Miracle-dz/UniFAR-FTUs huggingface dataset:
Leishmania donovani Dipeptidylcarboxypeptidase Inhibitor as a Potential Oral Treatment for Visceral Leishmaniasis

Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present several drawbacks, including moderate to severe toxicity, cost, long-term administration, patient compliance, and growing drug resistance. ABSTRACT Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present several drawbacks, including moderate to severe toxicity, cost, long-term administration, patient compliance, and growing drug resistance. Thus, the need for better treatment options against VL is a priority. In an endeavor to find an orally active and affordable antileishmanial agent, we evaluated the therapeutic potential of compounds belonging to the (2Z,2′Z)-3,3′-(ethane-1,2-diylbis(azanediyl))bis(1-(4-halophenyl)-6-hydroxyhex-2-en-1-ones) series, identified as inhibitor(s) of Leishmania donovani dipeptidylcarboxypeptidase, a novel drug target. Among them, compound 3c exhibited best in vivo antileishmanial efficacy via both intraperitoneal and oral routes. Therefore, the present study led to the identification of compound 3c as the lead candidate for treating VL.
Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients

Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease‐related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients.
Role of microRNAs in aquaporin 2 regulation

Purpose of review The current review aims to present the most recent achievements on the role of microRNAs (miRNAs) on the kidney function to stimulate research in the field and to expand new emerging concepts. Recent findings The focus is on the role of miRNAs in intercellular communication along the segments of the nephron and on the epi-miRNAs, namely the possibility of some miRNAs to modulate the epigenetic machinery and so gene expression. Indeed, recent evidence showed that miRNAs included in exosomes and released by proximal tubule cells can modulate ENaC activity on cells of collecting duct. These data, although, from in-vitro models open to a novel role for miRNAs to participate in paracrine signaling pathways. In addition, the role of miRNAs as epigenetic modulators is expanding not only in the cancer field, but also in the other kidney diseases. Recent evidence identified three miRNAs able to modulate the AQP2 promoter metilation and showing an additional level of regulation for the AQP2. Summary These evidence can inspire novel area of research both for renal physiology and drug discovery. The diseases involving the collecting duct are still missing disease modifying agents and the expanding miRNAs field could represent an opportunity.
NAT10 and DDX21 Proteins Interact with RNase H1 and Affect the Performance of Phosphorothioate Oligonucleotides

RNase H1-dependent phosphorothioate oligonucleotides (PS-ASOs) have been developed to treat various diseases through specific degradation of target RNAs. Although many factors or features of RNA and PS-ASOs have been demonstrated to affect antisense activity of PS-ASOs, little is known regarding the roles of RNase H1-associated proteins in PS-ASO performance. In this study, we report that two nucleolar proteins, NAT10 and DDX21, interact with RNase H1 and affect the potency and safety of PS-ASOs. The interactions of these two proteins with RNase H1 were determined using BioID proximity labeling in cells and confirmed biochemically. Reduction of NAT10 and DDX21 decreased PS-ASO activity in cells, and purified NAT10 and DDX21 proteins enhanced RNase H1 cleavage rates, indicating that these two proteins facilitate RNase H1 endoribonuclease activity. Consistently, reduction of these proteins increased the levels of R-loops, and impaired pre-rRNA processing. In addition, reduction of the two proteins increased the cytotoxicity of toxic PS-ASOs, and treatment of toxic PS-ASOs also altered the localization of these proteins. Together, this study shows for the first time that NAT10 and DDX21 interact with RNase H1 protein and enhance its enzymatic activity, contributing to the potency and safety of PS-ASOs.
Model Predictive Controller With Reduced Complexity for Grid-Tied Multilevel Inverters

Finite control set model predictive control (FCSMPC) has become popular for grid interactive applications due to its simplicity and ease of implementation. Since the implementation of FCSMPC requires all possible switching states of the inverter, the computational burden is an important issue, which needs to be addressed while applying FCSMPC to the control of multilevel inverters. This letter proposes a novel “S” factor scheme for the FCSMPC implementation, which reduces complexity while controlling grid current and balancing the capacitor voltages in neutral point clamped three-level inverters. The proposed scheme is very easy to implement and can be extended to any higher level inverter without any additional effort. In this method, at every sampling instant, redundant switching states are chosen suitably and the predicted reference inverter voltage (PRIV) vector is derived from predicted grid voltage, predicted reference current, and the present value of the actual current. Subsequently, “S” factor scheme is applied to select the switching state, which is close to the PRIV vector. The selected switching state is then applied at the same sampling instant. The proposed scheme is experimentally compared with a recent FCSMPC algorithm to validate the performance.
A brief nap during an acute stressor improves negative affect

Overnight sleep can reduce perceived stress, and improve associated cognitive disruptions and negative affect after an acute stressor. Whether a brief nap can also bestow these benefits in a non‐sleep‐restricted population is currently unknown. In this study that used a between‐subjects design, stress was triggered by administering a modified Trier Social Stress Test to two groups of participants (nap [n = 29], wake [n = 41]). All participants were instructed they would give a speech during the study but the topic would be withheld until later, and then completed a math task. After a 40‐min break in which participants watched a neutral video or took a nap monitored with electroencephalography, stress was reinforced by presenting the speech topics and giving participants a 10‐min preparation period. Next, instead of giving a speech, the study ended and participants were debriefed. Negative affect, perceived stress and working memory were measured at multiple time points before and after the break. Both groups showed lower perceived stress and improved working memory after the break than before, but a nap did not confer additional benefits for perceived stress or working memory beyond taking a break. However, the nap group exhibited lower negative affect after the break than the wake group, and only the nap group showed a reduction in negative affect compared with initial negative affect levels. These results indicate a nap can improve negative emotions accompanying a stressor to a greater extent than taking a break, and suggest that brief naps may be a useful way to improve mood while experiencing an acute stressor.
A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a rare disorder that affects both upper and lower motor neurons. Mutations in Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) correlates with three similar but distinctive syndromes, including the juvenile form of ALS. An Iranian Kurdish family was involved in this study and all members were evaluated with relevant clinical guidelines. Whole exome sequencing and sanger sequencing were applied to all family members to undermine the possible genetic factors. A substitution c. 2110 C>T (p. Arg704X) identified in the ALS2 gene. Bioinformatics analysis indicated the mutation is located in the well-conserved and functional domain of the protein. This study recognized a novel mutation in the ALS2 gene in a proband with the juvenile form of ALS. To our knowledge, this is the first identified ALS2 mutation among the Iranian population.
Melanin protects Cryptococcus neoformans from spaceflight effects

Summary As human activity in space continues to increase, understanding how biological assets respond to spaceflight conditions is becoming more important. Spaceflight conditions include exposure to ionizing radiation, microgravity, spacecraft vibrations and hypervelocity; all of which can affect the viability of biological organisms. Previous studies have shown that melanin‐producing fungi are capable of surviving the vacuum of space and Mars‐simulated conditions in Low Earth Orbit. This survival has been associated in part with the protective effects of melanin, but a comparison of fungal viability in the presence or absence of melanin following spaceflight has never been tested. In this study, we evaluated the protective effects of melanin by comparing the viability of melanized and non‐melanized clones of Cryptococcus neoformans yeasts following a roundtrip to the International Space Station. Yeast colonies were placed inside two MixStix silicone tubes; one stayed on Earth and the other was transported inside for 29 days before returning to Earth. Post‐flight analysis based on colony‐forming unit numbers shows that melanized yeast viability was 50% higher than non‐melanized yeasts, while no difference was observed between the Earth‐bound control samples. The results suggest that fungal melanin could increase the lifespan of biological assets in space.
Genome-wide screening identifies DNA methylation sites that regulate the blood proteome.

Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight.
Emotion regulation in substance use disorders: a systematic review and meta‐analysis

Abstract Background and aims The ability to regulate emotions effectively has been associated with resilience to psychopathology. Individuals with substance use disorders (SUDs) have been shown to have higher levels of negative emotionality, with some evidence suggesting impairment in emotion regulation compared with individuals without SUDs. However, no previous attempt has been made to systematically review the literature to assess the magnitude of this difference. We aimed to assess the association between SUD diagnosis and emotion regulation as measured by the Difficulties in Emotion Regulation Scale (DERS) and Emotion Regulation Questionnaire (ERQ) through a systematic review and meta‐analysis of existing findings. Methods The systematic review was conducted using PubMed, PsycINFO and Embase. We examined cross‐sectional studies that compared a SUD group with a control group and measured emotion regulation using the DERS or the ERQ. The primary analysis focused on papers using the DERS, as this was the predominant instrument in the literature. Results Twenty‐two studies met our primary analysis criteria, representing 1936 individuals with a SUD and 1567 controls. Individuals with SUDs relative to controls had significantly greater DERS scores, with a mean difference of 21.44 [95% confidence interval (CI) = 16.49–26.40, P < 0.001] and Hedges’ g = 1.05 (95% CI = 0.86–1.24, P < 0.001). The difference was robust, remaining significant after removing outliers and studies with high risk of bias. Individuals with SUDs demonstrated poorer emotion regulation on each subscale of the DERS, with the largest deficits in the Strategies and Impulse subscales. The ERQ analysis revealed greater use of expressive suppression in those with SUDs relative to controls (Hedges’ g = 0.76, 95% CI = 0.25–1.28, P = 0.004). Conclusions People with substance use disorders appear to have greater difficulties in emotion regulation than people without substance use disorders.
Sheltering of deleterious mutations explains the stepwise extension of recombination suppression on sex chromosomes and other supergenes

Many organisms have sex chromosomes with large nonrecombining regions that have expanded stepwise, generating “evolutionary strata” of differentiation. The reasons for this remain poorly understood, but the principal hypotheses proposed to date are based on antagonistic selection due to differences between sexes. However, it has proved difficult to obtain empirical evidence of a role for sexually antagonistic selection in extending recombination suppression, and antagonistic selection has been shown to be unlikely to account for the evolutionary strata observed on fungal mating-type chromosomes. We show here, by mathematical modeling and stochastic simulation, that recombination suppression on sex chromosomes and around supergenes can expand under a wide range of parameter values simply because it shelters recessive deleterious mutations, which are ubiquitous in genomes. Permanently heterozygous alleles, such as the male-determining allele in XY systems, protect linked chromosomal inversions against the expression of their recessive mutation load, leading to the successive accumulation of inversions around these alleles without antagonistic selection. Similar results were obtained with models assuming recombination-suppressing mechanisms other than chromosomal inversions and for supergenes other than sex chromosomes, including those without XY-like asymmetry, such as fungal mating-type chromosomes. However, inversions capturing a permanently heterozygous allele were found to be less likely to spread when the mutation load segregating in populations was lower (e.g., under large effective population sizes or low mutation rates). This may explain why sex chromosomes remain homomorphic in some organisms but are highly divergent in others. Here, we model a simple and testable hypothesis explaining the stepwise extensions of recombination suppression on sex chromosomes, mating-type chromosomes, and supergenes in general.
WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia

In cystic fibrosis (CF), reduced HCO3− secretion acidifies the airway surface liquid (ASL), and the acidic pH disrupts host defenses. Thus, understanding the control of ASL pH (pHASL) in CF may help identify novel targets and facilitate therapeutic development. In diverse epithelia, the WNK (with-no-lysine [K]) kinases coordinate HCO3− and Cl− transport, but their functions in airway epithelia are poorly understood. Here, we tested the hypothesis that WNK kinases regulate CF pHASL. In primary cultures of differentiated human airway epithelia, inhibiting WNK kinases acutely increased both CF and non-CF pHASL. This response was HCO3− dependent and involved downstream SPAK/OSR1 (Ste20/SPS1-related proline-alanine-rich protein kinase/oxidative stress responsive 1 kinase). Importantly, WNK inhibition enhanced key host defenses otherwise impaired in CF. Human airway epithelia expressed two WNK isoforms in secretory cells and ionocytes, and knockdown of either WNK1 or WNK2 increased CF pHASL. WNK inhibition decreased Cl− secretion and the response to bumetanide, an NKCC1 (sodium-potassium-chloride cotransporter 1) inhibitor. Surprisingly, bumetanide alone or basolateral Cl− substitution also alkalinized CF pHASL. These data suggest that WNK kinases influence the balance between transepithelial Cl− versus HCO3− secretion. Moreover, reducing basolateral Cl− entry may increase HCO3− secretion and raise pHASL, thereby improving CF host defenses.
Association between abnormal brain oscillations and cognitive performance in patients with bipolar disorder: Molecular mechanisms and clinical evidence

Brain oscillations have gained great attention in neuroscience during recent decades as functional building blocks of cognitive‐sensory processes. Research has shown that oscillations in “alpha,” “beta,” “gamma,” “delta,” and “theta” frequency windows are highly modified in brain pathology, including in patients with cognitive impairment like bipolar disorder (BD). The study of changes in brain oscillations can provide fundamental knowledge for exploring neurophysiological biomarkers in cognitive impairment. The present article reviews findings from the role and molecular basis of abnormal neural oscillation and synchronization in the symptoms of patients with BD. An overview of the results clearly demonstrates that, in cognitive‐sensory processes, resting and evoked/event‐related electroencephalogram (EEG) spectra in the delta, theta, alpha, beta, and gamma bands are abnormally changed in patients with BD showing psychotic features. Abnormal oscillations have been found to be associated with several neural dysfunctions and abnormalities contributing to BD, including abnormal GABAergic neurotransmission signaling, hippocampal cell discharge, abnormal hippocampal neurogenesis, impaired cadherin and synaptic contact‐based cell adhesion processes, extended lateral ventricles, decreased prefrontal cortical gray matter, and decreased hippocampal volume. Mechanistically, impairment in calcium voltage‐gated channel subunit alpha1 I, neurotrophic tyrosine receptor kinase proteins, genes involved in brain neurogenesis and synaptogenesis like WNT3 and ACTG2, genes involved in the cell adhesion process like CDH12 and DISC1, and gamma‐aminobutyric acid (GABA) signaling have been reported as the main molecular contributors to the abnormalities in resting‐state low‐frequency oscillations in BD patients. Findings also showed the association of impaired synaptic connections and disrupted membrane potential with abnormal beta/gamma oscillatory activity in patients with BD. Of note, the synaptic GABA neurotransmitter has been found to be a fundamental requirement for the occurrence of long‐distance synchronous gamma oscillations necessary for coordinating the activity of neural networks between various brain regions.
Reconstruction-Assisted Feature Encoding Network for Histologic Subtype Classification of Non-Small Cell Lung Cancer

Accurate histological subtype classification between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using computed tomography (CT) images is of great importance to assist clinicians in determining treatment and therapy plans for non-small cell lung cancer (NSCLC) patients. Although current deep learning approaches have achieved promising progress in this field, they are often difficult to capture efficient tumor representations due to inadequate training data, and in consequence show limited performance. In this study, we propose a novel and effective reconstruction-assisted feature encoding network (RAFENet) for histological subtype classification by leveraging an auxiliary image reconstruction task to enable extra guidance and regularization for enhanced tumor feature representations. Different from existing reconstruction-assisted methods that directly use generalizable features obtained from shared encoder for primary task, a dedicated task-aware encoding module is utilized in RAFENet to perform refinement of generalizable features. Specifically, a cascade of cross-level non-local blocks are introduced to progressively refine generalizable features at different levels with the aid of lower-level task-specific information, which can successfully learn multi-level task-specific features tailored to histological subtype classification. Moreover, in addition to widely adopted pixel-wise reconstruction loss, we introduce a powerful semantic consistency loss function to explicitly supervise the training of RAFENet, which combines both feature consistency loss and prediction consistency loss to ensure semantic invariance during image reconstruction. Extensive experimental results show that RAFENet effectively addresses the difficult issues that cannot be resolved by existing reconstruction-based methods and consistently outperforms other state-of-the-art methods on both public and in-house NSCLC datasets. Supplementary material is available at https://github.com/lhch1994/Rafenet_sup_material.
Purple acid phosphatase2 stimulates a futile cycle of lipid synthesis and degradation and mitigates the negative growth effects of triacylglycerol accumulation in vegetative tissues.

Storage lipids (mostly triacylglycerols, TAGs) serve as an important energy and carbon reserve in plants and hyperaccumulation of TAG in vegetative tissues can cause negative effects on plant growth. Purple acid phosphatase2 (PAP2) was shown previously to affect carbon metabolism and boost plant growth. However, the effects of PAP2 on lipid metabolism remain unknown. Here, we demonstrated PAP2 as a factor that can stimulate a futile cycle of fatty acid (FA) synthesis and degradation and mitigate negative growth effects associated with high levels of TAG accumulation in vegetative tissues. Constitutive expression of PAP2 in Arabidopsis thaliana enhanced both lipid synthesis and degradation in leaves and led to substantial increase in seed oil yield. Suppressing lipid degradation in a PAP2-overexpressing line by disrupting sugar-dependent1 (SDP1), a predominant TAG lipase, significantly elevated vegetative TAG content and improved plant growth. Diverting FAs from membrane lipids to TAGs in PAP2-overexpressing plants by constitutively expressing phospholipid:diacylglycerol acyltransferase1 (PDAT1) greatly increased TAG contents in vegetative tissues without compromising biomass yield. These results highlight the potential of combining PAP2 with TAG-promoting factors to enhance carbon assimilation, FA synthesis and allocation to TAGs for optimized plant growth and storage lipid accumulation in vegetative tissues.