Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Non-Coding Regulatory Elements in the Control of GR-Dependent Gene Expression

The glucocorticoid receptor (GR, also known as NR3C1) coordinates molecular responses to stress. It is a potent transcription activator and repressor that influences hundreds of genes. Enhancers are non-coding DNA regions outside of the core promoters that increase transcriptional activity via long-distance interactions. Active GR binds to pre-existing enhancer sites and recruits further factors, including EP300, a known transcriptional coactivator. However, it is not known how the timing of GR-binding-induced enhancer remodeling relates to transcriptional changes. Here we analyze data from the ENCODE project that provides ChIP-Seq and RNA-Seq data at distinct time points after dexamethasone exposure of human A549 epithelial-like cell line. This study aimed to investigate the temporal interplay between GR binding, enhancer remodeling, and gene expression. By investigating a single distal GR-binding site for each differentially upregulated gene, we show that transcriptional changes follow GR binding, and that the largest enhancer remodeling coincides in time with the highest gene expression changes. A detailed analysis of the time course showed that for upregulated genes, enhancer activation persists after gene expression changes settle. Moreover, genes with the largest change in EP300 binding showed the highest expression dynamics before the peak of EP300 recruitment. Overall, our results show that enhancer remodeling may not directly be driving gene expression dynamics but rather be a consequence of expression activation.
Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment

Asthma in children remains a significant public health challenge affecting 5–20% of children in Europe and is associated with increased morbidity and societal healthcare costs. The high variation in asthma incidence among countries may be attributed to differences in genetic susceptibility and environmental factors. This respiratory disorder is described as a heterogeneous syndrome of multiple clinical manifestations (phenotypes) with varying degrees of severity and airway hyper-responsiveness, which is based on patient symptoms, lung function and response to pharmacotherapy. However, an accurate diagnosis is often difficult due to diversities in clinical presentation. Therefore, identifying early diagnostic biomarkers and improving the monitoring of airway dysfunction and inflammatory through non-invasive methods are key goals in successful pediatric asthma management. Given that asthma is caused by the interaction between genes and environmental factors, an emerging approach, metabolomics—the systematic analysis of small molecules—can provide more insight into asthma pathophysiological mechanisms, enable the identification of early biomarkers and targeted personalized therapies, thus reducing disease burden and societal cost. The purpose of this review is to present evidence on the utility of metabolomics in pediatric asthma through the analysis of intermediate metabolites of biochemical pathways that involve carbohydrates, amino acids, lipids, organic acids and nucleotides and discuss their potential application in clinical practice. Also, current challenges on the integration of metabolomics in pediatric asthma management and needed next steps are critically discussed.
Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

Candida auris is an emerging and frequently multidrug-resistant pathogen against which the echinocandins are the preferred therapeutic option. We compared killing activities of anidulafungin, caspofungin, micafungin, and rezafungin against 13 isolates representing four C. auris clades (South Asian n = 3; East Asian n = 3; South African n = 3; South American n = 4, of which two were of environmental origin). Minimum inhibitory concentration MICs and killing kinetics in RPMI-1640 and RPMI-1640 plus 50% serum (50% serum) were determined. The four echinocandins were never fungicidal and induced large aggregates in RPMI-1640 and, less markedly, in 50% serum. Colony forming unit CFU decreases were found more consistently in 50% serum than in RPMI-1640. Isolates from the East Asian clade were killed at ≥1–≥ 4 mg/L with all echinocandins regardless of media. Anidulafungin and micafungin produced killing at peak drug serum concentration (8 mg/L) against environmental but not clinical isolates from the South American and the South African clades. Micafungin at ≥8 mg/L but not anidulafungin produced CFU decreases against the South Asian clade as well. In 50% serum, rezafungin at ≥1–≥ 8 mg/L produced killing against all four clades. The next generation echinocandin, rezafungin, showed the same or better activity at clinically attainable trough concentration regardless of media, compared with anidulafungin, caspofungin, and micafungin against all four tested C. auris clades.
STUDY OF ELECTRON TRANSFER THROUGH THE REDUCTASE DOMAIN OF NEURONAL NITRIC OXIDE SYNTHASE AND DEVELOPMENT OF BACTERIAL NITRIC OXIDE SYNTHASE INHIBITORS

Crystal structure of neuronal Nitric Oxide Synthase reductase (nNOSr) implies that large-scale domain motion is essential for electron transfer. However, the details are not well understood. To address this, we generated a functioning “Cys-lite” version of nNOSr and then replaced the nNOSr Glu and Arg residues with Cys in the FMN and FAD domains (CL5SS) in order to allow cross-domain disulfide bond formation under pH 9 or to cross-linking using bis-maleimides. Cross-linked CL5SS exhibited a ≥95% decrease in cytochrome c reductase activity and reduction of the disulfide bond restored the activities. The results demonstrate that a conformational equilibrium involving FMN domains motion is essential for the electron transfer. A graded lengthening of the bis-maleimide cross-linkers was associated with an increase in activity, thus helping to define the distance constraints for domain opening. Stopped-flow kinetic
Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.
A Detailed Characterisation of Appetite, Sensory Perceptional, and Eating-Behavioural Effects of COVID-19: Self-Reports from the Acute and Post-Acute Phase of Disease

Sensory perception alterations are common in relation to COVID-19 disease, but less is known about the characteristic of the sensory alterations, and how they associate with alterations in appetite and eating behaviour. The current study aims to investigate the acute and long-term effects of COVID-19 disease on (1) the desire for food, hunger, and satiety sensations; (2) smell, taste, and flavour perception; (3) meals and intake of food types; and (4) the frequency of commonly applied strategies to tackle potential changes in appetite and sensory perception. An online survey was conducted among Danish adults (n = 102) who had experienced changes in appetite, sensory perception, and/or food-related pleasure due to COVID-19 disease. Key results include appetite-altering effects at all times during the day when suffering from COVID-19 and often associated with impaired sensory function. Severe sensory perception alterations were found, namely, for the perception of taste, ageusia > hypogeusia > hypergeusia, and for the perception of smell, anosmia > parosmia > hyposmia > hyperosmia. Eating behavioural changes included alteration in quantitative and qualitative aspects of intake. The effects were, in general, more pronounced during the acute phase of disease than during the post-acute phase. The findings illustrate the complexity by which COVID-19 affects human appetite, sensory perception, and eating behaviour, but also point to strategies to cope with these changes.
Lateral Sagittal Versus Costoclavicular Approaches for Ultrasound-Guided Infraclavicular Brachial Plexus Block: A Comparison of Block Dynamics Through A Randomized Clinical Trial

Introduction In this study, our objective was to compare the lateral sagittal infraclavicular block (LS-ICB) with the costoclavicular infraclavicular block (CC-ICB) for ultrasound (US)-guided infraclavicular brachial plexus block in terms of block dynamics as well as patient and surgeon satisfaction levels. Methods A total of 100 patients, falling under the American Society of Anaesthesiologists (ASA) I-III categories, who were aged 18-65 years and scheduled for elective forearm and hand surgery were enrolled in the study. The patients were randomly allocated to receive a US-guided LS-ICB or US‑guided CC-ICB. The local anesthetic (LA) agent used (20-ml 0.5% bupivacaine) was identical in all subjects. The block performance time and the motor and sensory block onset times were determined to be the primary outcomes. Results The block performance time and the sensory block onset time were shorter in the CC-ICB group compared to the LS-ICB group [median (interquartile range): three (2.5-3.3) vs. two (1.5-2.3) minutes, p: <0.001; five (4.4-6) vs. four (3.8-6) minutes, p = 0.022, respectively]. The number of needle redirections was lower in the CC-ICB [three (2.7-4) vs. two (one to two) times, p: <0.001]. The motor block onset time and the motor-sensory block times were similar in both groups. There were more patients with a complete sensory blockade at five and 10 minutes in the CC-ICB group than in the LS-ICB group (30% vs. 12%, p = 0.027; 66% vs. 26%, p: <0.001, respectively). No complications were observed with regard to both techniques, and patient and surgeon satisfaction levels observed were similar for both groups. Conclusion Based on our findings, the CC approach provided a shorter performance time and a faster onset of the sensory block compared to the LS approach. However, no complications were reported with respect to either technique, and similar patient and surgeon satisfaction levels were observed.
Interventions to Promote Healthy Meals in Full-Service Restaurants and Canteens: A Systematic Review and Meta-Analysis

Out-of-home eating is increasing, but evidence about its healthiness is limited. The present systematic review and meta-analysis aimed to elucidate the effectiveness of full-service restaurant and canteen-based interventions in increasing the dietary intake, food availability, and food purchase of healthy meals. Studies from 2000–2020 were searched in Medline, Scopus, and Cochrane Library using the PRISMA checklist. A total of 35 randomized controlled trials (RCTs) and 6 non-RCTs were included in the systematic review and analyzed by outcome, intervention strategies, and settings (school, community, workplace). The meta-analysis included 16 RCTs (excluding non-RCTs for higher quality). For dietary intake, the included RCTs increased healthy foods (+0.20 servings/day; 0.12 to 0.29; p < 0.001) and decreased fat intake (−9.90 g/day; −12.61 to −7.19; p < 0.001), favoring the intervention group. For food availability, intervention schools reduced the risk of offering unhealthy menu items by 47% (RR 0.53; 0.34 to 0.85; p = 0.008). For food purchases, a systematic review showed that interventions could be partially effective in improving healthy foods. Lastly, restaurant- and canteen-based interventions improved the dietary intake of healthy foods, reduced fat intake, and increased the availability of healthy menus, mainly in schools. Higher-quality RCTs are needed to strengthen the results. Moreover, from our results, intervention strategy recommendations are provided.
The Effect of Rosemary (Rosmarinus officinalis) and Blackcurrant Extracts (Ribes nigrum) Supplementation on Performance Indices and Oxidative Stability of Chicken Broiler Meat

Simple Summary The common practice of supplementing broiler feeds with oils rich in omega-3 fatty acids to improve the ratio of omega-6 to omega-3 fatty acids in chicken muscles results in a reduced oxidative stability of the meat and accelerated intensity of lipid peroxidation during storage. This study evaluated the effects of commercial rosemary (RO) and blackcurrant (BC) extracts rich in polyphenolic antioxidants added to broiler diets on the oxidative stability of meat and chicken production parameters. In this study, 120 one-day-old male Hubbard Flex broiler chicks were randomly allocated to 5 experimental groups, and for 35 days, were fed control starter and grower diets or the same basal diets containing two concentrations (2.5 and 5 g/kg) of the RO or BC extracts. The inclusion of RO and BC in the birds’ diet had no significant effect on broiler weight gain, feed conversion ratio, or carcass characteristics. The enrichment of chicken diet with RO and BC did not affect the oxidative stability of chicken breast muscles, but reduced the malondialdehyde (MDA) formation in frozen thigh muscles. Abstract The effects of dietary supplementation with extracts of rosemary (RO) and blackcurrant (BC) on the performance indices and the oxidative stability of broiler meat were investigated during a 35-d experiment. For the experiment, 120 one-day-old male Hubbard Flex broiler chicks were randomly allocated to 5 experimental groups (control group and 4 treatments, each in 6 replications, 24 birds per group, 4 birds per replicate) and fed control starter and grower diets or basal diets containing two concentrations (2.5 and 5 g/kg) of the RO and BC extracts. Basic performance traits (body weight gain, feed intake, feed conversion) were recorded during the trial. At the end of the experiment, pectoral and thigh muscles were collected. Thiobarbituric acid (TBA) assays using the muscles samples were performed after 1 and 5 d of chilling (4 °C) and after 90 d of frozen storage (−18 °C). The inclusion of RO and BC in the birds’ diet had no significant effects on weight gain and feed conversion ratio of chickens, or on carcass characteristics, compared with control group. Enrichment of chicken diet with RO and BC did not affect the oxidative stability of chicken breast muscles, but the tested extracts significantly reduced the malondialdehyde (MDA) formation in frozen thigh muscles.
Green Leaf Volatile Confers Management of Late Blight Disease: A Green Vaccination in Potato

Yield losses of crops due to plant pathogens are a major threat in all agricultural systems. In view of environmental issues and legislative limitations for chemical crop protection products, the need to design new environmentally friendly disease management strategies has gained interest. Despite the unique capability of green leaf volatiles (GLVs) to suppress a broad spectrum of plant pathogens, their capacity to control the potato late-blight-causing agent Phytophthora infestans has not been well studied. This study addresses the potential role of the GLV Z-3-hexenyl acetate (Z-3-HAC) in decreasing the severity of late blight and the underlying gene-based evidence leading to this effect. Nine-week-old potato plants (Solanum tuberosum L.) were exposed to Z-3-HAC before they were inoculated with P. infestans genotypes at different time points. These pre-exposed potato plants exhibited slower disease development after infection with the highly pathogenic genotype of P. infestans (EU-13-A2) over time. Qualitative assessment showed that the exposed, infected plants possessed significantly lower sporulation intensity and disease severity compared to the control plants. Hypersensitive response (HR)-like symptoms were observed on the treated leaves when inoculated with different pathogen genotypes. No HR-like lesions were detected on the untreated leaves after infection. It was shown that the transcript levels of several defense-related genes, especially those that are involved in reactive oxygen species (ROS) production pathways were significantly expressed in plants at 48 and 72 h postexposure to the Z-3-HAC. The current work provides evidence on the role of Z-3-HAC in the increased protection of potato plants against late blight through plant immunity and offers new opportunities for the sustainable control of potato diseases.
Association Study of SLC6A4 (5-HTTLPR) Polymorphism and Its Promoter Methylation with Rehabilitation Outcome in Patients with Subacute Stroke

Recently it has been suggested that serotonin transporter (SLC6A4) and its 5HTTLPR polymorphism could be involved in post stroke recovery. Here, we characterized the methylation profile of two different CpG islands within the SLC6A4 promoter region in the whole blood of 50 patients with subacute stroke before and after a six-week rehabilitation treatment. These patients were genotyped for 5HTTLPR polymorphism identifying patients on the basis of short (S) and L (L) alleles: 17 patients LL, 22 patients LS and 11 patients SS. At baseline, all CpG sites for both CpG islands displayed a heterogeneous methylation percentage that were not influenced by the different genotypes. After rehabilitation, we found a significant variation in the methylation levels (increase/decrease) in the specific CpG sites of both CpG islands. The statistical analysis showed a significant relationship between the LL, LS and SS alleles and the outcome of the rehabilitation intervention (χ2 (2,50) = 6.395, p = 0.041). Specifically, we found a significant difference between patients with or without a favorable outcome in the LL (11.1% with a favorable outcome) and in the SS (54.4% with a favorable outcome) groups. Our data suggest that 5-HTTLPR polymorphisms and SLC6A4 promoter methylation may be employed as a non-invasive biological marker of recovery in patients with stroke undergoing rehabilitation.
The Relationships between Sleep and Mental and Physical Health of Chinese Elderly: Exploring the Mediating Roles of Diet and Physical Activity

Sleep quality, diet quality, and physical activity are significant factors influencing physical and mental health. However, few studies have explored their underlying mechanisms, especially among the elderly population in East Asia, where people have food culture and lifestyles distinct from those living in Western countries. Therefore, the current study aimed to explore the relationships among sleep quality, diet quality, physical activity, and physical and mental health in a Chinese elderly sample. Sleep quality, diet quality, physical activity, physical health, and mental health were investigated among 313 Chinese elderly (aged 51–92 years, M = 67.90, SD = 7.94). Mediation analysis was used to examine the empirical model based on previous theories and literature. Close positive relationships were observed between all factors investigated (r = 0.22~0.73, p < 0.001). The relationships between sleep quality and physical and mental health were partially mediated by diet quality and physical activity. In clinical interventions, sleep quality, diet quality, and physical activity can be targeted to improve physical and mental health among the older adult populations.
Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment

Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D’s role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs and systems in the human body. This growing interest is mostly due to the evidence that modest-to-severe vitamin D deficiency is widely prevalent around the world. There is broad agreement that optimal vitamin D status is necessary for bones, muscles, and one’s general health, as well as for the efficacy of antiresorptive and anabolic bone-forming treatments. Food supplementation with vitamin D, or the use of vitamin D supplements, are current strategies to improve vitamin D levels and treat deficiency. This article reviews consolidated and emerging concepts about vitamin D/hormone D metabolism, food sources, deficiency, as well as the different vitamin D supplements available, and current recommendations on the proper use of these compounds.
Efficacy of Mechanical Thrombectomy using Penumbra ACETM Aspiration Catheter Compared to Stent Retriever SolitaireTM FR in Patients with Acute Ischemic Stroke

Background: Mechanical thrombectomy is the standard therapy in patients with acute ischemic stroke (AIS). The primary aim of our study was to compare the procedural efficacy of the direct aspiration technique, using Penumbra ACETM aspiration catheter, and the stent retriever technique, with a SolitaireTM FR stent. Secondarily, we investigated treatment-dependent and treatment-independent factors that predict a good clinical outcome. Methods: We analyzed our series of mechanical thrombectomies using a SolitaireTM FR stent and a Penumbra ACETM catheter. The clinical and radiographic data of 76 patients were retrospectively reviewed. Using binary logistic regression, we looked for the predictors of a good clinical outcome. Results: In the Penumbra ACETM group we achieved significantly higher rates of complete vessel recanalization with lower device passage counts, shorter recanalization times, shorter procedure times and shorter fluoroscopy times (p < 0.001) compared to the SolitaireTM FR group. We observed no significant difference in good clinical outcomes (52.4% vs. 56.4%, p = 0.756). Predictors of a good clinical outcome were lower initial NIHSS scores, pial arterial collateralization on admission head CT angiography scan, shorter recanalization times and device passage counts. Conclusions: The aspiration technique using Penumbra ACETM catheter is comparable to the stent retriever technique with SolitaireTM FR regarding clinical outcomes.