Miracle-dz/UniFAR-FTUs huggingface dataset:
Smart Sensors for Smart Grid Reliability

Sensors for monitoring electrical parameters over an entire electricity network infrastructure play a fundamental role in protecting smart grids and improving the network’s energy efficiency. When a short circuit takes place in a smart grid it has to be sensed as soon as possible to reduce its fault duration along the network and to reduce damage to the electricity infrastructure as well as personal injuries. Existing protection devices, which are used to sense the fault, range from classic analog electro-mechanics relays to modern intelligent electronic devices (IEDs). However, both types of devices have fixed adjustment settings (offline stage) and do not provide any coordination among them under real-time operation. In this paper, a new smart sensor is developed that offers the capability to update its adjustment settings during real-time operation, in coordination with the rest of the smart sensors spread over the network. The proposed sensor and the coordinated protection scheme were tested in a standard smart grid (IEEE 34-bus test system) under different short circuit scenarios and renewable energy penetration. Results suggest that the short-circuit fault sensed by the smart sensor is improved up to 80% and up to 64% compared with analog electromechanics relays and IEDs, respectively.
Characteristics and opinions of MD-PhD students and graduates from different European countries: a study from the European MD-PhD Association.

BACKGROUND MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates. PURPOSE This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe. METHODS Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression. RESULTS Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p <0.05) were observed for age group, resident status, clinical time allocation, duration of studies, sources of funding, publications, average impact factor of the journals in which the research was published, satisfaction with the duration of MD-PhD studies and future career choices of MD-PhD students. Responses related to self-perception about clinical and research competence and challenges faced during MD-PhD training did not show a significant country-wise difference. CONCLUSION The MD-PhD workforce in Europe is highly diverse in their demographics, programme characteristics and career paths but does not differ in opinions related to the challenges faced. The results of this study may be helpful for implementation and improvement of MD-PhD programmes.
Cyberknife radiosurgery on the brainstem metastases of non-small cell lung cancer

Abstract Objective Management of brainstem metastatic tumor is challenging. This study aimed to evaluate overall survival and quality-of-life in patients with non-small cell lung cancer (NSCLC) brainstem metastases who were treated with the Cyberknife stereotactic radiosurgery. Methods From August 2007 through August 2016, a total of 32 patients with 34 brainstem metastases of NSCLC were consecutively enrolled and treated with the Cyberknife radiosurgery (CKRS) at The Huashan Hospital. The study was limited to patients with NSCLC, which was confirmed by postoperative pathological examination. Patients were treated by CKRS as an initial treatment or a second treatment after whole-brain radiation therapy (WBRT). Quality of life was assessed by the SF-12 score and neurological examination. Results Four out of the 32 (12.5%) patients received WBRT before or concurrent with CKRS treatment. The mean survival time after CKRS was 10.0 (95%CI: 6.0–14.0) months. Karnofsky performance score was not the independent predictor of survival after radiosurgery as analyzed by log-rank test (p = 0.392). Age, however, was a significant predictor of improved survival as analyzed by multivariate analysis (p = 0.024). SF-12 physical component scores demonstrated no significant change after treatment. Conclusions The CKSR is a non-invasive, safe, and effective modality in the treatment of patients with brainstem metastases of NSCLC. Better therapeutic outcomes of CKSR for brainstem metastasis might be achieved in the patients older than 65 years old.
Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically

Supplemental Digital Content is available in the text. Background and Purpose— It is unclear which factors predict acute neurological deterioration in patients with large vessel occlusion and mild symptoms. We aim to evaluate the frequency, timing, and potential predictors of acute neurological deterioration ≥4 National Institutes of Health Stroke Scale (NIHSS) points in medically managed patients with large vessel occlusion and mild presentation. Methods— Single-center retrospective study of patients with consecutive minor stroke (defined as NIHSS score of ≤5 on presentation) and large vessel occlusion from January 2014 to December 2017. Primary outcome was acute neurological deterioration ≥4 NIHSS points during the hospitalization. Secondary outcomes included ΔNIHSS (defined as discharge minus admission NIHSS score). Results— Among 1133 patients with acute minor strokes, 122 (10.6%) had visible occlusions on computed tomography angiography/magnetic resonance angiography. Twenty-four (19.7%) patients had ≥4 points deterioration on NIHSS at a median of 3.6 (1–16) hours from arrival. No clinical or radiological predictors of acute neurological deterioration ≥4 NIHSS points were observed on multivariable analysis. Rescue endovascular thrombectomy was performed more often in the ones with acute neurological deterioration ≥4 NIHSS points compared with patients with no deterioration (54% versus 0%; P<0.001). Acute neurological deterioration ≥4 NIHSS points was associated with ΔNIHSS ≥4 points (33% versus 4.9%; P<0.01) and a trend toward lower independence rates at discharge (50% versus 70%; P=0.06) compared with the group with no deterioration. In patients with any degree of neurological worsening, patients who underwent rescue thrombectomy were more likely to be independent at discharge (73% versus 38%; P=0.02) and to have a favorable ΔNIHSS (−2 [−3 to 0] versus 0 [−1 to 6]; P=0.05) compared with the ones not offered rescue thrombectomy. Conclusions— Acute neurological deterioration ≥4 NIHSS points was observed in a fifth of patients with large vessel occlusion and mild symptoms, occurred very early in the hospital course, impacted functional outcomes, and could not be predicted by any of the studied clinical and radiological variables. Rescue thrombectomy was associated with improved clinical outcomes at discharge in patients with neurological deterioration.
The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.
Hydroxychloroquine and COVID-19

Hydroxychloroquine and chloroquine are medications that have been used for a long time. Their most common use is for the treatment and prophylaxis of malaria. However, these antimalarial drugs are known to also have anti-inflammatory and antiviral effects and are used for several chronic diseases such as systemic lupus erythematosus with low adverse effects. The antiviral action of hydroxychloroquine and chloroquine has been a point of interest to different researchers due to its mechanism of action. Several in vitro studies have proven their effectiveness on severe acute respiratory syndrome virus and currently both in vitro and in vivo studies have been conducted on 2019 novel coronavirus (covid-19). The purpose of this article is to review the history and mechanism of actions of these drugs and the potential use they can have on the current covid-19 pandemic.
The Multifarious Role of 14-3-3 Family of Proteins in Viral Replication

The 14-3-3 proteins are a family of ubiquitous and exclusively eukaryotic proteins with an astoundingly significant number of binding partners. Their binding alters the activity, stability, localization, and phosphorylation state of a target protein. The association of 14-3-3 proteins with the regulation of a wide range of general and specific signaling pathways suggests their crucial role in health and disease. Recent studies have linked 14-3-3 to several RNA and DNA viruses that may contribute to the pathogenesis and progression of infections. Therefore, comprehensive knowledge of host–virus interactions is vital for understanding the viral life cycle and developing effective therapeutic strategies. Moreover, pharmaceutical research is already moving towards targeting host proteins in the control of virus pathogenesis. As such, targeting the right host protein to interrupt host–virus interactions could be an effective therapeutic strategy. In this review, we generated a 14-3-3 protein interactions roadmap in viruses, using the freely available Virusmentha network, an online virus–virus or virus–host interaction tool. Furthermore, we summarize the role of the 14-3-3 family in RNA and DNA viruses. The participation of 14-3-3 in viral infections underlines its significance as a key regulator for the expression of host and viral proteins.
Association between Self-Reported Eating Rate, Energy Intake, and Cardiovascular Risk Factors in a Multi-Ethnic Asian Population

Eating faster is associated with greater body mass index (BMI), but less is known about the relationships between eating rate, energy intake, body composition, and cardio-metabolic risk factors in different Asian ethnic groups. Using data from the Singapore Multi-Ethnic Cohort (n = 7011; 21–75 y), we investigated associations between self-reported eating rate (SRER), with energy intake, body composition, blood pressure, and blood lipids. SRER and lifestyle was assessed using interviewer-administered questionnaires. Multivariable models were used to examine the associations of SRER with energy intake, body composition, blood pressure, and blood lipids after adjusting for covariates. General and abdominal overweight were defined as BMI ≥ 23 kg/m2 and waist circumference >90 cm (men) and > 80 cm (women), respectively. On average, faster eaters (vs. slower eaters) consumed 105 kcal/day more (p = 0.034), had ~5 kg higher body weight (p < 0.001), 1.3 kg/m2 higher BMI (p < 0.001), and 3.1 cm larger waist-circumference (p < 0.001). Faster eaters had significantly higher blood pressure, circulating triglycerides, and total-to-high-density lipoprotein cholesterol ratio than slower eaters. Faster eaters were twice as likely to develop general (multivariable-OR: 2.2; 95% CI, 1.8–2.6; p < 0.001), and abdominal (OR: 1.8; 95% CI, 1.5–2.2; p < 0.001) overweight than slower eaters. This association was observed across all subgroups by age, sex, and ethnicity. Findings suggest that SRER is a robust behavioral marker for increased risk of higher energy intake, obesity, and poor cardio-metabolic health, and a modifiable behavioral risk-factor for obesity prevention.
Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort

OBJECTIVE To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). RESULTS Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.
Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity

Significance We here present a transcriptional map of peripheral nerve cells in health and autoimmunity. Identified marker genes of nonmyelinating Schwann cells and nerve-associated fibroblasts will facilitate a better understanding of the complex cellular architecture of peripheral nerves. The two distinct populations of nerve-resident homeostatic myeloid cells suggest an unexpectedly unique and heterogeneous local immune repertoire in peripheral nerves with signs of heterogeneous ontogenetic origin. Complex changes of local cell–cell communication networks indicate autoimmune neuritis as a disease affecting “immune networks” rather than single cell types. The findings also suggest that immunological features are partially shared and conserved across different parts of the nervous system. Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell–cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.
Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial

Supplemental Digital Content is available in the text. Background and Purpose— Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods— We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results— In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0–3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions— A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration— URL: https://www.clinicaltrials. gov; Unique identifier: NCT02313909.
IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism

The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp160 in the 49-kDa subunit, located deep in the interior of a previously proposed quinone-access channel. However, contrary to the other inhibitors, IACS-010759 direction-dependently inhibited forward and reverse electron transfer and did not suppress binding of the quinazoline-type inhibitor [125I]AzQ to the N terminus of the 49-kDa subunit. Photoaffinity labeling experiments revealed that the photoreactive derivative [125I]IACS-010759-PD1 binds to the middle of the membrane subunit ND1 and that inhibitors that bind to the 49-kDa or PSST subunit cannot suppress the binding. We conclude that IACS-010759's binding location in complex I differs from that of any other known inhibitor of the enzyme. Our findings, along with those from previous study, reveal that the mechanisms of action of complex I inhibitors with widely different chemical properties are more diverse than can be accounted for by the quinone-access channel model proposed by structural biology studies.
Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy

Recombinant tissue plasminogen activator (rtPA) is the only thrombolytic agent that has been approved by the FDA for treatment of ischemic stroke. However, a high dose intravenous infusion is required to maintain effective drug concentration, owing to the short half-life of the thrombolytic drug, whereas a momentous limitation is the risk of bleeding. We envision a dual targeted strategy for rtPA delivery will be feasible to minimize the required dose of rtPA for treatment. For this purpose, rtPA and fibrin-avid peptide were co-immobilized to poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (PMNP) to prepare peptide/rtPA conjugated PMNPs (pPMNP-rtPA). During preparation, PMNP was first surface modified with avidin, which could interact with biotin. This is followed by binding PMNP-avidin with biotin-PEG-rtPA (or biotin-PEG-peptide), which was prepared beforehand by binding rtPA (or peptide) to biotin-PEG-maleimide while using click chemistry between maleimide and the single –SH group in rtPA (or peptide). The physicochemical property characterization indicated the successful preparation of the magnetic nanoparticles with full retention of rtPA fibrinolysis activity, while biological response studies underlined the high biocompatibility of all magnetic nanoparticles from cytotoxicity and hemolysis assays in vitro. The magnetic guidance and fibrin binding effects were also confirmed, which led to a higher thrombolysis rate in vitro using PMNP-rtPA or pPMNP-rtPA when compared to free rtPA after static or dynamic incubation with blood clots. Using pressure-dependent clot lysis model in a flow system, dual targeted pPMNP-rtPA could reduce the clot lysis time for reperfusion by 40% when compared to free rtPA at the same drug dosage. From in vivo targeted thrombolysis in a rat embolic model, pPMNP-rtPA was used at 20% of free rtPA dosage to restore the iliac blood flow in vascular thrombus that was created by injecting a blood clot to the hind limb area.