E. coli is likely to utilize an iron-dependent enzyme(s) that becomes oxidized and inactivated during oxidative challenges. We propose that manganese remetallates these or alternative enzymes to allow genomic DNA replication to resume, although with reduced fidelity. ABSTRACT Divalent metals such as iron and manganese play an important role in the cellular response to oxidative challenges and are required as cofactors by many enzymes. However, how these metals affect replication after oxidative challenge is not known. Here, we show that replication in Escherichia coli is inhibited following a challenge with hydrogen peroxide and requires manganese for the rapid recovery of DNA synthesis. We show that the manganese-dependent recovery of DNA synthesis occurs independent of lesion repair, modestly improves cell survival, and is associated with elevated rates of mutagenesis. The Mn-dependent mutagenesis involves both replicative and translesion polymerases and requires prior disruption by H2O2 to occur. Taking these findings together, we propose that replication in E. coli is likely to utilize an iron-dependent enzyme(s) that becomes oxidized and inactivated during oxidative challenges. The data suggest that manganese remetallates these or alternative enzymes to allow genomic DNA replication to resume, although with reduced fidelity. IMPORTANCE Iron and manganese play important roles in how cell’s cope with oxygen stress. However, how these metals affect the ability of cells to replicate after oxidative challenges is not known. Here, we show that replication in Escherichia coli is inhibited following a challenge with hydrogen peroxide and requires manganese for the rapid recovery of DNA synthesis. The manganese-dependent recovery of DNA synthesis occurs independently of lesion repair and modestly improves survival, but it also increases the mutation rate in cells. The results imply that replication in E. coli is likely to utilize an iron-dependent enzyme(s) that becomes oxidized and inactivated during oxidative challenges. We propose that manganese remetallates these or alternative enzymes to allow genomic DNA replication to resume, although with reduced fidelity.
IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti–IL-2Rα therapies

Significance Interleukin-2 (IL-2), a cytokine produced by activated T cells, acting in a paracrine/autocrine fashion, is essential for T cell proliferation. In adult T cell leukemia (ATL) and in autoimmune/graft-vs.-host diseases, anti–IL-2Rα antibody therapies were established to inhibit proliferation, with only limited success. We demonstrated that IL-2/15 receptors start to assemble in the endoplasmic reticulum/Golgi and demonstrated signaling by Jak1/Jak3 in the Golgi. Thus, in T cells also producing IL-2 (e.g., ATL cells), signaling can already take place before receptors reach cell membranes. This scenario explains resistance to antibody therapies targeting receptors at cell surfaces. Our study sheds light on an autocrine signaling mechanism, in which an intracellularly synthesized ligand activates its receptor en route toward the cell surface. Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their β- and γc-chains, but have distinct α-chains. Anti–IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti–IL-2 efficiently blocked IL-2–induced proliferation of IL-2–dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2–producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2–producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γc-chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface.
Hepatocyte spheroids as a viable in vitro model for recapitulation of complex in vivo metabolism pathways of loratadine in humans

Abstract Accurate prediction of in vivo metabolic pathways in humans can be challenging because in vitro liver matrices may fail to produce certain in vivo metabolites. Rat and human spheroids, generated from cryopreserved hepatocytes in media that contained minimal amount of serum, maintained morphology, viability and cytochrome P450 (CYP) activities for at least a week without media exchange. With spheroid cultures, multiple Phase I and Phase II metabolites were observed in rat and human spheroid cultures that were incubated with loratadine (LOR) for multiple days. Consistent with in vivo observations, 3-hydroxydesloratadine, (3-OH-DL), along with its glucuronide, were observed in human spheroids, but not in rat spheroids. Interestingly, the putative intermediate metabolite leading to 3-OH-DL, DL-N-glucuronide, was observed in incubations with both rat and human spheroids. In conclusion, hepatocyte spheroid were capable of recapitulating the inter-species differences in metabolism between human and rat for LOR, therefore, it may represent a viable model for studying complex metabolic pathways.
Long-term Apomorphine Infusion Users Versus Short-term Users: An International Dual-center Analysis of the Reasons for Discontinuing Therapy.

OBJECTIVES A retrospective analysis at 2 specialist centers was undertaken to determine the long-term efficacy of subcutaneous apomorphine infusion (APO), rates and reasons for discontinuation, and factors that might contribute to discontinuation. METHODS Demographics, clinical outcomes data, and reasons for discontinuation were collected for patients treated with APO at Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Bangkok, Thailand (n = 36) and Fundacion Jimemez Diaz Universidad Autonoma de Madrid, Spain (n = 16). RESULTS There were 19 (52.7%) patients in the Thai cohort and 10 (62.5%) patients in the Spanish cohort who discontinued treatment within around 6 months of initiation, most commonly due to skin nodules (Thai cohort) and perceived lack of efficacy (Spanish cohort). Those who continued APO tended to stay on treatment. In both cohorts, APO resulted in significant reductions in Unified Parkinson's Disease Rating Scale 3 motor scores, daily OFF time, and levodopa-equivalent dose in patients who subsequently stopped therapy, suggesting APO is clinically effective even when "lack of efficacy" is stated as a reason for discontinuing. Daily OFF hours after APO therapy was found to be a significant predictive factor for APO discontinuation with an odds ratio of 5.952 (P = 0.040). The cutoff point that determined APO discontinuation was calculated to be 1.75 or more OFF hours (sensitivity, 84.6%; specificity, 63.2%). CONCLUSIONS Apomorphine infusion is a minimally invasive therapy and therefore very easy to discontinue if difficulties arise. This fact might explain the high dropout rate of this technique. Successful long-term adherence to APO therapy requires a multidisciplinary health care team approach including regular patient follow-up and assessment and prompt resolution of queries and concerns.
microRNA-19b predicts widespread pain and posttraumatic stress symptom risk in a sex-dependent manner following trauma exposure.

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent co-morbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in which predicted targeting of PTWP or PTSS genes was most enriched. Expression of the leading candidate miRNA to target PTWP/PTSS related genes, miR-19b, has been shown to be influenced by estrogen and stress exposure. We evaluated whether peritraumatic miR-19b blood expression levels predicted PTWP and PTSS development in women and men experiencing trauma of motor vehicle collision (MVC; n=179) and in women experiencing sexual assault trauma (n=74). A sex-dependent relationship was observed between miR-19b expression levels and both PTWP (β=-2.41, p=0.034) and PTSS (β=-3.01, p=0.008) development six months following MVC. The relationship between miR-19b and PTSS (but not PTWP) was validated in sexual assault survivors (β=-0.91, p=0.013). Sex-dependent expression of miR-19b was also observed in blood and nervous tissue from two relevant animal models. Further, in support of increasing evidence indicating a role for the circadian rhythm (CR) in PTWP and PTSS pathogenesis, miR-19b targets were enriched in CR gene transcripts. Human cohort and in vitro analyses assessing miR-19b regulation of key CR transcripts, CLOCK and RORA, supported the potential importance of miR-19b to regulating the CR pathway. Together, these results highlight the potential role that sex-dependent expression of miR-19b might play in PTWP and PTSS development following trauma/stress exposure.
Neural dynamics of semantic composition

Significance The rapid comprehension of speech is a remarkable but poorly understood human capacity. Central to this process is the integration of the meaning of each word, as it is heard, into the listener’s interpretation of the utterance. Here we focus on the real-time flow of neural activity that underpins this combinatorial process, using multivariate pattern analysis and computational semantic models to discover the contextual constraints that are constructed as each word is heard, and to determine how these constraints guide the interpretation of future words in the utterance. This combination of methods reveals a continuous information flow across the left-hemisphere language system, strongly constraining the immediate activation of word meanings and providing a neural substrate for seamless real-time speech comprehension. Human speech comprehension is remarkable for its immediacy and rapidity. The listener interprets an incrementally delivered auditory input, millisecond by millisecond as it is heard, in terms of complex multilevel representations of relevant linguistic and nonlinguistic knowledge. Central to this process are the neural computations involved in semantic combination, whereby the meanings of words are combined into more complex representations, as in the combination of a verb and its following direct object (DO) noun (e.g., “eat the apple”). These combinatorial processes form the backbone for incremental interpretation, enabling listeners to integrate the meaning of each word as it is heard into their dynamic interpretation of the current utterance. Focusing on the verb-DO noun relationship in simple spoken sentences, we applied multivariate pattern analysis and computational semantic modeling to source-localized electro/magnetoencephalographic data to map out the specific representational constraints that are constructed as each word is heard, and to determine how these constraints guide the interpretation of subsequent words in the utterance. Comparing context-independent semantic models of the DO noun with contextually constrained noun models reflecting the semantic properties of the preceding verb, we found that only the contextually constrained model showed a significant fit to the brain data. Pattern-based measures of directed connectivity across the left hemisphere language network revealed a continuous information flow among temporal, inferior frontal, and inferior parietal regions, underpinning the verb’s modification of the DO noun’s activated semantics. These results provide a plausible neural substrate for seamless real-time incremental interpretation on the observed millisecond time scales.
FSH1 regulates the phenotype and pathogenicity of the pathogenic dermatophyte Microsporum canis

Microsporum canis (M. canis) is a common pathogen that causes tinea capitis and is present worldwide. The incidence of M. canis infection, particularly tinea capitis, has been increasing in China. In our previous studies, family of serine hydrolases 1 (FSH1) was identified as a potential virulence factor in tinea capitis infection caused by M. canis. To determine the function of this gene in M. canis, FSH1 was knocked down using double-stranded RNA interference mediated by Agrobacterium tumefaciens. Reverse transcription-quantitative PCR analysis was used to confirm gene knockdown. Loss of FSH1 expression by RNAi resulted in a minor phenotype alteration, but M. canis pathogenicity in guinea pig cutaneous infection was decreased compared with the wild-type strain. To the best of our knowledge, the present study is the first to demonstrate that FSH1 is associated with macroconidia septa formation and is an important contributor to M. canis virulence. These findings may advance the understanding of the function of the FSH1 gene and provide a foundation for future studies on macroconidia septa formation and pathogenicity of M. canis.
Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men

The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short‐term RET remain poorly defined.