Miracle-dz/UniFAR-FTUs huggingface dataset:
Moderate DNA methylation changes associated with nitrogen remobilization and leaf senescence in Arabidopsis

The lifespan of plants and tissues is restricted by environmental and genetic components. Following the transition to reproductive growth, leaf senescence ceases cellular life in monocarpic plants to remobilize nutrients to storage organs. We observed altered leaf to seed ratios, faster senescence progression and enhanced nitrogen remobilization from the leaves in two methylation mutants (ros1 and the triple dmr1/2 cmt3 knockout). DNA methylation in wild type Col-0 leaves initially moderately declined with progressing leaf senescence, predominantly in the CG context, while the ultimate phase of leaf discoloration was associated with moderate de novo methylation of cytosines, primarily in the CHH context. Relatively few differentially methylated regions, including one in the ROS1 promoter linked to the down-regulation of ROS1, were present, but these were unrelated to known senescence-associated genes. Differential methylation patterns were identified in transcription factor binding sites, such as the W-boxes that are targeted by WRKYs, which impaired transcription factor binding when methylated in vitro. Mutants that are defective in DNA methylation showed distinct nitrogen remobilization, which was associated with altered patterns of leaf senescence progression. But moderate methylome changes during leaf senescence were not specifically associated with up-regulated genes during senescence.
Multi-objective prioritisation of candidate epitopes for diagnostic test development

Background The development of peptide-based diagnostic tests requires the identification of epitopes that are at the same time highly immunogenic and, ideally, unique to the pathogen of interest, to minimise the chances of cross-reactivity. Existing computational pipelines for the prediction of linear B-cell epitopes tend to focus exclusively on the first objective, leaving considerations of cross-reactivity to later stages of test development. Results We present a multi-objective approach to the prioritisation of candidate epitopes for experimental validation, in the context of diagnostic test development. The dual objectives of uniqueness (measured as dissimilarity from known epitope sequences from other pathogens) and predicted immunogenicity (measured as the probability score returned by the prediction model) are considered simultaneously. Validation was performed using data from three distinct pathogens (namely the nematode Onchocerca volvulus, the Epstein-Barr Virus and the Hepatitis C Virus), with predictions derived using an organism-specific prediction approach. The multi-objective rankings returned sets of non-dominated solutions as potential targets for the development of diagnostic tests with lower probability of false positives due to cross-reactivity. Conclusions The application of the proposed approach to three test pathogens led to the identification of 20 new potential epitopes, with both high probability and a high degree of exclusivity to the target organisms. The results indicate the potential of the proposed approach to provide enhanced filtering and ranking of potential candidates, highlighting potential cross-reactivities and including this information into the test development process right from the target identification and prioritisation step.
Reciprocally inhibitory circuits operating with distinct mechanisms are differently robust to perturbation and modulation

What features are important for circuit robustness? Reciprocal inhibition is a building block in many circuits. We used dynamic clamp to create reciprocally inhibitory circuits from GM neurons of the crab stomatogastric ganglion by injecting artificial synaptic and hyperpolarization-activated inward (H) currents. In “release”, the active neuron controls the off/on transitions. In “escape”, the inhibited neuron controls the transitions. We characterized the robustness of escape and release circuits to alterations in circuit parameters, temperature, and neuromodulation. Escape circuits rely on tight correlations between synaptic and H conductances to generate bursting but are resilient to temperature increase. Release circuits are robust to variations in synaptic and H conductances but fragile to temperature increase. The modulatory current (IMI) restores oscillations in release circuits but has little effect in escape. Thus, the same perturbation can have dramatically different effects depending on the circuits’ mechanism of operation that may not be observable from circuit output. Highlights The synaptic threshold determines the mode of reciprocal inhibitory circuits. Robust oscillatory escape mode circuits rely on tight conductance correlations. Release mode circuits are sensitive to temperature and neuromodulation. Mixed mode circuits are sensitive to neuronal excitability differences.
Spatial working memory representations in human cortex are robust to a task-irrelevant interrupting stimulus

Visual working memory (WM) enables the maintenance and manipulation of information no longer accessible in the visual world. Previous research has identified spatial WM representations in activation patterns in visual, parietal, and frontal cortex. In natural vision, the period between the encoding of information into WM and the time when it is used to guide behavior (the delay period) is rarely “empty”, as is the case in most of the above laboratory experiments. In naturalistic conditions, eye movements, movement of the individual, and events in the environment result in visual signals which may overwrite or impair the fidelity of WM representations, especially in early sensory cortices. Here, we evaluated the extent to which a brief, irrelevant interrupting visual stimulus presented during a spatial WM delay period impaired behavioral performance and WM representation fidelity assayed using an image reconstruction technique (inverted encoding model). On each trial, participants (both sexes) viewed two target dots and were immediately post-cued to remember the precise spatial position of one dot. On 50% of trials, a brief interrupter stimulus appeared. While we observed strong transient univariate visual responses to the distracter stimulus, we saw no change in reconstructed neural WM representations under distraction, nor a change in behavioral performance on a continuous recall task. This suggests that spatial WM representations may be particularly robust to interference from incoming task-irrelevant visual information, perhaps related to their role in guiding movements.
Adeno-Associated Virus-Mediated Gain-of-Function mPCSK9 Expression in the Mouse Induces Hypercholesterolemia, Monocytosis, Neutrophilia, and a Hypercoagulative State

Hypercholesterolemia has previously been induced in the mouse by a single intravenous injection of adeno-associated virus (AAV)-based vector harboring gain-of-function pro-protein convertase subtilisin/kexin type 9. Despite the recent emergence of the PCSK9-AAV model, the profile of hematological and coagulation parameters associated with it has yet to be characterized. We injected 1.0 × 1011 viral particles of mPCSK9-AAV or control AAV into juvenile male C57BL/6N mice and fed them with either a Western-type high-fat diet (HFD) or standard diet over the course of 3 weeks. mPCSK9-AAV mice on HFD exhibited greater plasma PCSK9 concentration and lower low-density lipoprotein levels, concomitant with increased total cholesterol and non-high-density lipoprotein (non-HDL)-cholesterol concentrations, and lower HDL-cholesterol concentrations than control mice. Furthermore, mPCSK9-AAV-injected mice on HFD exhibited no signs of atherosclerosis at 3 weeks after the AAV injection. Hypercholesterolemia was associated with a thromboinflammatory phenotype, as neutrophil levels, monocyte levels, and neutrophil-to-lymphocyte ratios were higher and activated partial thromboplastin times (aPTTs) was lower in HFD-fed mPCSK9-AAV mice. Therefore, the mPCSK9-AAV is a suitable model of hypercholesterolemia to examine the role of thromboinflammatory processes in the pathogenesis of cardiovascular and cerebrovascular diseases.
Direct Evidence of Endothelial Dysfunction and Glycocalyx Loss in Dermal Biopsies of Patients With Chronic Kidney Disease and Their Association With Markers of Volume Overload

Cardiovascular morbidity is a major problem in patients with chronic kidney disease (CKD) and endothelial dysfunction (ED) is involved in its development. The luminal side of the vascular endothelium is covered by a protective endothelial glycocalyx (eGC) and indirect evidence indicates eGC loss in CKD patients. We aimed to investigate potential eGC loss and ED in skin biopsies of CKD patients and their association with inflammation and volume overload. During living kidney transplantation procedure, abdominal skin biopsies were taken from 11 patients with chronic kidney disease stage 5 of whom 4 were treated with hemodialysis and 7 did not receive dialysis treatment. Nine healthy kidney donors served as controls. Biopsies were stained and quantified for the eGC marker Ulex europaeus agglutinin-1 (UEA1) and the endothelial markers vascular endothelial growth factor-2 (VEGFR2) and von Willebrand factor (vWF) after double staining and normalization for the pan-endothelial marker cluster of differentiation 31. We also studied associations between quantified log-transformed dermal endothelial markers and plasma markers of inflammation and hydration status. Compared to healthy subjects, there was severe loss of the eGC marker UEA1 (P < 0.01) while VEGFR2 was increased in CKD patients, especially in those on dialysis (P = 0.01). For vWF, results were comparable between CKD patients and controls. Skin water content was identical in the three groups, which excluded dermal edema as an underlying cause in patients with CKD. The dermal eGC/ED markers UEA1, VEGFR2, and vWF all associated with plasma levels of NT-proBNP and sodium (all R2 > 0.29 and P < 0.01), except for vWF that only associated with plasma NT-proBNP. This study is the first to show direct histopathological evidence of dermal glycocalyx loss and ED in patients with CKD. In line with previous research, our results show that ED associates with markers of volume overload arguing for strict volume control in CKD patients.
Hyperuricemia in Psoriatic Arthritis: Epidemiology, Pathophysiology, and Clinical Implications

Psoriatic arthritis (PsA) represents the articular component of the systemic psoriatic disease and the extra-cutaneous disorder most frequently found in patients with psoriasis. Besides the articular involvement, PsA is associated with several metabolic abnormalities such as insulin resistance, hypertension, diabetes and hyperuricemia. Uric acid is the final product of purine metabolism and the etiological substrate of gout. Accumulating evidence highlights the emerging role of hyperuricemia as a major cardiovascular risk factor. Moreover, different studies evaluated the interplay between hyperuricemia and psoriatic disease, suggesting that individuals affected by psoriasis or PsA might present higher serum levels of uric acid and that hyperuricemia might affect severity of clinical manifestations and degree of inflammation in PsA patients. In this review, we focus on the bidirectional relationship between uric acid and PsA, analyzing how uric acid may be involved in the pathogenesis of psoriasis/PsA and how clinical manifestations of PsA and inflammatory mediators are affected by uric acid concentrations. Finally, the effects of anti-rheumatic drugs on uric acid levels and the potential benefit of urate-lowering therapies on psoriasis and PsA were summarized.
Arterial Hypertension and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

Background: Off-target effects in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) are associated with cardiovascular toxicity. Hypertension represents an important cardiovascular complication and, if not appropriately managed, can contribute to developing thrombotic events. Third-generation TKI ponatinib is associated with hypertension development, and its use is more restricted than in the past. Few data are reported for second-generation TKI, nilotinib, dasatinib, and bosutinib. The aim of this article was to evaluate with a systematic review and meta-analysis the real incidence of hypertension in CML patients treated with second- or third-generation TKI. Methods: The PubMed database, Web of Science, Scopus, and ClinicalTrials.gov were systematically searched for studies published between January 1, 2000, and January 30, 2021; the following terms were entered in the database queries: Cardiovascular, Chronic Myeloid Leukemia, CML, Tyrosine kinases inhibitor, TKI, and Hypertension. The study was carried out according to the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement. Results: A pooled analysis of hypertension incidence was 10% for all new-generation TKI, with an even higher prevalence with ponatinib (17%). The comparison with the first-generation imatinib confirmed that nilotinib was associated with a significantly increased risk of hypertension (RR 2; 95% CI; 1.39-2.88, I2=0%, z=3.73, p=0.0002). The greatest risk was found with ponatinib (RR 9.21; 95% CI; 2.86-29.66, z=3.72, p=0.0002). Conclusion: Hypertension is a common cardiovascular complication in CML patients treated with second- or third-generation TKI.
Use of Hypnosis in Paediatric Gastrointestinal Endoscopy: A Pilot Study

Objectives: Experience of hypnosis in gastrointestinal (GI) endoscopy is scarce in children. Our aims were to assess the rate of successful GI endoscopy performed using hypnosis alone or in combination with midazolam, with or without additional equimolar mixture of oxygen and nitrous oxide (EMONO), and to identify predictive factors of successful endoscopy in children. Methods: This prospective single-centre study included children older than 6 years requiring a diagnostic esophagogastroduodenoscopy (EGD) or rectosigmoidoscopy. Ericksonian hypnosis was performed alone or in combination with midazolam, with or without additional EMONO. Successful endoscopy was defined by a complete and well-tolerated procedure. Levels of satisfaction of the endoscopist, nurse, and patient were assessed. Results: One hundred forty children [70 boys, median age: 12 years (Q1–Q3: 9–14)] were included over a 14-month period. They underwent EGD in 51.4% (n = 72) and rectosigmoidoscopy in 48.6% (n = 68) of cases. EMONO and midazolam were combined with hypnosis in 136 cases (97.1%). Successful endoscopy rate reached 82.9%. The procedure was interrupted due to poor tolerance and was rescheduled under general anaesthesia in 11 patients (7.9%). Predictive factors for successful endoscopy were older age (13 vs. 8 years, OR: 1.34, CI 95% [1.10–1.62], p = 0.003) and type of endoscopy (EGD vs. rectosigmoidoscopy, OR: 16.34 [2.14–124.68], p = 0.007). A good cooperation of the patient was reported by the endoscopist and the nurse in 88.4 and 86.9% of cases, respectively. Ninety-two per cent of patients mentioned that the procedure went well. Conclusions: Our study suggests that hypnosis combined with EMONO and/or midazolam is of additional value to perform diagnostic EGD or rectosigmoidoscopy in children older than 6 years without systematic need for general anaesthesia.
Rapid Real-Time Polymerase Chain Reaction for Salmonella Serotyping Based on Novel Unique Gene Markers by Pangenome Analysis

An accurate diagnostic method for Salmonella serovars is fundamental to preventing the spread of associated diseases. A diagnostic polymerase chain reaction (PCR)-based method has proven to be an effective tool for detecting pathogenic bacteria. However, the gene markers currently used in real-time PCR to detect Salmonella serovars have low specificity and are developed for only a few serovars. Therefore, in this study, we explored the novel unique gene markers for 60 serovars that share similar antigenic formulas and show high prevalence using pangenome analysis and developed a real-time PCR to detect them. Before exploring gene markers, the 535 Salmonella genomes were evaluated, and some genomes had serovars different from the designated serovar information. Based on these analyses, serovar-specific gene markers were explored. These markers were identified as genes present in all strains of target serovar genomes but absent in strains of other serovar genomes. Serovar-specific primer pairs were designed from the gene markers, and a real-time PCR method that can distinguish between 60 of the most common Salmonella serovars in a single 96-well plate assay was developed. As a result, real-time PCR showed 100% specificity for 199 Salmonella and 29 non-Salmonella strains. Subsequently, the method developed was applied successfully to both strains with identified serovars and an unknown strain, demonstrating that real-time PCR can accurately detect serovars of strains compared with traditional serotyping methods, such as antisera agglutination. Therefore, our method enables rapid and economical Salmonella serotyping compared with the traditional serotyping method.
Statin Use and Outcomes of Patients With Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Systematic Review and Meta-Analysis

Background: The data on the relationship between statin use and clinical outcomes after intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) are in controversy. Objective: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of statins administered prior to onset and during hospitalization in patients with AIS treated with IVT. Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception until June 8, 2021. Comparative studies investigating statin effect on intracranial hemorrhage (ICH), functional outcomes, and mortality in adults with AIS treated with IVT were screened. Random-effect meta-analyses of odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were performed. The protocol was registered in PROSPERO (CRD42021254919). Results: Twenty-two observational studies were included, which involved 17,554 patients. The pooled estimates showed that pre-stroke statin use was associated with a higher likelihood of symptomatic ICH (OR 1.31; 95% CI 1.07–1.59; p = 0.008) and any ICH (OR 1.21; 95% CI 1.03–1.43; p = 0.02). However, the pre-stroke statin use was not significantly associated with the 3-month mortality, 3-month favorable functional outcome (FFO, modified Rankin Scale [mRS] score 0–1), and 3-month functional independence (FI; mRS score 0–2). However, in-hospital statin use was associated with a reduced risk of symptomatic ICH (OR 0.46; 95% CI 0.21–1.00; p = 0.045), any ICH (OR 0.51; 95% CI 0.27–0.98; p = 0.04), and 3-month mortality (OR 0.42; 95% CI 0.29–0.62; p < 0.001) and an increased probability of 3-month FFO (OR 1.33; 95% CI 1.02–1.744; p = 0.04) and 3-month FI (OR 1.41; 95% C, 1.11–1.80; p = 0.005). Conclusions: The present systematic review and meta-analysis suggests that in-hospital statin use after IVT may be safe and may have a favorable impact on clinical outcomes, a finding not observed in studies restricted to patients with pre-stroke statin use.
6-Gingerol Alleviates Neonatal Hypoxic-Ischemic Cerebral and White Matter Injury and Contributes to Functional Recovery

Hypoxic-ischemic encephalopathy (HIE) is one main cause of neonatal death and disability, causing substantial injury to white and gray matter, which can lead to severe neurobehavioral dysfunction, including intellectual disability and dyskinesia. Inflammation, nerve cell death, and white matter injury are important factors in the pathological process of HIE. 6-Gingerol is a ginger extract, which reduces inflammatory response and cell death. However, the role of 6-Gingerol in neonatal hypoxic-ischemic brain injury (HIBI) remains unknown. In this study, we constructed a mouse HIBI model and analyzed the protective effect of 6-Gingerol on HIBI by using behavioral tests, histological staining, qPCR and western blot. Here, we found that 6-Gingerol treatment could alleviate HIBI and improve short-term reflex performance, which is closely related to cell death and neuroinflammation. Additionally, 6-Gingerol reduced neuronal apoptosis, pro-inflammatory factor release, as well as microglial activation. Furthermore, 6-Gingerol significantly improved motor disability, which is associated with white matter damage. Thus, our results showed that 6-Gingerol could reduce the loss of myelin sheaths, alleviate cell death of oligodendrocytes, and stimulate the maturation of oligodendrocytes. In terms of mechanism, we found that 6-Gingerol decreased histone H3K27me3 levels, activated AKT pathway and inhibited the activation of ERK and NF-κB pathway at 3 days post-HIBI. Taken together, our data clearly indicate that 6-Gingerol plays a neuroprotective role against HIBI by epigenetic modification and regulation of AKT, ERK, and NF-κB pathways, inhibiting inflammatory responses and reducing cell death.
Sex-Specific Differences in the Effect of Free Testosterone on Sarcopenia Components in Older Adults

Objective The association of free testosterone (FT) with sarcopenia and its components is well known in men but incompletely understood in women. We examined the association of baseline FT with the prevalence and incidence of sarcopenia and its components in community-dwelling older adults. Design Cross-sectional and longitudinal analysis from the prospective population-based Korean Frailty and Aging Cohort Study. Methods A total of 1,879 community-dwelling older adults aged 70–84 years were enrolled for cross-sectional analysis and 1,583 subjects who participated in the 2-year follow-up survey were included for longitudinal analysis. Baseline FT levels was measured by radioimmunoassay. Skeletal muscle mass, handgrip strength, and physical performance tests were measured at baseline and after 2-year follow-up. Sarcopenia was defined by the diagnostic criteria of the Asian Working Group for Sarcopenia (AWGS). Results Continuous FT levels was positively associated with the prevalence of sarcopenia in men (odds ratio [OR]=0.95; 95% confidence interval [CI]=0.89–1.00)] and women (OR=0.64, 95% CI=0.42–0.99) after adjusting for multiple confounders. In prospective analysis, low FT levels was associated with a decrease in handgrip strength in women (β=-0.61; p=0.010) and a reduction in Timed “Up and Go” (TUG) test (β=0.53; p=0.008) in men after 2 years. No significant correlations were found between FT levels and the incidence of sarcopenia. Conclusions Low levels of FT may be a significant determinant of decreases in muscle strength in women and declines in physical performance in men after 2 years. Low FT do not predict loss of muscle mass in both men and women.
Complementary Approaches Towards a Universal Model of Glacier Surges

Although many convincing, diverse, and sometimes competing models of glacier surging have been proposed, the observed behavior of surging glaciers does not fit into distinct categories, and suggests the presence of a universal mechanism driving all surges. On the one hand, recent simulations of oscillatory flow behavior through the description of transient basal drag hint at a fundamental underlying process. On the other hand, the proposition of a unified model of oscillatory flow through the concept of enthalpy adopts a systems based view, in an attempt to rather unify different mechanisms through a single universal measure. While these two general approaches differ in perspective, they are not mutually exclusive, and seem likely to complement each other. A framework incorporating both approaches would see the mechanics of basal drag describing ice flow velocity and surge propagation as a function of forcing by conditions at the glacier bed, in turn modulated through the unified measure of enthalpy.