Miracle-dz/UniFAR-FTUs huggingface dataset:
First mitochondrial genome-wide association study with metabolomics

Abstract In the era of personalized medicine with more and more patient-specific targeted therapies being used, we need reliable, dynamic, faster and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA (mtDNA) in metabolic regulation, aging and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA and thereby contributes to a range of pathophysiological alterations observed in complex diseases. We performed an inverted mitochondrial genome-wide association analysis between mitochondrial nucleotide variants (mtSNVs) and concentration of metabolites. We used 151 metabolites and the whole sequenced mitochondrial genome from 2718 individuals to identify the genetic variants associated with metabolite profiles. Because of the high coverage, next-generation sequencing-based analysis of the mitochondrial genome allows for an accurate detection of mitochondrial heteroplasmy and for the identification of variants associated with the metabolome. The strongest association was found for mt715G > A located in the MT-12SrRNA with the metabolite ratio of C2/C10:1 (P-value = 6.82*10−09, β = 0.909). The second most significant mtSNV was found for mt3714A > G located in the MT-ND1 with the metabolite ratio of phosphatidylcholine (PC) ae C42:5/PC ae C44:5 (P-value = 1.02*10−08, β = 3.631). A large number of significant metabolite ratios were observed involving PC aa C36:6 and the variant mt10689G > A, located in the MT-ND4L gene. These results show an important interconnection between mitochondria and metabolite concentrations. Considering that some of the significant metabolites found in this study have been previously related to complex diseases, such as neurological disorders and metabolic conditions, these associations found here might play a crucial role for further investigations of such complex diseases. Understanding the mechanisms that control human health and disease, in particular, the role of genetic predispositions and their interaction with environmental factors is a prerequisite for the development of safe and efficient therapies for complex disorders.
Cognitive Functionality of Patients with Delirium after Stroke.

BACKGROUND Delirium is a syndrome that occurs in all age groups and in many clinical departments, and is most common in intensive care units. It is an emergency, in the overlapping fields of somatic medicine, neurology and psychiatry. Delirium occurs suddenly, dramatically, and requires a quick reaction, recognition and treatment. There are only a small number of studies that have reported delirium after a stroke. In our study, the goal was to determine the cognitive functionality of patients with delirium after a stroke. SUBJECTS AND METHODS This is a prospective study in which a group of 100 delirium patients in the acute phase of a stroke were evaluated for cognitive function. The control group consisted of the same number of patients with acute stroke who were not diagnosed with delirium. Neurological, neuropsychiatric and neuropsychological tests were performed in all patients at five different time periods. In these time periods, all patients were evaluated: Glasgow Coma Scale; Delirium Assessment Scale; The American National Institutes of Health Scale Assessment; Information-Memory-Concentration test; Dementia Score; Mini-Mental Test. The findings of computed tomography of the brain and magnetic resonance imaging of the brain were interpreted by a radiologist who was not familiar with the goals of this study. RESULTS Cognitive functioning of delirious patients is statistically significantly worse after three and six months, and one year from stroke compared to those without delirium. There is no statistically significant difference in cognitive functioning between delirious patients in relation to gender, age, location and type of stroke and patients without delirium throughout one year from stroke. There is no significant difference in cognitive functioning between delirious patients during one year from stroke in relation to severity and type of delirium, and statistically significantly higher degree of cognitive dysfunction has those older than ≥65 years. CONCLUSIONS Delirium significantly reduces the cognitive functioning of patients after a stroke.
Bile Acid Profiling Reveals Distinct Signatures in Undernourished Children with Environmental Enteric Dysfunction

ABSTRACT Background Intestinal inflammation and malabsorption in environmental enteric dysfunction (EED) are associated with early childhood growth faltering in impoverished settings worldwide. Objectives The goal of this study was to identify candidate biomarkers associated with inflammation, EED histology, and as predictors of later growth outcomes by focusing on the liver-gut axis by investigating the bile acid metabolome. Methods Undernourished rural Pakistani infants (n = 365) with weight-for-height Z score (WHZ) < –2 were followed up to the age of 24 mo and monitored for growth, infections, and EED. Well-nourished local children (n = 51) were controls, based on consistent WHZ > 0 and height-for-age Z score (HAZ) > –1 on 2 consecutive visits at 3 and 6 mo. Serum bile acid (sBA) profiles were measured by tandem MS at the ages of 3–6 and 9 mo and before nutritional intervention. Biopsies and duodenal aspirates were obtained following upper gastrointestinal endoscopy from a subset of children (n = 63) that responded poorly to nutritional intervention. BA composition in paired plasma and duodenal aspirates was compared based on the severity of EED histopathological scores and correlated to clinical and growth outcomes. Results Remarkably, >70% of undernourished Pakistani infants displayed elevated sBA concentrations consistent with subclinical cholestasis. Serum glycocholic acid (GCA) correlated with linear growth faltering (HAZ, r = –0.252 and –0.295 at the age of 3–6 and 9 mo, respectively, P <0.001) and biomarkers of inflammation. The proportion of GCA positively correlated with EED severity for both plasma (rs = 0.324 P = 0.02) and duodenal aspirates (rs = 0.307 P = 0.06) in children with refractory wasting that underwent endoscopy, and the proportion of secondary BA was low in both undernourished and EED children. Conclusions Dysregulated bile acid metabolism is associated with growth faltering and EED severity in undernourished children. Restoration of intestinal BA homeostasis may offer a novel therapeutic target for undernutrition in children with EED. This trial was registered at clinicaltrials.gov as NCT03588013.
The distinct RNA-interaction modes of a small ZnF domain underlay TUT4(7) diverse action in miRNA regulation

ABSTRACT TUT4 and the closely related TUT7 are non-templated poly(U) polymerases required at different stages of development, and their mis-regulation or mutation has been linked to important cancer pathologies. While TUT4(7) interaction with its pre-miRNA targets has been characterized in detail, the molecular bases of the broader target recognition process are unclear. Here, we examine RNA binding by the ZnF domains of the protein. We show that TUT4(7) ZnF2 contains two distinct RNA binding surfaces that are used in the interaction with different RNA nucleobases in different targets, i.e that this small domain encodes diversity in TUT4(7) selectivity and molecular function. Interestingly and unlike other well-characterized CCHC ZnFs, ZnF2 is not physically coupled to the flanking ZnF3 and acts independently in miRNA recognition, while the remaining CCHC ZnF of TUT4(7), ZnF1, has lost its intrinsic RNA binding capability. Together, our data suggest that the ZnFs of TUT4(7) are independent units for RNA and, possibly, protein-protein interactions that underlay the protein’s functional flexibility and are likely to play an important role in building its interaction network.
Germinal Center-Induced Immunity Is Correlated With Protection Against SARS-CoV-2 Reinfection But Not Lung Damage

Abstract Germinal centers (GCs) elicit protective humoral immunity through a combination of antibody-secreting cells and memory B cells, following pathogen invasion or vaccination. However, the possibility of a GC response inducing protective immunity against reinfection following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. We found GC activity was consistent with seroconversion observed in recovered macaques and humans. Rechallenge with a different clade of virus resulted in significant reduction in replicating virus titers in respiratory tracts in macaques with high GC activity. However, diffuse alveolar damage and increased fibrotic tissue were observed in lungs of reinfected macaques. Our study highlights the importance of GCs developed during natural SARS-CoV-2 infection in managing viral loads in subsequent infections. However, their ability to alleviate lung damage remains to be determined. These results may improve understanding of SARS-CoV-2–induced immune responses, resulting in better coronavirus disease 2019 (COVID-19) diagnosis, treatment, and vaccine development.
Pharmacokinetic Profile of Incremental Oral Doses of Dietary Nitrate in Young and Older Adults: A Crossover Randomized Clinical Trial

ABSTRACT Background Dietary nitrate consumption can increase concentrations of nitrate and nitrite in blood, saliva, and urine. Whether the change in concentrations is influenced by age is currently unknown. Objectives We aimed to measure changes in nitrate and nitrite concentrations in plasma, urine, and saliva and exhaled NO concentrations after single incremental doses of dietary nitrate in young and older healthy adults. Methods Twelve young (18–35 y old) and 12 older (60–75 y old) healthy, nonsmoking participants consumed single doses of 100 g, 200 g, 300 g whole beetroot (BR) and 1000 mg potassium nitrate (positive control) ≥7 d apart in a crossover, randomized clinical trial. Plasma nitrate and nitrite concentrations and exhaled NO concentrations were measured over a 5-h period. Salivary nitrate and nitrite concentrations were measured over a 12-h period and urinary nitrate over a 24-h period. Time, intervention, age, and interaction effects were measured with repeated-measures ANOVAs. Results Dose-dependent increases were seen in plasma, salivary, and urinary nitrate after BR ingestion (all P ≤ 0.002) but there were no differences between age groups at baseline (all P ≥ 0.56) or postintervention (all P ≥ 0.12). Plasma nitrite concentrations were higher in young than older participants at baseline (P = 0.04) and after consumption of 200 g (P = 0.04; +25.7 nmol/L; 95% CI: 0.97, 50.3 nmol/L) and 300 g BR (P = 0.02; +50.3 nmol/L; 95% CI: 8.57, 92.1 nmol/L). Baseline fractional exhaled NO (FeNO) concentrations were higher in the younger group [P = 0.03; +8.60 parts per billion (ppb); 95% CI: 0.80, 16.3 ppb], and rose significantly over the 5-h period, peaking 5 h after KNO3 consumption (39.4 ± 4.5 ppb; P < 0.001); however, changes in FeNO were not influenced by age (P = 0.276). Conclusions BR is a source of bioavailable dietary nitrate in both young and older adults and can effectively raise nitrite and nitrate concentrations. Lower plasma nitrite and FeNO concentrations were found in older subjects, confirming the impact of ageing on NO bioavailability across different systems. This trial was registered at www.isrctn. com as ISRCTN86706442.
To Blame is Human: A Quantitative Systematic Review of the Relationship Between Outcome Severity of Large‐Scale Crises and Attributions of Blame

In crisis situations, time is of the essence. Effective messaging to individuals at risk is critical to mitigating the most severe outcomes. Extant crisis communication literature has focused on differentiating crisis types based on perceived blame, particularly in cases of for‐profit company malfeasance, but less work has been done to understand how the public makes these types of attributions. This quantitative systematic review investigates the relationship between severity of a large‐scale crisis outcome and attributions of blame toward relevant entities. Moderators of interest include the attribution term used with participants (e.g., blame, responsibility), the type of crisis event, and the entity presented as at fault. Overall, a small but significant positive relationship is identified in the majority of studies between severity of a large‐scale crisis outcome and attributions of blame. Results suggest that while crisis type and entity to blame are moderators, the attribution term(s) used with participants plays a less significant role. Implications and future directions are considered.
Cerebral white matter vasculature: still uncharted?

White matter vasculature plays a major role in the pathophysiology of permanent neurological deficits following a stroke or progressive cognitive alteration related to small vessel disease. Thus, knowledge of the complex vascularization and functional aspects of the deep white matter territories is paramount to comprehend clinical manifestations of brain ischemia. This review provides a structured presentation of the existing knowledge of the vascularization of the human cerebral white matter from seminal historical studies to the current literature. First, we revisit the highlights of prenatal development of the endoparenchymal telencephalic vascular system that are crucial for the understanding of vessel organization in the adult. Second, we reveal the tangled history of debates on the existence, clinical significance, and physiological role of leptomeningeal anastomoses. Then, we present how conceptions on white matter vascularization transitioned from the mixed ventriculopetal/ventriculofugal theory, in which a low-flow area was interposed in between concurrent arterial flows, to the purely ventriculopetal theory. The latter model explains variable white matter sensitivity to ischemia by various organizations of ventriculopetal vessel terminals having different origin/length properties and interconnection patterns. Next, arteries supplying primarily the white matter are described according to their length and overall structure. Furthermore, the known distribution territories, to date, are studied in relation to primary anatomical structures of the human cerebral white matter, emphasizing the sparsity of the "ground-truth" data available in the literature. Finally, the implications for both large vessel occlusion and chronic small vessel disease are discussed, as well as the insights from neuroimaging. All things considered, we identify the need for further research on deep white matter vascularization, especially regarding the arterial supply of white matter fiber tracts.
Examining Truth and State-Sponsored Media Campaigns as a Means of Decreasing Youth Smoking and Related Disparities in the U.S.

INTRODUCTION To analyze the impact of Truth and state-sponsored anti-tobacco media campaigns on youth smoking in the U.S., and their potential to reduce tobacco-related health disparities. METHODS Our study included data from the 2000-2015 Monitoring the Future study, an annual nationally representative survey of youth in 8 th (n=201,913), 10 th (n=194,468), and 12 th grades (n=178,379). Our primary exposure was Gross Ratings Points (GRPS) of Truth or state-sponsored anti-tobacco advertisements, from Nielsen Media Research. Modified Poisson regression was used to assess the impact of a respondent's GRPs on smoking intentions, past 30-day smoking participation, and first and daily smoking initiation. Additive interactions with sex, parental education, college plans, and race/ethnicity were used to test for differential effects of campaign exposure on each outcome. RESULTS Greater campaign exposure (80 th vs. 20 th GRP percentile) was associated with lower probabilities of smoking intentions among 8 th graders, smoking participation among 8 th and 12 th graders, and initiation among 8 th graders. Greater exposure was associated with a greater reduction in the likelihood of smoking participation among 10 th and 12 th grade males than females; 10 th and 12 th graders with parents of lower education versus those with a college degree; and 12 th graders who did not definitely plan to go to college relative to those who did. CONCLUSIONS Media campaign exposure was associated with a lower likelihood of youth smoking behaviors. Associations were more pronounced for groups disproportionately affected by smoking, including youth of lower socioeconomic status. Media campaigns may be useful in reducing smoking disparities and improving health equity. IMPLICATIONS Few recent studies have investigated the impact of anti-tobacco media campaigns on youth smoking and their potential to reduce tobacco-related health disparities in the U.S. We found media campaigns - specifically state-sponsored media campaigns - reduced the likelihood of several smoking outcomes among youth, with some evidence that they mitigate disparities for disproportionately affected groups.
Living Bacterial Hydrogels for Accelerated Infected Wound Healing

Damaged skin cannot prevent harmful bacteria from invading tissues, causing infected wounds and even serious tissue damage. Traditional treatments can not only kill pathogenic bacteria, but also suppress the growth of beneficial bacteria, thus destroying the balance of the damaged skin microbial ecosystem. Here, a living bacterial hydrogel scaffold is reported that accelerates infected wound healing through beneficial bacteria secreting antibacterial substances. Lactobacillus reuteri, a common probiotic, is encapsulated in hydrogel microspheres by emulsion polymerization and further immobilized in a hydrogel network by covalent cross‐linking of methacrylate‐modified hyaluronic acid. Owing to light‐initiated crosslinking, the hydrogel dressing can be generated in situ at the wound site. This hydrogel scaffold not only protects bacteria from immune system attack, but also prevents bacteria from escaping into the local environment, thus avoiding potential threats. Both in vitro and in vivo experiments show that it has excellent ability against harmful bacteria and anti‐inflammatory capabilities, promoting infected wound closure and new tissue regeneration. This work may open up new avenues for the application of living bacteria in the clinical management of infected wounds.
Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

ABSTRACT Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins’ putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.
Do crocodiles have a zona incerta?

In mammals, the zona incerta is thought to be involved in a number of behaviors: visceral activity, arousal, attention, and posture and locomotion. These diverse and complex features suggested that the zona incerta functions as a global or integrative node. Nevertheless, despite multiple investigations into its anatomy, physiology, and behavior in a variety of mammals, no specific character identifies the zona incerta besides its appearance in fiber‐stained material and its relationship to surrounding structures. One such structure is the thalamic reticular nucleus whose caudal pole often contains some intermingled cells of the zona incerta. In crocodilians, the entopeduncular nucleus (ep) abuts the caudal pole of the thalamic reticular nucleus and displays different immunohistochemical properties and soma size when compared with neurons in the thalamic reticular nucleus itself. To determine if neurons in the ep differed from those in the thalamic reticular nucleus in Alligator mississippiensis, the ep was investigated using Golgi methodology. The morphology and soma size of neurons in the ep differed from those in the thalamic reticular nucleus and indicated that these two areas are indeed separate neuronal aggregates. Based on these data and the known relationships of the zona incerta to surrounding structures in mammals, the ep of crocodilians is suggested to be the counterpart of the zona incerta of mammals.
Psychosocial factors associated with mask-wearing behavior during the COVID-19 pandemic

ABSTRACT Although increasing evidence has supported the efficacy of masks to prevent the spread of the coronavirus (COVID-19), inconsistent and noncompliant mask-wearing behavior has been observed among members of the society. Because mask-wearing is often considered a social contract, it is important to understand the psychosocial factors that influence people’s mask-wearing behavior in order to implement the necessary steps to respond to the pandemic. Based on the protection motivation theory (PMT), this study examined the cognitive factors (threat and coping appraisals) that contribute to mask-wearing behavior and the intention to engage in health protective behavior until the end of the pandemic. Furthermore, we examined the roles of social (perceived social norm) and affective (fear) factors in mask-wearing behavior and intention. The sample included 981 voluntary adults in the United States who completed an online survey for this study between 15 October 2020 and 28 November 2020. The results of hierarchical multiple regressions showed that all PMT variables (severity, susceptibility, response efficacy, and self-efficacy) were associated with mask-wearing behavior and intention to engage in health protective behavior until the end of the pandemic. Perceived social norm and fear provided unique, additive contributions to the predictability of mask-wearing behavior and intention. Overall findings suggest the importance of considering cognitive, social, and affective factors altogether in order to better understand an individual’ intention and behavior toward mask wearing during the pandemic.