Miracle-dz/UniFAR-FTUs huggingface dataset:
Protease-activated receptor 1 as a potential therapeutic target for COVID-19

Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2) has spread all over the world, since its discovery in 2019, Wuhan, China. This disease is called COVID-19 and already killed over 1 million people worldwide. The clinical symptoms include fever, dry cough, dyspnea, headache, dizziness, generalized weakness, vomiting, and diarrhea. Unfortunately, so far, there is no validated vaccine, and its management consists mainly of supportive care. Venous thrombosis and pulmonary embolism are highly prevalent in patients suffering from severe COVID-19. In fact, a prothrombotic state seems to be present in most fatal cases of the disease. SARS-CoV-2 leads to the production of proinflammatory cytokines, causing immune-mediated tissue damage, disruption of the endothelial barrier, and uncontrolled thrombogenesis. Thrombin is the key regulator of coagulation and fibrin formation. In severe COVID-19, a dysfunctional of physiological anticoagulant mechanisms leads to a progressive increase of thrombin activity, which is associated with acute respiratory distress syndrome development and a poor prognosis. Protease-activated receptor type 1 (PAR1) is the main thrombin receptor and may represent an essential link between coagulation and inflammation in the pathophysiology of COVID-19. In this review, we discuss the potential role of PAR1 inhibition and regulation in COVID-19 treatment.
Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.
Active site metals mediate an oligomeric equilibrium in Plasmodium M17 aminopeptidases

M17 leucyl aminopeptidases are metal-dependent exopeptidases that rely on oligomerization to diversify their functional roles. The M17 aminopeptidases from Plasmodium falciparum (PfA-M17) and Plasmodium vivax (Pv-M17) function as catalytically active hexamers to generate free amino acids from human hemoglobin and are drug targets for the design of novel antimalarial agents. However, the molecular basis for oligomeric assembly is not fully understood. In this study, we found that the active site metal ions essential for catalytic activity have a secondary structural role mediating the formation of active hexamers. We found that PfA-M17 and Pv-M17 exist in a metal-dependent dynamic equilibrium between active hexameric species and smaller inactive species that can be controlled by manipulating the identity and concentration of metals available. Mutation of residues involved in metal ion binding impaired catalytic activity and the formation of active hexamers. Structural resolution of Pv-M17 by cryoelectron microscopy and X-ray crystallography together with solution studies revealed that PfA-M17 and Pv-M17 bind metal ions and substrates in a conserved fashion, although Pv-M17 forms the active hexamer more readily and processes substrates faster than PfA-M17. On the basis of these studies, we propose a dynamic equilibrium between monomer ↔ dimer ↔ tetramer ↔ hexamer, which becomes directional toward the large oligomeric states with the addition of metal ions. This sophisticated metal-dependent dynamic equilibrium may apply to other M17 aminopeptidases and underpin the moonlighting capabilities of this enzyme family.
"Fan-zhen Jie-ci" acupuncture therapy for treatment of discogenic sciatica: protocol for a single-blind, randomized controlled clinical trial.

BACKGROUND Curative medical treatment for patients with discogenic sciatica is limited. Acupuncture is an important non-pharmacological therapy reported to have positive therapeutic effects on discogenic sciatica. According to traditional Chinese acupuncture theory, discogenic sciatica is a channel tendon disease which can be treated by a special "Fan-zhen Jie-ci (FZJC)" method. Our recent preliminary clinical evidence indicated that the FZJC method had a positive treatment effect on the disease. This study will further evaluate the efficacy and safety of FZJC on patients with discogenic sciatica. METHODS A single-blind randomized controlled clinical trial will be conducted, assigning 76 participants with discogenic sciatica to a randomly assigned FZJC group or a control group. Acupuncture treatment combined with the FZJC method will be applied in the FZJC group while routine acupuncture treatment only will be applied in the control group. Treatments will be administered three times a week for a total of 3 consecutive weeks. The primary outcome of this trial is change in the visual analogue scale of leg pain (VASLP), and the secondary outcomes are changes in the visual analogue scale of back pain (VAS-BP), the Brief Pain Inventory (BPI), the Oswestry Disability Index (ODI), the 36-Item Short Form Health Survey (SF-36), and serum concentrations of mitochondrial DNA (mtDNA) and high sensitivity C reactive protein (hsCRP). DISCUSSION The results of this study will provide insight into the efficacy and safety of FZJC acupuncture as a treatment for discogenic sciatica. TRIAL REGISTRATION The trial has been registered at the Chinese Clinical Trial Registry (ChiCTR1900026272) and the Acupuncture-Moxibustion Clinical Trial Registry (AMCTR-IOR-19000275).
Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part I: which parameters from human studies are most relevant for toxicological assessments?

Abstract The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.
If I was minister of health I would prioritise addressing all health inequalities

Before university, I always considered myself immune to the socio-political frenzy that captivated my peers. But as six years at medical school ticked by, I became increasingly inquisitive about National Health Service politics. I began engaging in conversations with nurses, doctors, physiotherapists and anyone who could spare a minute, eager to hear what their experience of the National Health Service had been and what they would do to improve it. But too many of these corridor conversations and frustrations are swallowed up by the daily grind of working life; their ideas and conclusions lost among the sea of people and squeaking trolley wheels. There is a lot to be changed within the National Health Service, but the most prominent health issue of today is staring us in the face; it is in our news and all over our socialmedia; it is protesting in our streets and dominating our conversations. It is as poignant and topical as ever: it is inequality.
Target: Stroke Was Associated With Faster Intravenous Thrombolysis and Improved One-Year Outcomes for Acute Ischemic Stroke in Medicare Beneficiaries

Supplemental Digital Content is available in the text. Background: The benefit of intravenous thrombolytic therapy for acute ischemic stroke is time dependent. To assist hospitals in providing faster thrombolytic treatment, the American Heart Association launched target: stroke quality initiative in January 2010 which disseminated feasible strategies to shorten door-to-needle times for thrombolytic therapy. This study aimed to examine whether target: stroke was associated with improved door-to-needle times and 1-year outcomes. Methods: We analyzed Medicare beneficiaries aged ≥65 years receiving intravenous thrombolytic treatment for acute ischemic stroke at 1490 Get With The Guidelines-Stroke hospitals during January 2006 and December 2009 (preintervention, n=10 804) and January 2010 and December 2014 (postintervention, n=31 249). The median age was 80 years and 42.7% were male. Results: The median door-to-needle times decreased from 80 minutes for the preintervention to 68 minutes for the postintervention (P<0.001). The proportion of patients receiving intravenous thrombolysis with door-to-needle times 45 minutes and 60 minutes increased from 9.6% and 24.8% for preintervention to 17.1% and 40.6% for postintervention, respectively (P<0.001). The annual rate of increase in the door-to-needle times of 60 minutes or less accelerated from 0.20% (95% CI, −0.43% to 0.83%) per each 4 quarters for preintervention to 5.68% (95% CI, 5.23%–6.13%) for postintervention (P<0.001) which was further confirmed in piecewise multivariable generalized estimating analysis (adjusted odds ratio, 1.27 [95% CI, 1.19–1.35]). Cox proportional hazards analysis, after adjusting for patient and hospital characteristics and within-hospital clustering, showed that target: stroke was associated with lower all-cause readmission (40.4% versus 44.1%; hazard ratio, 0.91 [95% CI, 0.88–0.95]), cardiovascular readmission (19.7% versus 22.9%; hazard ratio, 0.85 [95% CI, 0.80–0.89]), and composite of all-cause mortality or readmission (56.0% versus 58.4%; hazard ratio, 0.96 [95% CI, 0.93–1.00]). The risk decline in all-cause mortality dissipated after risk adjustment (adjusted hazard ratio, 0.98 [95% CI, 0.94–1.02]). Conclusions: Target: stroke quality initiative was associated with faster thrombolytic treatment times for acute ischemic stroke and modestly lower 1-year all-cause and cardiovascular readmissions.
Myocardial Infarction with and without ST-segment Elevation: a Contemporary Reappraisal of Similarities and Differences

Understanding the similarities and differences between myocardial infarction with or without ST-segment elevation is an essential step for proper patients’ management in current practice. Both syndromes are caused by critical stenosis or total occlusion of coronary arteries (mostly due to thrombosis on atherosclerotic plaque), and manifest with a similar clinical presentation. Recent epidemiologic studies show that the relative incidence of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) moves in an opposite fashion (decreasing and increasing respectively), with a prognosis that is worse at short-term follow-up for STEMI but comparable at long-term. Current management differs, as for STEMIs, immediate reperfusion is recommended, while for NSTEMIs, risk stratification is mandatory in order to stratify patients’ risk, and then decide the timing for coronary angiography. Periprocedural and technical aspects of the interventional management, as well as antithrombotic medications, are for the most similarly implemented in the two types of MI, with routine radial access, DES implant, and novel P2Y12 inhibitors representing the standard of care in both cases. The following review article aims to compare the two types of MI, with and without persistent ST-segment elevation. The main purpose is to explore their similarities and differences and address areas of uncertainty with regards to clinical presentation, therapeutic management, and prognosis. The identification of high-risk NSTEMI patients is important as they may require an individualised approach that can substantially overlap with current STEMI recommendations, and their mortality remains high if their management is delayed.
Dietary oleic acid supplementation and blood inflammatory markers: a systematic review and meta-analysis of randomized controlled trials

Abstract The aim of this systematic review and meta-analysis was to analyze data from randomized controlled trials (RCTs) assessing the effects of oleic acid (OA) supplementation on blood inflammatory markers in adults. PubMed, EMBASE and Cochrane Library databases were systematically searched from 1950 to 2019, with adults and a minimum intervention duration of 4 weeks. The effect size was estimated, adopting standardized mean difference (SMD) and 95% confidence interval (CI). Of the 719 identified studies, thirty-one RCTs involving 1634 subjects were eligible. The results of this study revealed that increasing OA supplementation significantly reduced C-reactive protein (CRP) (SMD: −0.11, 95% CI: −0.21, −0.01, P = 0.038). However, dietary OA consumption did not significantly affect tumor necrosis factor (TNF) (SMD: −0.05, 95% CI: −0.19, 0.10, P = 0.534), interleukin 6 (IL-6) (SMD: 0.01, 95% CI: −0.10, 0.13, P = 0.849), fibrinogen (SMD: 0.08, 95% CI: −0.16, 0.31, P = 0.520), plasminogen activator inhibitor type 1 (PAI-1) activity (SMD: −0.11, 95% CI: −0.34, 0.12, P = 0.355), soluble intercellular adhesion molecule-1 (sICAM-1) (SMD: −0.06, 95% CI: −0.26, 0.13, P = 0.595) or soluble vascular cell adhesion molecule-1 (sVCAM-1) (SMD: −0.04, 95% CI: −0.27, 0.18, P = 0.701). Overall, the meta-analysis demonstrated that dietary OA supplementation significantly reduced CRP, yet did not affect other inflammatory markers including TNF, IL-6, fibrinogen, PAI-1 activity, sICAM-1or sVCAM-1.
Deploying MMEJ using MENdel in precision gene editing applications for gene therapy and functional genomics

Abstract Gene-editing experiments commonly elicit the error-prone non-homologous end joining for DNA double-strand break (DSB) repair. Microhomology-mediated end joining (MMEJ) can generate more predictable outcomes for functional genomic and somatic therapeutic applications. We compared three DSB repair prediction algorithms – MENTHU, inDelphi, and Lindel – in identifying MMEJ-repaired, homogeneous genotypes (PreMAs) in an independent dataset of 5,885 distinct Cas9-mediated mouse embryonic stem cell DSB repair events. MENTHU correctly identified 46% of all PreMAs available, a ∼2- and ∼60-fold sensitivity increase compared to inDelphi and Lindel, respectively. In contrast, only Lindel correctly predicted predominant single-base insertions. We report the new algorithm MENdel, a combination of MENTHU and Lindel, that achieves the most predictive coverage of homogeneous out-of-frame mutations in this large dataset. We then estimated the frequency of Cas9-targetable homogeneous frameshift-inducing DSBs in vertebrate coding regions for gene discovery using MENdel. 47 out of 54 genes (87%) contained at least one early frameshift-inducing DSB and 49 out of 54 (91%) did so when also considering Cas12a-mediated deletions. We suggest that the use of MENdel helps researchers use MMEJ at scale for reverse genetics screenings and with sufficient intra-gene density rates to be viable for nearly all loss-of-function based gene editing therapeutic applications.
Heatwaves, medications, and heat-related hospitalization in older Medicare beneficiaries with chronic conditions

Background Heatwaves kill more people than floods, tornadoes, and earthquakes combined and disproportionally affect older persons and those with chronic conditions. Commonly used medications for chronic conditions, e.g., diuretics, antipsychotics disrupt thermoregulation or fluid/electrolyte balance and may sensitive patients to heat. However, the effect of heat-sensitizing medications and their interactions with heatwaves are not well-quantified. We evaluated effects of potentially heat-sensitizing medications in vulnerable older patients. Methods US Medicare data were linked at the zip code level to climate data with surface air temperatures for June-August of 2007–2012. Patients were Medicare beneficiaries aged ≥65 years with chronic conditions including diabetes, dementia, and cardiovascular, lung, or kidney disease. Exposures were potentially heat-sensitizing medications including diuretics, anticholinergics, antipsychotics, beta blockers, stimulants, and anti-hypertensives. A heatwave was defined as ≥2 days above the 95th percentile of historical zip code-specific surface air temperatures. We estimated associations of heat-sensitizing medications and heatwaves with heat-related hospitalization using self-controlled case series analysis. Results We identified 9,721 patients with at least one chronic condition and heat-related hospitalization; 42.1% of these patients experienced a heatwave. Heatwaves were associated with an increase in heat-related hospitalizations ranging from 21% (95% CI: 7% to 38%) to 33% (95% CI: 14% to 55%) across medication classes. Several drug classes were associated with moderately elevated risk of heat-related hospitalization in the absence of heatwaves, with rate ratios ranging from 1.16 (95% CI: 1.00 to 1.35) to 1.37 (95% CI: 1.14 to 1.66). We did not observe meaningful synergistic interactions between heatwaves and medications. Conclusions Older patients with chronic conditions may be at heightened risk for heat-related hospitalization due to the use of heat-sensitizing medications throughout the summer months, even in the absence of heatwaves. Further studies are needed to confirm these findings and also to understand the effect of milder and shorter heat exposure.
The Short Lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 Protect HaCaT Keratinocytes from Bacterial Damage Caused by Staphylococcus aureus Infection in a Co-Culture Model

The search for new antimicrobial strategies is of major importance since there is a growing resistance of both bacteria and fungi to existing antimicrobials. Lipopeptides are promising and potent antimicrobial compounds. For translation into clinically useful molecules, effectiveness of peptide treatment against human infections must be proved in complex in vitro wound models. The aim of this study was to examine if the synthesized short lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 can protect HaCaT keratinocytes from bacterial damage caused by Staphylococcus aureus infection in a coculture model. After 1 h, 24 h, and 48 h incubation, cellular ATP level and release of the cytotoxicity marker LDH as well as the proinflammatory cytokines interleukin-6 and interleukin-1α were measured. Infection of the keratinocytes resulted in strong bacterial damage of HaCaT cells along with low cellular ATP levels and high release of LDH, IL-6, and IL-1α after 24 h and 48 h. Incubation of the infected human keratinocytes with (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 resulted in protection of the keratinocytes from bacterial damage caused by Staphylococcus aureus infection with ATP, LDH, IL-6, and IL-1α levels comparable to the untreated control. Hence, both synthesized lipopeptides are promising candidates with high therapeutic potential in dermatology for the treatment of topical infections.
PED in 2021: a major update of the protein ensemble database for intrinsically disordered proteins

Abstract The Protein Ensemble Database (PED) (https://proteinensemble.org), which holds structural ensembles of intrinsically disordered proteins (IDPs), has been significantly updated and upgraded since its last release in 2016. The new version, PED 4.0, has been completely redesigned and reimplemented with cutting-edge technology and now holds about six times more data (162 versus 24 entries and 242 versus 60 structural ensembles) and a broader representation of state of the art ensemble generation methods than the previous version. The database has a completely renewed graphical interface with an interactive feature viewer for region-based annotations, and provides a series of descriptors of the qualitative and quantitative properties of the ensembles. High quality of the data is guaranteed by a new submission process, which combines both automatic and manual evaluation steps. A team of biocurators integrate structured metadata describing the ensemble generation methodology, experimental constraints and conditions. A new search engine allows the user to build advanced queries and search all entry fields including cross-references to IDP-related resources such as DisProt, MobiDB, BMRB and SASBDB. We expect that the renewed PED will be useful for researchers interested in the atomic-level understanding of IDP function, and promote the rational, structure-based design of IDP-targeting drugs.
Lactococcus lactis and Resveratrol Decrease Body Weight and Increase Benefic Gastrointestinal Microbiota in Mice.

BACKGROUND The microbiome is now known for its important role in whole-body homeostasis. A dysbiosis of the normal microbiota is correlated with metabolic disorders. In this sense, the search for compounds able to modulate the microbiome is needed. Resveratrol, a natural compound found in grapes seems to be a promising candidate. OBJECTIVE In this study, our motivation was to evaluate the effects of the association between Resveratrol and Lactococcus lactis, a probiotic, on the composition of the gastrointestinal microbiota and body weight of mice. METHODS Twenty female mice were divided into 4 groups: (1) standard diet, (2) standard diet plus Lactococcus lactis, (3) standard diet plus resveratrol, and (4) standard diet plus Lactococcus lactis and resveratrol. At the end of the treatment peri-od, samples of blood, mucus, stomach, and small and large intestines were collected for analysis. Total levels of Immuno-globulin A and Immunoglobulin E, Lac+ and Lac- bacteria and Lactobacillus were measured. RESULTS The main results indicate that the association between resveratrol and probiotics was able to decrease mice body weight, as compared to the other groups, in addition to decrease the number of Lac- bacteria and increasing the number of Lac+ bacteria. The levels of secretory IgA were also decreased, compared to the animals treated with only probiotics or resveratrol. CONCLUSION We observed potential synergism between Resveratrol and Lactococcus lactis mainly in modulating the stom-ach and intestinal microbiota.