Miracle-dz/UniFAR-FTUs huggingface dataset:
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus–North; Salvador–Northeast; Rondonópolis–Midwest and Rio de Janeiro–Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 –recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima’s D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.
Numerical Characterization of Chemical Fragments, Molecules and Clusters using Skeletal Numbers and Nuclearity Trees

The recently introduced skeletal numbers have made categorization of fragments, molecules and clusters exceedingly easy and rapid. This has made it possible to categorize the clusters according to nuclearity series and trees. A nuclearity tree keeps the number of skeletal elements constant but varies the electron density on the skeletal elements and in so doing the skeletal structure of the cluster changes as well. A close analysis of the series has revealed a deeper meaning of a skeletal number as an indicator of an electron pair deficit.
Gastrointestinal (GI)-Tract Microbiome Derived Neurotoxins and their Potential Contribution to Inflammatory Neurodegeneration in Alzheimer’s Disease (AD)

The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial complexity even amongst healthy individuals-this has made it difficult to link specific microbial abundance patterns with age-related neurological disease. GI-tract commensal microorganisms are generally beneficial to human metabolism and immunity, however enterotoxigenic forms of microbes possess significant potential to secrete what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include toxic glycolipids such as lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA. One major microbial species of the GI-tract microbiome, about ~100-fold more abundant than Escherichia coli in deep GI-tract regions is Bacteroides fragilis, an anaerobic, rod-shaped Gram-negative bacterium. B. fragilis can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); and (ii) a zinc-metalloproteinase known as B. fragilis-toxin (BFT) or fragilysin. Ongoing studies indicate that BF-LPS and/or BFT disrupt paracellular-and transcellular-barriers by cleavage of intercellular-proteins resulting in ‘leaky’ barriers. These barriers: (i) become defective and more penetrable with aging and disease; and (ii) permit entry of microbiome-derived neurotoxins into the systemic-circulation from which they next transit the blood-brain barrier and gain access to the CNS. Here LPS accumulates and significantly alters homeostatic patterns of gene expression. The affinity of LPS for neuronal nuclei is significantly enhanced in the presence of amyloid beta 42 (Aβ42) peptides. Recent research on the appearance of the brain thanatomicrobiome at the time of death and the increasing likelihood of a complex brain microbiome are reviewed and discussed. This paper will also highlight some recent advances in this extraordinary research area that links the pro-inflammatory exudates of the GI-tract microbiome with innate-immune disturbances and inflammatory-signaling within the CNS with reference to Alzheimer’s disease (AD) wherever possible.
The MAGENTA model for individual prediction of in-hospital mortality in chronic obstructive pulmonary disease with acute exacerbation in resource-limited countries: A development study

Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common undesirable event associated with significant morbidity and mortality. Several clinical prediction tools for predicting in-hospital mortality in patients with AECOPD have been developed in the past decades. However, some issues concerning the validity and availability of some predictors in the existing models may undermine their clinical applicability in resource-limited clinical settings. Methods We developed a multivariable model for predicting in-hospitality from a retrospective cohort of patients admitted with AECOPD to one tertiary care center in Thailand from October 2015 to September 2017. Multivariable logistic regression with fractional polynomial algorithms and cluster variance correction was used for model derivation. Results During the study period, 923 admissions from 600 patients with AECOPD were included. The in-hospital mortality rate was 1.68 per 100 admission-day. Eleven potential predictors from the univariable analysis were included in the multivariable logistic regression. The reduced model, named MAGENTA, incorporated seven final predictors: age, body temperature, mean arterial pressure, the requirement of endotracheal intubation, serum sodium, blood urea nitrogen, and serum albumin. The model discriminative ability based on the area under the receiver operating characteristic curve (AuROC) was excellent at 0.82 (95% confidence interval 0.77, 0.86), and the calibration was good. Conclusion The MAGENTA model consists of seven routinely available clinical predictors upon patient admissions. The model can be used as an assisting tool to aid clinicians in accurate risk stratification and making appropriate decisions to admit patients for intensive care.
Sex Differences in the Association Between Risk of Obstructive Sleep Apnea, Insomnia, and Frailty in Older Adults

Purpose To analyze the association between risk of obstructive sleep apnea (OSA), insomnia, sleepiness and self-assessed sleep duration with frailty in older adults. Patients and Methods Cross-sectional study with 1643 older adults (60 to 97 years old) who participated in round 6 (2019) of the Cohort of Obesity Sarcopenia and Obesity in Older Adults of the Mexican Institute of Social Security. The Berlin Questionnaire was used to assess risk of OSA, the Athens Insomnia Scale for insomnia, the Epworth Scale for sleepiness, and sleep duration by self-report. Frailty was assessed with the frailty criteria proposed by Fried. Sociodemographic and health variables were also collected. Statistical analysis was performed with logistic regression and was stratified by sex. Results This study included 1643 participants (823 men and 820 women). Mean age was 67.1 ± 5.9 years. The percentage of frail older adults was 10.5% (n = 172), with risk of OSA 26.1% (n = 429), with insomnia 30.3% (n = 497) and with sleepiness 18.9% (n = 310). In all participants, risk of OSA and insomnia were associated with frailty. In the stratified analysis by sex, the association between risk of OSA and frailty was observed in women (odds ratio (OR) = 1.84, 95% confidence interval (CI) 1.05, 3.22), but not in men (OR = 1.19, 95% CI: 0.65, 2.19). Insomnia was significantly associated with frailty in women (OR = 2.38, 95% CI: 1.35, 4.20) and in men (OR = 1.88, 95% CI: 1.01, 3.52). Neither sleepiness nor sleep duration was associated with frailty. Conclusion In community-dwelling older adults, both the risk of OSA and insomnia conferred greater odds of presenting frailty in women. It is required to implement strategies aimed at improving sleep hygiene and detecting patients with OSA and insomnia.
Insulin and 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Differentially Regulate the Skeletal Muscle Cell Secretome

Skeletal muscle is a major contributor to whole-body glucose homeostasis and is an important endocrine organ. To date, few studies have undertaken the large-scale identification of skeletal muscle-derived secreted proteins (myokines), particularly in response to stimuli that activate pathways governing energy metabolism in health and disease. Whereas the AMP-activated protein kinase (AMPK) and insulin-signaling pathways have received notable attention for their ability to independently regulate skeletal muscle substrate metabolism, little work has examined their ability to re-pattern the secretome. The present study coupled the use of high-resolution MS-based proteomics and bioinformatics analysis of conditioned media derived from 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR—an AMPK activator)- and insulin-treated differentiated C2C12 myotubes. We quantified 858 secreted proteins, including cytokines and growth factors such as fibroblast growth factor-21 (Fgf21). We identified 377 and 118 proteins that were significantly altered by insulin and AICAR treatment, respectively. Notably, the family of insulin growth factor binding-proteins (Igfbp) was differentially regulated by each treatment. Insulin- but not AICAR-induced conditioned media increased the mitochondrial respiratory capacity of myotubes, potentially via secreted factors. These findings may serve as an important resource to elucidate secondary metabolic effects of insulin and AICAR stimulation in skeletal muscle.
Vaccine Hesitancy towards COVID-19 Vaccination: Investigating the Role of Information Sources through a Mediation Analysis

Mass vaccination campaigns have been implemented worldwide to counteract the SARS-CoV-2/COVID-19 pandemic, however their effectiveness could be challenged by vaccine hesitancy. The tremendous rise in the use of social media have made them acquire a leading role as an information source, thus representing a crucial factor at play that could contribute to increase or mitigate vaccine hesitancy, as information sources play a pivotal role in shaping public opinion and perceptions. The aims of the study were to investigate if information sources could affect the attitude towards COVID-19 vaccination and if they could act as a mediator in the relationship between individual characteristics and vaccine hesitancy. A cross-sectional online survey was conducted by a professional panellist on a representative sample of 1011 citizens from the Emilia-Romagna region in Italy in January 2021. A mediation analysis using structural equation modelling was performed. Our results show how social media directly or indirectly increases vaccine hesitancy towards COVID-19 vaccination, while the opposite effect was observed for institutional websites. Given the global widespread use of social media, their use should be enhanced to disseminate scientifically sound information to a greater audience to counteract vaccine hesitancy, while at the same time continuing to promote and update institutional websites that have proven to be effective in reducing vaccine hesitancy.
Are We Paving the Way to Dig Out of the “Pandemic Hole”? A Narrative Review on SARS-CoV-2 Vaccination: From Animal Models to Human Immunization

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new pathogen agent causing the coronavirus infectious disease (COVID-19). This novel virus originated the most challenging pandemic in this century, causing economic and social upheaval internationally. The extreme infectiousness and high mortality rates incentivized the development of vaccines to control this pandemic to prevent further morbidity and mortality. This international scenario led academic scientists, industries, and governments to work and collaborate strongly to make a portfolio of vaccines available at an unprecedented pace. Indeed, the robust collaboration between public systems and private companies led to resolutive actions for accelerating therapeutic interventions and vaccines mechanism. These strategies contributed to rapidly identifying safe and effective vaccines as quickly and efficiently as possible. Preclinical research employed animal models to develop vaccines that induce protective and long-lived immune responses. A spectrum of vaccines is worldwide under investigation in various preclinical and clinical studies to develop both individual protection and safe development of population-level herd immunity. Companies employed and developed different technological approaches for vaccines production, including inactivated vaccines, live-attenuated, non-replicating viral vector vaccines, as well as acid nucleic-based vaccines. In this view, the present narrative review provides an overview of current vaccination strategies, taking into account both preclinical studies and clinical trials in humans. Furthermore, to better understand immunization, animal models on SARS-CoV-2 pathogenesis are also briefly discussed.
Evaluating the Consistency of Subjective Activity Assessments and Their Relation to Cognition in Older Adults

(1) Background: Research examining whether activity engagement is related to cognitive functioning in older adults has been limited to using retrospective reports of activity which may be affected by biases. This study compared two measurements (estimated weekly versus reported daily), and whether these activity assessments were related to cognition in older adults; (2) Methods: Participants from US (n = 199) and Australian (n = 170) samples completed a weekly estimate of activity, followed by 7 consecutive days of daily reporting. Differences between weekly estimates and daily reports were found, such that estimations at the weekly level were lower than self-reported daily information. Multivariate multiple regression was used to determine whether total activity, activity domains and the discrepancy between assessment types (i.e., weekly/daily) predicted cognitive performance across three cognitive domains (fluid, verbal, memory); (3) Results: When activity assessments were totaled, neither predicted cognition; however, when activity was grouped by domain (cognitive, social, physical), different domains predicted different cognitive outcomes. Daily reported cognitive activity significantly predicted verbal performance (β = 1.63, p = 0.005), while weekly estimated social activity predicted memory performance (β = −1.81, p = 0.050). Further, while the magnitude of discrepancy in total activity did not significantly predict cognitive performance, domain specific differences did. Differences in physical activity reported across assessments predicted fluid performance (β = −1.16, p = 0.033); (4) Conclusions: The significant discrepancy between the measurement types shows that it is important to recognize potential biases in responding when conducting activity and cognition research.
Pain and Opioid Use: Evidence for Integrating Acupuncture Into Treatment Planning

The epidemics of pain and opioid use pose unique challenges. Comprehensive approaches are required to address minds, bodies and spirits of individuals who live with pain and/or opioid use. The lack of an effective “quick fix” for either condition necessitates developing effective, innovative and multi-disciplinary avenues for treatment. This analytic article reviews epidemiological and demographic factors associated with pain and with opioid use and additional challenges posed by the Covid-19 epidemic. Several large-scale studies and meta-analyses have examined the role of acupuncture as a nonpharmacological approach to pain management as well as a component of comprehensive strategies to address opioid use disorder. We review and describe these in the context of safety, effectiveness, access and cost-related factors. With one in four U.S. hospitals as well as 88% of Veterans Health Administration facilities incorporating acupuncture, the feasibility of mobilizing and scaling up these treatment resources is being developed and demonstrated. We also identify potential facilitators and barriers to implementing acupuncture treatment. As part of a multi-disciplinary approach to pain management and/or opioid use disorder, we suggest that integrating acupuncture into treatment protocols may represent a viable strategy that is based on and consistent with public health principles.
Paliperidone to Treat Psychotic Disorders

Purpose of Review: This is a comprehensive review of the literature regarding the use of paliperidone in the treatment of schizophrenia and schizoaffective disorder. It covers the background and presentation of schizophrenia and schizoaffective disorder, as well as the mechanism of action and drug information for paliperidone. It covers the existing evidence of the use of paliperidone for the treatment of schizophrenia and schizoaffective disorder. Recent Findings: Schizophrenia and schizoaffective disorder lead to significant cognitive impairment. It is thought that dopamine dysregulation is the culprit for the positive symptoms of schizophrenia and schizoaffective disorder. Similar to other second-generation antipsychotics, paliperidone has affinity for dopamine D2 and serotonin 5-HT2A receptors. Paliperidone was granted approval in the United States in 2006 to be used in the treatment of schizophrenia and in 2009 for schizoaffective disorder. Summary: Schizophrenia and schizoaffective disorder have a large impact on cognitive impairment, positive symptoms and negative symptoms. Patients with either of these mental illnesses suffer from impairments in everyday life. Paliperidone has been shown to reduce symptoms of schizophrenia and schizoaffective disorder.
Synthesis, Characterization and DNA-Binding Affinity of a New Zinc(II) Bis(5-methoxy-indol-3-yl)propane-1,3-dione Complex

The novel zinc(II) µ-oxo-bridged-dimeric complex [Zn2(µ-O)2(BMIP)2] (BMIP = 1,3-bis(5-methoxy-1-methyl-1H-indol-3-yl)propane-1,3-dione), 1, was synthetized and fully characterized. The spectral data indicate a zincoxane molecular structure, with the BMIP ligand coordinating in its neutral form via its oxygen atoms. Structural changes in 1 in dimethylsulfoxide (DMSO) were evidenced by means of spectroscopic techniques including infrared absorption and nuclear magnetic resonance, showing DMSO entrance in the coordination sphere of the metal ion. The resulting complex [Zn2(µ-O)2(BMIP)2(DMSO)], 2, readily reacts in the presence of N-methyl-imidazole (NMI), a liquid-phase nucleoside mimic, to form [Zn2(µ-O)2(BMIP)2(NMI)], 3, through DMSO displacement. The three complexes show high thermal stability, demonstrating that 1 has high affinity for hard nucleophiles. Finally, with the aim of probing the suitability of this system as model scaffold for new potential anticancer metallodrugs, the interactions of 1 with calf thymus DNA were investigated in vitro in pseudo-physiological environment through UV-Vis absorption and fluorescence emission spectroscopy, as well as time-resolved fluorescence studies. The latter analyses revealed that [Zn2(µ-O)2(BMIP)2(DMSO)] binds to DNA with high affinity upon DMSO displacement, opening new perspectives for the development of optimized drug substances.
Evaluation of skin sensitization induced by four ionic liquids

Ionic liquids (ILs) are synthetic solvents used as replacements for volatile organic solvents. Human exposure occurs through dermal or oral routes. In rodents, several ILs were reported to induce dermal toxicity, irritation, and sensitization. Due to the potential for occupational exposure, and industrial use as nonvolatile solvents, 1‐ethyl‐3‐methylimidazolium chloride (EMIM, 6.25% to 50% v/v), 1‐butyl‐3‐methylimidazolium chloride (BMIM, 3.12% to 12.5% v/v), 1‐butyl‐1‐methylpyrrolidinium chloride (BMPY, 0.825% to 6.25% v/v), and N‐butylpyridinium chloride (NBuPY, 0.825% to 12.5% v/v) were nominated to the National Toxicology Program and evaluated for skin sensitization. The test compound was applied to the ears of female BALB/c mice daily for 3 days in a primary irritancy (IRR)/local lymph node assay (LLNA). Sensitization was assessed in vitro in the direct peptide reactivity assay (DPRA), KeratinoSens™ assay, and human cell line activation test (h‐CLAT). In the LLNA, the butylated ILs, BMIM, and BMPY were more potent than NBuPY (butylated) or EMIM (ethylated), which was neither an irritant nor a sensitizer. NBuPY induced skin irritation in vivo at ≥3.12% (p ≤ 0.01), and sensitization in vitro in the KeratinoSens™ assay and h‐CLAT, but was negative for sensitization in vivo and in the DPRA. Although SI3 was not achieved, dermal treatment with 12.5% BMIM or 6.25% BMPY increased (p ≤ 0.01) lymph node cell proliferation in the LLNA. In vitro, BMIM was positive for sensitization in the h‐CLAT, and BMPY was positive in the h‐CLAT and KeratinoSens™ assay; both were negative in the DPRA. Integrated data analyses, weighted toward in vivo data, suggested that BMIM and BMPY may induce weak to mild sensitization.
Development and Characterization of Pectin Films with Salicornia ramosissima: Biodegradation in Soil and Seawater

Pectin films were developed by incorporating a halophyte plant Salicornia ramosissima (dry powder from stem parts) to modify the film’s properties. The films’ physicomechanical properties, Fourier-transform infrared spectroscopy (FTIR), and microstructure, as well as their biodegradation capacity in soil and seawater, were evaluated. The inclusion of S. ramosissima significantly increased the thickness (0.25 ± 0.01 mm; control 0.18 ± 0.01 mm), color parameters a* (4.96 ± 0.30; control 3.29 ± 0.16) and b* (28.62 ± 0.51; control 12.74 ± 0.75), water vapor permeability (1.62 × 10−9 ± 1.09 × 10−10 (g/m·s·Pa); control 1.24 × 10−9 ± 6.58 × 10−11 (g/m·s·Pa)), water solubility (50.50 ± 5.00%; control 11.56 ± 5.56%), and elongation at break (5.89 ± 0.29%; control 3.91 ± 0.62%). On the other hand, L* (48.84 ± 1.60), tensile strength (0.13 ± 0.02 MPa), and Young’s modulus (0.01 ± 0 MPa) presented lower values compared with the control (L* 81.20 ± 1.60; 4.19 ± 0.82 MPa; 0.93 ± 0.12 MPa), while the moisture content varied between 30% and 45%, for the film with S. ramosissima and the control film, respectively. The addition of S. ramosissima led to opaque films with relatively heterogeneous microstructures. The films showed also good biodegradation capacity—after 21 days in soil (around 90%), and after 30 days in seawater (fully fragmented). These results show that pectin films with S. ramosissima may have great potential to be used in the future as an eco-friendly food packaging material.