Miracle-dz/UniFAR-FTUs huggingface dataset:
Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B

Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. ABSTRACT Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. LF was broadly and consistently active against all yeast species tested (MICs, 8 to 64 μg/ml), with the extent of activity being strongly affected by iron saturation. LF was synergistic with amphotericin B (AMB) against 19 out of 22 yeast species tested, and synergy was unaffected by iron saturation but was affected by the extent of LF digestion. LF-AMB combination therapy significantly prolonged the survival of Galleria mellonella wax moth larvae infected with Candida albicans or Cryptococcus neoformans and decreased the fungal burden 12- to 25-fold. Evidence that LF directly interacts with the fungal cell surface was seen via scanning electron microscopy, which showed pore formation, hyphal thinning, and major cell collapse in response to LF-AMB synergy. Important virulence mechanisms were disrupted by LF-AMB treatment, which significantly prevented biofilms in C. albicans and C. glabrata, inhibited hyphal development in C. albicans, and reduced cell and capsule size and phenotypic diversity in Cryptococcus. Our results demonstrate the potential of LF-AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with the synergy being attributed to the presence of one or more LF peptides.
Insights into the Structure, Function, and Dynamics of the Bacterial Cytokinetic FtsZ-Ring.

The FtsZ protein is a highly conserved bacterial tubulin homolog. In vivo, the functional form of FtsZ is the polymeric, ring-like structure (Z-ring) assembled at the future division site during cell division. While it is clear that the Z-ring plays an essential role in orchestrating cytokinesis, precisely what its functions are and how these functions are achieved remain elusive. In this article, we review what we have learned during the past decade about the Z-ring's structure, function, and dynamics, with a particular focus on insights generated by recent high-resolution imaging and single-molecule analyses. We suggest that the major function of the Z-ring is to govern nascent cell pole morphogenesis by directing the spatiotemporal distribution of septal cell wall remodeling enzymes through the Z-ring's GTP hydrolysis-dependent treadmilling dynamics. In this role, FtsZ functions in cell division as the counterpart of the cell shape-determining actin homolog MreB in cell elongation. Expected final online publication date for the Annual Review of Biophysics, Volume 49 is May 6, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
The Forgotten Agenda of Wasting in Southeast Asia: Burden, Determinants and Overlap with Stunting: A Review of Nationally Representative Cross-Sectional Demographic and Health Surveys in Six Countries

Childhood wasting is among the most prevalent forms of undernutrition globally. The Southeast Asia region is home to many wasted children, but wasting is not recognized as a public health problem and its epidemiology is yet to be fully examined. This analysis aimed to determine the burden of wasting, its predictors, and the level of wasting and stunting concurrence. Datasets from Demographic and Health Surveys and Multiple Indicator Cluster Surveys in six countries in the region were analyzed. The pooled weighted prevalence for wasting and concurrent wasting and stunting among children 0–59 months in the six countries was 8.9%, 95% CI (8.0–9.9) and 1.6%, 95% CI (1.5–1.8), respectively. This prevalence is approximately 12-fold higher than the 0.7% prevalence of high-income countries; and translated into an absolute number of 1,088,747 children affected by wasting and 272,563 concurrent wasting and stunting. Wasting prevalence was 50 percent higher in the 0–23-month age group. Predictors for wasting included source of drinking water, wealth index, urban residence, child’s age and history of illness and mother’s body mass index. In conclusion, our analysis showed that wasting is a serious public health problem in the region that should be addressed urgently using both preventive and curative approaches.
Cinnamomum verum Bark Extract Mediated Green Synthesis of ZnO Nanoparticles and Their Antibacterial Potentiality

Cinnamomum verum plant extract mediated propellant chemistry route was used for the green synthesis of zinc oxide nanoparticles. Prepared samples were confirmed for their nano regime using advanced characterization techniques such as powder X-ray diffraction and microscopic techniques such as scanning electron microscopy and transmission electron microscopy. The energy band gap of the green synthesized zinc oxide (ZnO)-nanoparticles (NPs) were found between 3.25–3.28 eV. Fourier transmission infrared spectroscopy shows the presence of Zn-O bond within the wave number of 500 cm−1. SEM images show the specific agglomeration of particles which was also confirmed by TEM studies. The green synthesized ZnO-NPs inhibited the growth of Escherichia coli and Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 125 µg mL−1 and 62.5 µg mL−1, respectively. The results indicate the prepared ZnO-NPs can be used as a potential antimicrobial agent against harmful pathogens.
The operating room as a learning arena: Nurse anaesthetist and student nurse anaesthetist perceptions.

AIM The study objective was to examine which competencies mentors and student nurse anaesthetists perceive as important in a clinical anaesthesia education practice. BACKGROUND Mentoring during clinical placement in the operating room can be challenging from the viewpoint of both a nurse anaesthetist and their students. The operating room is a work environment with many restrictions, and the nurse anaesthetist's work requires prompt decisions and actions. Simultaneously, the mentor is tasked with guiding and supporting the student. METHOD A qualitative approach including two focus group interviews was used. The analysis was conducted using systematic text condensation. The COREQ checklist for qualitative studies was applied. RESULT The analysis yielded two main categories, including two sub-categories for each. The first, "Mentoring in the operating room", contained sub-categories "Application of knowledge and expectations" and "Mentoring experiences", and the second, "Creating a good climate for learning", contained sub-categories "Impact on mentoring: human factors" and "Impact on mentoring: obstacle factors. " The mentor's knowledge of human relationships and learning strategies emerged as an important factor with the potential to influence the students' learning and self-confidence. Another valuable consideration was the ability to give constructive feedback, from the perspective of both. However, production pressure was a negative factor for effective knowledge transition. CONCLUSIONS The ability to give constructive feedback and having an awareness of one's own attitude - which should ideally be positive and inclusive - are crucial mentoring skills. Mutual expectations must be clearly communicated before the clinical placement period, including learning assumptions, a progression plan and learning outcomes. This will facilitate the planning and help to direct the optimal course of learning. IMPLICATIONS FOR CLINICAL PRACTICE This study highlights that an awareness of the student's vulnerability as well as the mentor's pedagogical competence and learning strategy are crucial factors to take into account.
Cu2+-based distance measurements by pulsed EPR provide distance constraints for DNA backbone conformations in solution

Abstract Electron paramagnetic resonance (EPR) has become an important tool to probe conformational changes in nucleic acids. An array of EPR labels for nucleic acids are available, but they often come at the cost of long tethers, are dependent on the presence of a particular nucleotide or can be placed only at the termini. Site directed incorporation of Cu2+-chelated to a ligand, 2,2′dipicolylamine (DPA) is potentially an attractive strategy for site-specific, nucleotide independent Cu2+-labelling in DNA. To fully understand the potential of this label, we undertook a systematic and detailed analysis of the Cu2+-DPA motif using EPR and molecular dynamics (MD) simulations. We used continuous wave EPR experiments to characterize Cu2+ binding to DPA as well as optimize Cu2+ loading conditions. We performed double electron-electron resonance (DEER) experiments at two frequencies to elucidate orientational selectivity effects. Furthermore, comparison of DEER and MD simulated distance distributions reveal a remarkable agreement in the most probable distances. The results illustrate the efficacy of the Cu2+-DPA in reporting on DNA backbone conformations for sufficiently long base pair separations. This labelling strategy can serve as an important tool for probing conformational changes in DNA upon interaction with other macromolecules.
A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks

This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p–dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival. Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. Significance: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p–dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.
Clinical and laboratory characteristics of clozapine-treated patients with schizophrenia referred to a national immunodeficiency clinic reveals a B-cell signature resembling common variable immunodeficiency (CVID)

Aims An association between antibody deficiency and clozapine use in individuals with schizophrenia has recently been reported. We hypothesised that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns. Methods Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunological features for individuals with diagnosis of schizophrenia-like illness. Results 1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizoaffective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI: 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT. Conclusions Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency common variable immunodeficiency, however appears reversible on drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group.
Shift Work and Prostate Cancer: An Updated Systematic Review and Meta-Analysis

The International Agency of Research in Cancer (IARC) has recently confirmed shift work as a type 2A carcinogen. The results presented in published epidemiological studies regarding prostate cancer are inconsistent and the association remains controversial. The aims of this study were: (a) to investigate the possible association between shift work and prostate cancer incidence, identifying possible sources of heterogeneity; and (b) to analyze the potential effect of publication bias. A search for cohort and case-control studies published from January 1980 to November 2019 was conducted. The quality of the articles was assessed using the Newcastle–Ottawa Scale. Pooled OR were calculated using random-effects models. Heterogeneity was evaluated using Cochran’s Q test and data were stratified by potential sources of heterogeneity. Publication bias was analyzed. Eighteen studies were included. No association was found between rotating/night-shift work and prostate cancer, pooled OR 1.07 (95%CI 0.99 to 1.15), I2 = 45.7%, p = 0.016. Heterogeneity was eliminated when only cohort studies (pooled OR 1.03; 95%CI 0.96 to 1.10; I2 = 18.9%, p = 0.264) or high-quality studies (pooled OR 0.99; 95%CI 0.89 to 1.08; I2 = 0.0%, p = 0.571) were considered. A publication bias was detected. An association between shift work and prostate cancer cannot be confirmed with the available current data. Future analytical studies assessing more objective homogeneous exposure variables still seem necessary.
Targeting Mitochondrial Calcium Uptake with the Natural Flavonol Kaempferol, to Promote Metabolism/Secretion Coupling in Pancreatic β-cells

Pancreatic β-cells secrete insulin to lower blood glucose, following a meal. Maintenance of β-cell function is essential to preventing type 2 diabetes. In pancreatic β-cells, mitochondrial matrix calcium is an activating signal for insulin secretion. Recently, the molecular identity of the mitochondrial calcium uniporter (MCU), the transporter that mediates mitochondrial calcium uptake, was revealed. Its role in pancreatic β-cell signal transduction modulation was clarified, opening new perspectives for intervention. Here, we investigated the effects of a mitochondrial Ca2+-targeted nutritional intervention strategy on metabolism/secretion coupling, in a model of pancreatic insulin-secreting cells (INS-1E). Acute treatment of INS-1E cells with the natural plant flavonoid and MCU activator kaempferol, at a low micromolar range, increased mitochondrial calcium rise during glucose stimulation, without affecting the expression level of the MCU and with no cytotoxicity. Enhanced mitochondrial calcium rises potentiated glucose-induced insulin secretion. Conversely, the MCU inhibitor mitoxantrone inhibited mitochondrial Ca2+ uptake and prevented both glucose-induced insulin secretion and kaempferol-potentiated effects. The kaempferol-dependent potentiation of insulin secretion was finally validated in a model of a standardized pancreatic human islet. We conclude that the plant product kaempferol activates metabolism/secretion coupling in insulin-secreting cells by modulating mitochondrial calcium uptake.
Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials

The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.
Leveraging the experience of stressors: the role of adaptive systematic self-reflection

ABSTRACT Background: To date, little attention has been paid to the processes by which resilience is developed, and how the likelihood of a resilient outcome may be enhanced over the life course. Objective: This study investigates the potential for adaptive systematic self-reflection to support the development of situation resilience via stressor exposure. Design: An experimental randomized controlled design was conducted. Participants were randomly assigned to either the Systematic Self-reflection intervention (n = 61) or disengagement control group (n = 60). Method: Participants were 121 university students (female = 68%) ranging in age from 18 to 56 years. Participants experienced two psychosocial stressors and completed a baseline survey, a second survey occurred post-stressor 1, and a third post-stressor 2. Salivary cortisol was taken pre stressor 2, immediately post stressor 2, and at 10 min intervals until 30 min. Results: The intervention was associated with greater reductions in negative affect, than a disengagement control task, and prevented the continued reduction in positive affect observed in the disengagement control condition. Moreover, the intervention promoted a steeper cortisol recovery trajectory, than the control condition for those with higher pre-stressor cortisol. Conclusions: This study provides further evidence that certain self-reflective practices may be involved in the development of resilience from stressor exposure.
Minimally invasive transforaminal and anterior lumbar interbody fusion surgery at level L5-S1

Abstract This paper presents a finite element analysis to investigate the biomechanical changes caused by transforaminal (TLIF) and anterior lumbar interbody fusion (ALIF) at the L5-S1 level, applying two different implants: T_PAL (TLIF) and SynFix (ALIF). The main objective is to determine which one is more stable for patients. Numerical simulations of segmental motion show that, in the early postoperative phase, displacements and rotation angles obtained in ALIF are greater than the corresponding ones obtained in TLIF, as well as the principal stress values on the ligaments. So, TLIF performed with T_PAL is more stable than ALIF, especially during the recovery phase.
Nucleocytoplasmic transport of intrinsically disordered proteins studied by high‐speed super‐resolution microscopy

Both natively folded and intrinsically disordered proteins (IDPs) destined for the nucleus need to transport through the nuclear pore complexes (NPCs) in eukaryotic cells. NPCs allow for passive diffusion of small folded proteins while barricading large ones, unless they are facilitated by nuclear transport receptors. However, whether nucleocytoplasmic transport of IDPs would follow these rules remains unknown. By using a high‐speed super‐resolution fluorescence microscopy, we have measured transport kinetics and 3D spatial locations of transport routes through native NPCs for various IDPs. Our data revealed that the rules executed for folded proteins are not well followed by the IDPs. Instead, both large and small IDPs can passively diffuse through the NPCs. Furthermore, their diffusion efficiencies and routes are differentiated by their content ratio of charged (Ch) and hydrophobic (Hy) amino acids. A Ch/Hy‐ratio mechanism was finally suggested for nucleocytoplasmic transport of IDPs.
A Rapid Fluorescence-Based Microplate Assay to Investigate the Interaction of Membrane Active Antimicrobial Peptides with Whole Gram-Positive Bacteria

Background: Membrane-active antimicrobial peptides (AMPs) are interesting candidates for the development of novel antimicrobials. Although their effects were extensively investigated in model membrane systems, interactions of AMPs with living microbial membranes are less known due to their complexity. The aim of the present study was to develop a rapid fluorescence-based microplate assay to analyze the membrane effects of AMPs in whole Staphylococcus aureus and Staphylococcus epidermidis. Methods: Bacteria were exposed to bactericidal and sub-inhibitory concentrations of two membrane-active AMPs in the presence of the potential-sensitive dye 3,3′-dipropylthiadicarbocyanine iodide (diSC3(5)) and the DNA staining dye propidium iodide (PI), to simultaneously monitor and possibly distinguish membrane depolarization and membrane permeabilization. Results: The ion channel-forming gramicidin D induced a rapid increase of diSC3(5), but not PI fluorescence, with slower kinetics at descending peptide concentrations, confirming killing due to membrane depolarization. The pore-forming melittin, at sub-MIC and bactericidal concentrations, caused, respectively, an increase of PI fluorescence in one or both dyes simultaneously, suggesting membrane permeabilization as a key event. Conclusions: This assay allowed the distinction between specific membrane effects, and it could be applied in the mode of action studies as well as in the screening of novel membrane-active AMPs.