Miracle-dz/UniFAR-FTUs huggingface dataset:
Acute stroke treatment during coronavirus disease 2019 pandemic

Purpose of review The coronavirus disease 2019 (COVID-19) pandemic has caused a major impact on stroke care. This review synthesizes the available data and provides a framework for optimal management of stroke patients with confirmed or suspected COVID-19 infection and eligible to reperfusion treatments. Recent findings Reorganization of health services has led to the conversion of stroke units and relocation of stroke staff to COVID units. During the pandemic surge, there has been a general decline of stroke presentations, increased time delays, and reduced activity across all areas of stroke care, specifically the delivery of acute treatment. Moreover, COVID-19 patients seem to have a worse outcome despite prompt recanalization. Periprocedural monitoring studies are needed in these patients to target a more adequate therapy. Summary The COVID-19 pandemic has jeopardized the ability of stroke centers to provide timely assessment and acute therapies such as reperfusive treatments. Yet, as stroke remains a medical emergency, efforts to maintain stroke teams and safe provision of highly effective stroke treatments should be prioritized despite healthcare systems reorganization. This can be accomplished through the activation of telestroke networks, protected stroke pathways, 24/7 open-access high-quality stroke centers, and stroke awareness programs.
Management of Brain and Leptomeningeal Metastases from Breast Cancer

The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. This review aims to provide an overview of the clinical and molecular factors involved in the selection of patients for local and/or systemic therapy, as well as the results of clinical trials on advanced BC. Moreover, insight on promising therapeutic options and potential directions of future therapeutic targets against BBB and microenvironment are discussed.
Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase

Soluble epoxide hydrolases (sEHs) catalyze the hydrolysis of epoxides to their corresponding vicinal diols. One property of a number of these enzymes is that they can catalyze the hydrolysis of some racemic substrates in an enantioconvergent one-enzyme fashion. Here, we have used the dispersion-corrected B3LYP-D3 density functional theory method to investigate the enantioconvergent conversion of styrene oxide (SO) by sEH from Solanum tuberosum (StEH1). A large cluster model of the active site, consisting of 279 atoms, is designed on the basis of the X-ray crystal structure of StEH1 in complex with the competitive inhibitor valpromide. Different substrate orientations of the two enantiomers of SO are examined, and the full reaction mechanisms for epoxide opening at the two carbons are calculated, including both the alkylation and hydrolysis half-reactions. The calculated overall reaction energy profiles show that the rate-determining step is associated with the dissociation of the covalent intermediate, wh.
Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress

Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high 25 mM glucose (glucotoxicity), and high 25 mM glucose combined with 0.4 mM oleate and/or palmitate (glucolipotoxicity). Then, we profiled the mitochondrial carriers and associated genes with RNA-Seq. Diabetogenic conditions, and in particular glucotoxicity, increased expression of several mitochondrial solute carriers in human islets, such as the malate carrier DIC, the α-ketoglutarate-malate exchanger OGC, and the glutamate carrier GC1. Glucotoxicity also induced a general upregulation of the electron transport chain machinery, while palmitate largely counteracted this effect. Expression of different components of the TOM/TIM mitochondrial protein import system was increased by glucotoxicity, whereas glucolipotoxicity strongly upregulated its receptor subunit TOM70. Expression of the mitochondrial calcium uniporter MCU was essentially preserved by metabolic stresses. However, glucotoxicity altered expression of regulatory elements of calcium influx as well as the Na+/Ca2+ exchanger NCLX, which mediates calcium efflux. Overall, the expression profile of mitochondrial carriers and associated genes was modified by the different metabolic stresses exhibiting nutrient-specific signatures.
A More Extensive Lymphadenectomy Enhances Survival After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma

Objective: We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Summary of Background Data: Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy. Methods: We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and DFS were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions. Results: In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16–27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio, 0.98; confidence interval, 0.97–1.00; P = 0.013; DFS: hazard ratio, 0.99; confidence interval, 0.98–1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response. Conclusions: The optimal extent of lymphadenectomy to enhance both staging and survival after chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.
Identification of Three New GGDEF and EAL Domain-Containing Proteins Participating in the Scr Surface Colonization Regulatory Network in Vibrio parahaemolyticus

A key survival decision, in the environment or the host, is whether to emigrate or aggregate. In bacteria, c-di-GMP signaling almost universally influences solutions to this dilemma. ABSTRACT Vibrio parahaemolyticus rapidly colonizes surfaces using swarming motility. Surface contact induces the surface-sensing regulon, including lateral flagellar genes, spurring dramatic shifts in physiology and behavior. The bacterium can also adopt a sessile, surface-associated lifestyle and form robust biofilms. These alternate colonization strategies are influenced reciprocally by the second messenger c-di-GMP. Although V. parahaemolyticus possesses 43 predicted proteins with the c-di-GMP-forming GGDEF domain, none have been previously been identified as contributors to surface colonization. We sought to explore this knowledge gap by using a suppressor transposon screen to restore the swarming motility of a nonswarming, high-c-di-GMP strain. Two diguanylate cyclases, ScrJ and ScrL, each containing tetratricopeptide repeat-coupled GGDEF domains, were demonstrated to contribute additively to swarming gene repression. Both proteins required an intact catalytic motif to regulate. Another suppressor mapped in lafV, the last gene in a lateral flagellar operon. Containing a degenerate phosphodiesterase (EAL) domain, LafV repressed transcription of multiple genes in the surface sensing regulon; its repressive activity required LafK, the primary swarming regulator. Mutation of the signature EAL motif had little effect on LafV’s repressive activity, suggesting that LafV belongs to the subclass of EAL-type proteins that are regulatory but not enzymatic. Consistent with these activities and their predicted effects on c-di-GMP, scrJ and scrL but not lafV, mutants affected the transcription of the c-di-GMP-responsive biofilm reporter cpsA::lacZ. Our results expand the knowledge of the V. parahaemolyticus GGDEF/EAL repertoire and its roles in this surface colonization regulatory network. IMPORTANCE A key survival decision, in the environment or the host, is whether to emigrate or aggregate. In bacteria, c-di-GMP signaling almost universally influences solutions to this dilemma. In V. parahaemolyticus, c-di-GMP reciprocally regulates swarming and sticking (i.e., biofilm formation) programs of surface colonization. Key c-di-GMP-degrading phosphodiesterases responsive to quorum and nutritional signals have been previously identified. c-di-GMP binding transcription factors programming biofilm development have been studied. Here, we further develop the blueprint of the c-di-GMP network by identifying new participants involved in dictating the complex decision of whether to swarm or stay. These include diguanylate cyclases with tetratricopeptide domains and a degenerate EAL protein that, analogously to the negative flagellar regulator RflP/YdiV of enteric bacteria, serves to regulate swarming.
Prone positioning.

Prone positioning prevents ventilator-induced lung injury caused by high positive end expiratory pressure (PEEP), hyperinflation of the alveoli, and oxygen toxicity. Studies have shown prone positioning improves oxygenation between 60 to 80% compared to patients who were not proned (Hudack, 2013). Early initiation of prone ventilation is most effective and should be reserved for the following patients (Malholtra & Kacmarek, 2019):
CRISPR/Cas9‐induced nos2b mutant zebrafish display behavioral abnormalities

The immunomodulatory function of nitric oxide synthase (NOS2) has been extensively studied. However, some behavioral abnormalities caused by its mutations have been found in a few rodent studies, of which the molecular mechanism remains elusive. In this research, we generated nos2b gene knockout zebrafish (nos2bsou2/sou2) using CRISPR/Cas9 approach and investigated their behavioral and molecular changes by doing a series of behavioral detections, morphological measurements, and molecular analyses. We found that, compared with nos2b+/+ zebrafish, nos2bsou2/sou2 zebrafish exhibited enhanced motor activity; additionally, nos2bsou2/sou2 zebrafish were characterized by smaller brain size, abnormal structure of optic tectum, reduced mRNA level of presynaptic synaptophysin and postsynaptic homer1, and altered response to sodium nitroprusside/methylphenidate hydrochloride treatment. These findings will likely contribute to future studies of behavioral regulation.
Genomics and the Evolutionary History of Equids.

The equid family contains only one single extant genus, Equus, including seven living species grouped into horses on the one hand and zebras and asses on the other. In contrast, the equine fossil record shows that an extraordinarily richer diversity existed in the past and provides multiple examples of a highly dynamic evolution punctuated by several waves of explosive radiations and extinctions, cross-continental migrations, and local adaptations. In recent years, genomic technologies have provided new analytical solutions that have enhanced our understanding of equine evolution, including the species radiation within Equus; the extinction dynamics of several lineages; and the domestication history of two individual species, the horse and the donkey. Here, we provide an overview of these recent developments and suggest areas for further research. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 9 is February 16, 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Developing an Individual Glucose Prediction Model Using Recurrent Neural Network

In this study, we propose a personalized glucose prediction model using deep learning for hospitalized patients who experience Type-2 diabetes. We aim for our model to assist the medical personnel who check the blood glucose and control the amount of insulin doses. Herein, we employed a deep learning algorithm, especially a recurrent neural network (RNN), that consists of a sequence processing layer and a classification layer for the glucose prediction. We tested a simple RNN, gated recurrent unit (GRU), and long-short term memory (LSTM) and varied the architectures to determine the one with the best performance. For that, we collected data for a week using a continuous glucose monitoring device. Type-2 inpatients are usually experiencing bad health conditions and have a high variability of glucose level. However, there are few studies on the Type-2 glucose prediction model while many studies performed on Type-1 glucose prediction. This work has a contribution in that the proposed model exhibits a comparative performance to previous works on Type-1 patients. For 20 in-hospital patients, we achieved an average root mean squared error (RMSE) of 21.5 and an Mean absolute percentage error (MAPE) of 11.1%. The GRU with a single RNN layer and two dense layers was found to be sufficient to predict the glucose level. Moreover, to build a personalized model, at most, 50% of data are required for training.
Combination of Augmented Reality Based Brain- Computer Interface and Computer Vision for High-Level Control of a Robotic Arm

Recent advances in robotics, neuroscience, and signal processing make it possible to operate a robot through electroencephalography (EEG)-based brain-computer interface (BCI). Although some successful attempts have been made in recent years, the practicality of the entire system still has much room for improvement. The present study designed and realized a robotic arm control system by combing augmented reality (AR), computer vision, and steady-state visual evoked potential (SSVEP)-BCI. AR environment was implemented by a Microsoft HoloLens. Flickering stimuli for eliciting SSVEPs were presented on the HoloLens, which allowed users to see both the robotic arm and the user interface of the BCI. Thus users did not need to switch attention between the visual stimulator and the robotic arm. A four-command SSVEP-BCI was built for users to choose the specific object to be operated by the robotic arm. Once an object was selected, the computer vision would provide the location and color of the object in the workspace. Subsequently, the object was autonomously picked up and placed by the robotic arm. According to the online results obtained from twelve participants, the mean classification accuracy of the proposed system was 93.96 ± 5.05%. Moreover, all subjects could utilize the proposed system to successfully pick and place objects in a specific order. These results demonstrated the potential of combining AR-BCI and computer vision to control robotic arms, which is expected to further promote the practicality of BCI-controlled robots.
Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes

β-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli, but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with ceftazidime has stimulated efforts to optimize the DBO core. ABSTRACT β-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli, but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with ceftazidime has stimulated efforts to optimize the DBO core. We report kinetic and structural studies, including four high-resolution crystal structures, concerning inhibition of the AmpC serine-β-lactamase from E. coli (AmpCEC) by clinically relevant DBO-based inhibitors: avibactam, relebactam, nacubactam, and zidebactam. Kinetic analyses and mass spectrometry-based assays were used to study their mechanisms of AmpCEC inhibition. The results reveal that, under our assay conditions, zidebactam manifests increased potency (apparent inhibition constant [Kiapp], 0.69 μM) against AmpCEC compared to that of the other DBOs (Kiapp = 5.0 to 7.4 μM) due to an ∼10-fold accelerated carbamoylation rate. However, zidebactam also has an accelerated off-rate, and with sufficient preincubation time, all the DBOs manifest similar potencies. Crystallographic analyses indicate a greater conformational freedom of the AmpCEC-zidebactam carbamoyl complex compared to those for the other DBOs. The results suggest the carbamoyl complex lifetime should be a consideration in development of DBO-based SBL inhibitors for the clinically important class C SBLs.
TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation

Significance Macrophages initiate inflammation to eliminate invading microbes. Following clearance of inflammatory stimuli, macrophages down-regulate inflammatory genes and express repair genes to protect host tissues from damage. Here, we find that the adaptor B-cell adapter for PI3K (BCAP) facilitates this transition of inflammatory macrophages to reparative macrophages. Absence of BCAP in macrophages limits the ability of mice to repair intestinal tissues following inflammatory damage. Following Toll-like receptor stimulation, macrophages undergo aerobic glycolysis that results in lactate production, a process compromised in BCAP-deficient macrophages. This lactate is incorporated into histone tails and is involved in reparative macrophage transition. We find defective lactate production by BCAP-deficient macrophages results in reduced histone lactylation and expression of tissue repair genes, thus blunting their reparative transition. Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined. Here, we find that the reparative macrophage transition is dictated by B-cell adapter for PI3K (BCAP). Mice harboring a macrophage-specific deletion of BCAP fail to recover from and succumb to dextran sulfate sodium-induced colitis due to prolonged intestinal inflammation and impaired tissue repair. Following microbial stimulation, gene expression in WT macrophages switches from an early inflammatory signature to a late reparative signature, a process that is hampered in BCAP-deficient macrophages. We find that absence of BCAP hinders inactivation of FOXO1 and GSK3β, which contributes to their enhanced inflammatory state. BCAP deficiency also results in defective aerobic glycolysis and reduced lactate production. This translates into reduced histone lactylation and decreased expression of reparative macrophage genes. Thus, our results reveal BCAP to be a critical cell-intrinsic switch that regulates transition of inflammatory macrophages to reparative macrophages by imprinting epigenetic changes.
Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis

To investigate the incidence and clinical significance of chromosomal mosaicism (CM) in prenatal diagnosis by G‐banding karyotyping and chromosomal microarray analysis (CMA). This is a single‐centre retrospective study of invasive prenatal diagnosis for CM. From 5758 karyotyping results and 6066 CMA results, 104 foetal cases with CM were selected and analysed further. In total, 50% (52/104) of foetal cases with CM were affected by ultrasound‐detectable phenotypes. Regardless of whether they were singleton or twin pregnancies, isolated structural defects in one system (51.35%, 19/37 in singletons; 86.67%, 13/15 in twins) and a single soft marker (18.92%, 7/37 in singletons; 13.33%, 2/15 in twins) were the most common ultrasound anomalies. Mosaic autosomal trisomy (19.23%, 20/104) was the most frequent type, and its rate was higher in phenotypic foetuses (28.85%, 15/52) than in non‐phenotypic foetuses (9.62%, 5/52). There was no difference in mosaic fractions between phenotypic and non‐phenotypic foetuses based on specimen sources or overall classification. Discordant mosaic results were observed in 16 cases (15.38%, 16/104) from different specimens or different testing methods. Genetic counselling and clinical management regarding CM in prenatal diagnosis remain challenging due to the variable phenotypes and unclear significance. Greater caution should be used in prenatal counselling, and more comprehensive assays involving serial ultrasound examinations, different specimens or testing methods verifications and follow‐up should be applied.