Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Membrane Potential on Entry of Lactoferricin B-Derived 6-Residue Antimicrobial Peptide into Single Escherichia coli Cells and Lipid Vesicles

Bacterial cells have a membrane potential (Δφ), but the effect of Δφ on the action of cell-penetrating peptide-type antimicrobial peptides (AMPs) is not clear. Here, we investigated the effect of Δφ on the action of a fluorescent probe-labeled AMP derived from lactoferricin B, Rh-LfcinB(4–9). ABSTRACT An antimicrobial peptide (AMP) derived from lactoferricin B, LfcinB(4–9) (RRWQWR), and lissamine rhodamine B red-labeled peptide [Rh-LfcinB(4–9)] exhibit strong antimicrobial activities, and they can enter Escherichia coli cells without damaging the cell membranes. Thus, these peptides are cell-penetrating peptide (CPP)-type AMPs. In this study, to elucidate the effect of the membrane potential (Δφ) on the action of the CPP-type AMP Rh-LfcinB(4–9), we investigated the interactions of Rh-LfcinB(4–9) with single E. coli cells and spheroplasts containing calcein in the cytosol using confocal laser scanning microscopy. At low peptide concentrations, Rh-LfcinB(4–9) entered the cytosol of single E. coli cells and spheroplasts without damaging the cell membranes, and the H+ ionophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) suppressed its entry. Studies using the time-kill method indicate that these low concentrations of peptide exhibit antimicrobial activity, but CCCP inhibits this activity. Next, we investigated the effect of Δφ on the interaction of Rh-LfcinB(4–9) with single giant unilamellar vesicles (GUVs) comprising E. coli polar lipid extracts and containing a fluorescent probe, Alexa Fluor 647 hydrazide. At low concentrations (0.2 to 0.5 μM), Rh-LfcinB(4–9) showed significant entry into the single GUV lumen without pore formation in the presence of Δφ. The fraction of entry of the peptide increased with increasing negative membrane potential, indicating that the rate of peptide entry into the GUV lumen increased with increasing negative membrane potential. These results indicate that Δφ enhances the entry of Rh-LfcinB(4–9) into single E. coli cells, spheroplasts, and GUVs and its antimicrobial activity. IMPORTANCE Bacterial cells have a membrane potential (Δφ), but the effect of Δφ on the action of cell-penetrating peptide-type antimicrobial peptides (AMPs) is not clear. Here, we investigated the effect of Δφ on the action of a fluorescent probe-labeled AMP derived from lactoferricin B, Rh-LfcinB(4–9). At low peptide concentrations, Rh-LfcinB(4–9) enters the cytosol of Escherichia coli cells and spheroplasts without damaging their cell membrane, but a protonophore suppresses this entry and its antimicrobial activity. The rate of entry of Rh-LfcinB(4–9) into the giant unilamellar vesicles (GUVs) comprising E. coli lipids without pore formation increases with increasing Δφ. These results indicate that Δφ enhances the antimicrobial activity of Rh-LfcinB(4–9) and, hence, LfcinB(4–9) by increasing the rate of their entry into the cytosol.
Current progress, challenges, and future prospects of testis organoids†

Abstract Spermatogenic failure is believed to be a major cause of male infertility. The establishment of a testis organoid model would facilitate the study of such pathological mechanisms and open the possibility of male fertility preservation. Because of the complex structures and cellular events occurring within the testis, the establishment of a compartmentalized testis organoid with a complete spermatogenic cycle remains a challenge in all species. Since the late 20th century, a great variety of scaffold-based and scaffold-free testis cell culture systems have been established to recapitulate de novo testis organogenesis and in vitro spermatogenesis. The utilization of the hydrogel scaffolds provides a 3D microenvironment for testis cell growth and development, facilitating the reconstruction of de novo testis tissue-like structures and spermatogenic differentiation. Using a combination of different strategies, including the use of various scaffolding biomaterials, the incorporation of the living cells with high self-assembling capacity, and the integration of the advanced fabrication techniques, a scaffold-based testis organoid with a compartmentalized structure that supports in vitro spermatogenesis may be achieved. This article briefly reviews the current progress in the development of scaffold-based testis organoids while focusing on the scaffolding biomaterials (hydrogels), cell sources, and scaffolding approaches. Key challenges in current organoid studies are also discussed along with recommendations for future research.
Potential Ecological and Human Health Risks of Heavy Metals in Soils in Selected Copper Mining Areas—A Case Study: The Bor Area

Surface soil samples were collected near the Open Pit Bor (S1) and Open Pit Cerovo (S2), a grassland along the Borska Reka River (S3) and an unpolluted garden near Slatina village (reference site). Spontaneous plants (dandelion, nettle, coltsfoot, and creeping buttercup) and vegetables (onion, garlic, carrot, parsley, celery, potatoes, dill, and sorrel) were obtained from the former three sites and the reference site, respectively. The samples were analyzed for Zn, Cu, Fe, Mn, and Pb via FAAS. Pollution indices indicated low-to-moderate soil contamination at sites S1, S2, and S3. Cu was the main contaminant of environmental concern, being above the maximum admitted concentration at site S1. Metal levels in spontaneous plants were below phytotoxic levels. Cu content of leafy vegetables and celery roots and Pb content of most vegetables were not safe for human consumption. Metal concentrations tended to be significantly lower in plants than in soils, with only Cu occurring at significantly elevated levels in celery roots and sorrel leaves. Non-carcinogenic risk assessment showed that consumption of carrot roots and especially celery roots grown on unpolluted soils from the Bor area might pose long-term health risks for females and males, with the main contributors being Cu and Fe.
Population Genomics Insights into the First Wave of COVID-19

Full-genome-sequence computational analyses of the SARS-coronavirus (CoV)-2 genomes allow us to understand the evolutionary events and adaptability mechanisms. We used population genetics analyses on human SARS-CoV-2 genomes available on 2 April 2020 to infer the mutation rate and plausible recombination events between the Betacoronavirus genomes in nonhuman hosts that may have contributed to the evolution of SARS-CoV-2. Furthermore, we localized the targets of recent and strong, positive selection during the first pandemic wave. The genomic regions that appear to be under positive selection are largely co-localized with regions in which recombination from nonhuman hosts took place. Our results suggest that the pangolin coronavirus genome may have contributed to the SARS-CoV-2 genome by recombination with the bat coronavirus genome. However, we find evidence for additional recombination events that involve coronavirus genomes from other hosts, i.e., hedgehogs and sparrows. We further infer that recombination may have recently occurred within human hosts. Finally, we estimate the parameters of a demographic scenario involving an exponential growth of the size of the SARS-CoV-2 populations that have infected European, Asian, and Northern American cohorts, and we demonstrate that a rapid exponential growth in population size from the first wave can support the observed polymorphism patterns in SARS-CoV-2 genomes.
Psychological Interventions to Improve Sleep in Young Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials

ABSTRACT Introduction The effects of impaired sleep on the wellbeing of young adults are profound, and the adverse outcomes for mental health are well documented in the research literature. Objective This systematic review and meta-analysis aimed to identify, summarize, and synthesize the available evidence from randomized-controlled trials (RCTs) investigating psychological interventions aimed at improving sleep and related secondary outcomes such as anxiety and depression in healthy young adults. Method Nine electronic databases (Cochrane Central Registry of Controlled Trials [CENTRAL], PubMed, Scopus, PsycNET, CINHAL, INFORMIT, Web of Science [Science and Social Citation Index], OpenSigle and EMBASE) were searched, returning 54 full-text papers for assessment, with 13 studies meeting inclusion criteria for the meta-analysis. Results A random effects meta-analysis showed that the combined effect of all interventions was moderate (ES = −0.53, 95% CIs [- 0.69, −0.36], p < .01), reflecting the efficacy of psychological interventions at improving sleep scores at post-intervention. Subgroup analyses of individual interventions showed that cognitive-behavioral interventions improved sleep (ES = −0.67, 95% CIs [−0.77, −0.57], p < .01) and secondary outcomes for anxiety (ES = −0.35, 95% CIs [−0.56, −0.15], p < .01) and depression (ES = −0.41, 95% CIs [−0.70, −0.13], p < .01) at post-intervention. Conclusion The results of the current review support the implementation of cognitive and behavioral interventions for sleep among young adults experiencing both sleep and comorbid mental health problems.
About adverse effects of high‐dose vitamin D supplementation on volumetric bone density

This report is of analyses on older healthy community dwellers from a previous randomized controlled trial (RCT), reported in detail elsewhere, that found adverse effects of higher doses of supplemental vitamin D3 (4000 or 10,000 IU/d), whereas the further analyses in the present report suggest adverse effects overall in subjects taking these supplemental intakes that were more severe in women than in men. There are several points, however, about the present analyses that would be useful to clarify because these findings, if confirmed, could lead to major changes in the advice provided on vitamin D intakes to older people for maintenance of their bone health. (i) Was the power adequate for the various analyses made on and between the smaller subgroups by dosage and, within each dosage group, by sex? (ii) Can the authors confirm that the data used for examining arithmetic means was normally distributed for each data subgroup as a whole or whether this was after exclusion of what look like outliers? (iii) Can the authors explain why subjects without deficiency were excluded from the original study and therefore from these analyses (as defined by serum 25(OH)D values <30 nmol/L) because unrecognized deficiency remains common globally, is often more marked in older than in younger people, and because people with deficiency at a level known to affect bone health adversely could be expected to be more likely to show beneficial effects of supplementation on bone health than those with initial 25(OH)D values >30 nmol/L? (iv) Because RCTs often show evidence of benefit only once certain levels of serum 25(OH)D are achieved, did any of the measures of bone health used in this study show trends for any benefits of supplementation across the range of baseline D status, possibly before a threshold for adverse effects was reached, with either 400, 4000, or 10,000 IU of vitamin D daily, when the measures used to assess bone heath are looked at against the baseline 25(OH)D values, which ranged from 30 to 125 nmol/L? Similarly, were there any differences in such findings, if present, between these findings for bone health indices with achieved D status between the three supplemented groups? (v) If the data analyses queried in (iv) happen to suggest either optimal 25(OH)D values for achieved status for bone health and/or threshold 25(OH)D values above which adverse effects appear in bone health indices, it would be useful to know if those threshold levels were the same in men and women for any, or all three, of the supplemental doses used because this would be important information to seek to validate for the formulation of advice to older adults on bone health generally and for direct patient care.
Exogenous NAD+ Postpones the D-Gal-Induced Senescence of Bone Marrow-Derived Mesenchymal Stem Cells via Sirt1 Signaling

Cell senescence is accompanied by decreased nicotinamide adenine dinucleotide (NAD+) levels; however, whether exogenous NAD+ affects bone marrow-derived mesenchymal stem cells (BMSCs) senescence and the involved mechanisms is still unclear. Here, we find that exogenous NAD+ replenishment significantly postpones BMSC senescence induced by D-galactose (D-gal). It is also shown that exogenous NAD+ leads to increased intracellular NAD+ levels and reduced intracellular reactive oxygen species in senescent BMSCs here. Further investigation showed that exogenous NAD+ weakened BMSC senescence by increasing Sirtuin 1 (Sirt1) expression. Moreover, exogenous NAD+ reduced senescence-associated-β-galactosidase activity, and downregulated poly (ADP-ribose) polymerase 1 expression. In addition, the reduced expression of Sirt1 by small interfering RNA abolished the beneficial effects of exogenous NAD+ in terms of postponing BMSCs senescence induced by D-gal. Taken together, our results indicate that exogenous NAD+ could postpone D-gal-induced BMSC senescence through Sirt1 signaling, providing a potential method for obtaining high quality BMSCs to support their research and clinical application.
Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation

Neuroinflammation is a common feature in neurodegenerative diseases, modulated by the Alzheimer's disease risk factor, apolipoprotein E (APOE). In the brain, apoE protein is synthesized by astrocytes and microglia. We examined primary cultures of astrocytes and microglia from human APOE (E2, E3, and E4) targeted‐replacement mice. Astrocytes secreted two species of apoE, whereas cellular apoE consisted of only one. Both forms of secreted astrocytic apoE were bound during glycoprotein isolation, and enzymatic removal of glycans produced a convergence of the two forms of apoE to a single form; thus, the two species of astrocyte‐secreted apoE are differentially glycosylated. Microglia released only a single species of apoE, while cellular apoE consisted of two forms; the secreted apoE and one of the two forms of cellular apoE were glycosylated. We treated the primary glia with either endogenous (TNFα) or exogenous (LPS) pro‐inflammatory stimuli. While LPS had no effect on astrocytic apoE, APOE2, and APOE3 microglia increased release of apoE; APOE4 microglia showed no effect. APOE4 microglia showed higher baseline secretion of TNFα compared to APOE2 and APOE3 microglia. TNFα treatment reduced the secretion and cellular expression of apoE only in APOE4 astrocytes. The patterns of apoE species produced by astrocytes and microglia were not affected by inflammation. No changes in APOE mRNA were observed in astrocytes after both treatments. Together, our data demonstrate that astrocytes and microglia differentially express and secrete glycosylated forms of apoE and that APOE4 astrocytes and microglia are deficient in immunomodulation compared to APOE2 and APOE3.
Towards an Optimized Fetal DHA Accretion: Differences on Maternal DHA Supplementation Using Phospholipids vs. Triglycerides during Pregnancy in Different Models

Docosahexaenoic acid (DHA) supplementation during pregnancy has been recommended by several health organizations due to its role in neural, visual, and cognitive development. There are several fat sources available on the market for the manufacture of these dietary supplements with DHA. These fat sources differ in the lipid structure in which DHA is esterified, mainly phospholipids (PL) and triglycerides (TG) molecules. The supplementation of DHA in the form of PL or TG during pregnancy can lead to controversial results depending on the animal model, physiological status and the fat sources utilized. The intestinal digestion, placental uptake, and fetal accretion of DHA may vary depending on the lipid source of DHA ingested by the mother. The form of DHA used in maternal supplementation that would provide an optimal DHA accretion for fetal brain development, based on the available data obtained most of them from different animal models, indicates no consistent differences in fetal accretion when DHA is provided as TG or PL. Other related lipid species are under evaluation, e.g., lyso-phospholipids, with promising results to improve DHA bioavailability although more studies are needed. In this review, the evidence on DHA bioavailability and accumulation in both maternal and fetal tissues after the administration of DHA supplementation during pregnancy in the form of PL or TG in different models is summarized.
Geographic Distribution, Genetic Variability and Biological Properties of Rice Orange Leaf Phytoplasma in Southeast Asia

Rice orange leaf phytoplasma (ROLP) causes clear orange to yellowish leaf discoloration and severe stunting in rice seedlings. The ecological and biological characteristics of ROLP are largely unknown because the disease has not widely caused serious problems in rice cultivated areas, thereby leading to the low accumulation of research data. However, in the past decade, the disease became a threat to rice production, particularly in South China and India; it has also been recognised in other Asian countries, such as Vietnam, Thailand and the Philippines. Here, we observed the occurrence of ROLP in paddies of the Southeast Asian counties (Cambodia, Vietnam and the Philippines) and found that the isolates in the Philippines and Vietnam were monophyletic, while those in India, Thailand and Cambodia were more diverse, suggesting their potential origins. In Cambodia, it was revealed that following polymerase chain reaction (PCR) detection, the known ROLP-insect vectors, N. virescens Distant and Recilia dorsalis Motchulsky, were ROLP-positive, indicating their roles in pathogen dispersal. Moreover, fluorescent and scanning electron microscopy revealed the intensive accumulation of the phytoplasma in phloem tissues and massive accumulation of storage starch in vascular bundle sheath and parenchyma. Altogether, this study illustrated the genetic variability of global ROLP isolates and the pathogen’s biological impact on rice tissue.
Cost-effectiveness analyses of targeted therapy and immunotherapy for advanced non-small cell lung cancer in the United States: a systematic review

ABSTRACT Introduction: Mutation-targeting and immuno-oncology drugs are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). Cost-effectiveness analyses (CEA) of these drugs have been conducted using various analytical methods and cost-effectiveness thresholds. This systematic review provides a comprehensive summary of the available evidence. Area covered: PubMed, Embase, and Cochrane Library were used to select for CEA of targeted therapies for NSCLC in the United States published between 2008 and 2020. Among the 28 included studies, a majority were published from 2017 to 2020 (n = 18) and more than half targeted non-squamous NSCLC (n = 15). The most frequently evaluated therapy was pembrolizumab (n = 11), followed by bevacizumab (n = 8) and erlotinib (n = 4). After 2009, all included studies applied $100,000 or more thresholds. Thresholds of studies supported by industry (median = $150,000) were more distributed than those of studies supported by nonprofits (median = $100,000). Expert commentary: Medications of interest have changed and are individualized to particular mutations. The cost-effectiveness thresholds varied among sponsors but generally trended to increase over time. This review provides an overview of the available cost-effectiveness findings for stakeholders and contributes to evidence-based practice.
The explanatory role of fatigue severity in the relation between COVID-19 perceived stress and depression, anxiety, and panic severity

ABSTRACT The COVID-19 pandemic has had an adverse effect on anxiety and depression symptoms and disorders in the United States and worldwide. As such, there is considerable interest in better understanding the relationship between COVID-19 and anxiety and depressive disorders. Although individual differences in perceived stress have shown to be related to anxiety and depression in non-COVID-19 work, research has not examined potential factors underlying this relation in the context of COVID-19. Fatigue severity may be a promising mechanistic construct for perceived stress and anxiety and depression relations, as some work has found that perceived stress may predict elevated fatigue symptoms. As such, the current study sought to examine the potential explanatory role of fatigue severity in the relation between COVID-19 specific perceived stress and depression, anxiety, and panic symptoms among 563 adults (41.9% female, Mage = 38.26 years, SD = 12.15). Results suggested that COVID-19 perceived stress, via fatigue severity, significantly predicted depression, anxiety, and panic symptoms. These results provide initial empirical support for the role of fatigue severity in the relation between COVID-19 perceived stress and depression, anxiety, and panic symptoms. Future work would benefit from using longitudinal data to evaluate the current model.
A comprehensive review on the antidiabetic activity of flavonoids targeting PTP1B and DPP-4: a structure-activity relationship analysis

Abstract Type 2 diabetes (T2D) is an expanding global health problem, resulting from defects in insulin secretion and/or insulin resistance. In the past few years, both protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4), as well as their role in T2D, have attracted the attention of the scientific community. PTP1B plays an important role in insulin resistance and is currently one of the most promising targets for the treatment of T2D, since no available PTP1B inhibitors were still approved. DPP-4 inhibitors are among the most recent agents used in the treatment of T2D (although its use has been associated with possible cardiovascular adverse events). The antidiabetic properties of flavonoids are well-recognized, and include inhibitory effects on the above enzymes, although hitherto not therapeutically explored. In the present study, a comprehensive review of the literature of both synthetic and natural isolated flavonoids as inhibitors of PTP1B and DPP-4 activities is made, including their type of inhibition and experimental conditions, and structure-activity relationship, covering a total of 351 compounds. We intend to provide the most favorable chemical features of flavonoids for the inhibition of PTP1B and DPP-4, gathering information for the future development of compounds with improved potential as T2D therapeutic agents.