Miracle-dz/UniFAR-FTUs huggingface dataset:
Measuring heritable contributions to Alzheimer’s disease: polygenic risk score analysis with twins

Abstract The heritability of Alzheimer’s disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer’s disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer’s disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer’s disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up (Mage = 85.28, SD = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P < 1 × 10−5, considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer’s disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer’s disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer’s disease risk, where APOE ɛ4 explained 9.3% and PRS.no.APOE dropped from 2.4 to 2.1%. The total genetic contribution to Alzheimer’s disease risk, measured and unmeasured, was 71% while environmental influences unique to each twin accounted for 29% of the risk. The APOE region accounts for much of the measurable genetic contribution to Alzheimer’s disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood.
Assessment of the intracellular distribution of copper in liver specimens from cats

The intracellular distribution of copper in the liver has been investigated in dogs and humans. However, this has not been reported in cats. This study aimed to assess the intracellular copper distribution in liver specimens from cats with a range of hepatic copper concentrations. Twenty-nine frozen liver specimens from cats were included. Each liver specimen was divided into two pieces for overall copper quantification and tissue fractionation. The copper concentrations in liver specimens and liver fractions were measured by flame atomic absorption spectroscopy. Five specimens had copper concentrations < 100 μg/g dry weight, eight had copper concentrations between 100 and 180 μg/g, 14 had copper concentrations between 181 and 700 μg/g, and two had copper concentrations >700 μg/g. Only one specimen had positive copper staining. Regardless of the overall concentrations, copper was mostly found in the cytosolic fraction followed by the nuclear, large granule, and microsomal fractions. Our findings indicate that similarly to other species, intracellular copper is predominantly found in the cytosolic and nuclear fractions in cats. The distribution in cats with copper-loaded conditions, such as primary copper hepatopathy, was not assessed but warrants evaluation.
Identifying SARS-COV-2 infected patients through canine olfactive detection on axillary sweat samples; study of observed sensitivities and specificities within a group of trained dogs

There is an increasing need for rapid, reliable, non-invasive, and inexpensive mass testing methods as the global COVID-19 pandemic continues. Detection dogs could be a possible solution to identify individuals infected with SARS-CoV-2. Previous studies have shown that dogs can detect SARS-CoV-2 on sweat samples. This study aims to establish the dogs’ sensitivity (true positive rate) which measures the proportion of people with COVID-19 that are correctly identified, and specificity (true negative rate) which measures the proportion of people without COVID-19 that are correctly identified. Seven search and rescue dogs were tested using a total of 218 axillary sweat samples (62 positive and 156 negative) in olfaction cones following a randomised and double-blind protocol. Sensitivity ranged from 87% to 94%, and specificity ranged from 78% to 92%, with four dogs over 90%. These results were used to calculate the positive predictive value and negative predictive value for each dog for different infection probabilities (how likely it is for an individual to be SARS-CoV-2 positive), ranging from 10–50%. These results were compared with a reference diagnostic tool which has 95% specificity and sensitivity. Negative predictive values for six dogs ranged from ≥98% at 10% infection probability to ≥88% at 50% infection probability compared with the reference tool which ranged from 99% to 95%. Positive predictive values ranged from ≥40% at 10% infection probability to ≥80% at 50% infection probability compared with the reference tool which ranged from 68% to 95%. This study confirms previous results, suggesting that dogs could play an important role in mass-testing situations. Future challenges include optimal training methods and standardisation for large numbers of detection dogs and infrastructure supporting their deployment.
Volumetric Bioprinting of Organoids and Optically Tuned Hydrogels to Build Liver‐Like Metabolic Biofactories

Organ‐ and tissue‐level biological functions are intimately linked to microscale cell–cell interactions and to the overarching tissue architecture. Together, biofabrication and organoid technologies offer the unique potential to engineer multi‐scale living constructs, with cellular microenvironments formed by stem cell self‐assembled structures embedded in customizable bioprinted geometries. This study introduces the volumetric bioprinting of complex organoid‐laden constructs, which capture key functions of the human liver. Volumetric bioprinting via optical tomography shapes organoid‐laden gelatin hydrogels into complex centimeter‐scale 3D structures in under 20 s. Optically tuned bioresins enable refractive index matching of specific intracellular structures, countering the disruptive impact of cell‐mediated light scattering on printing resolution. This layerless, nozzle‐free technique poses no harmful mechanical stresses on organoids, resulting in superior viability and morphology preservation post‐printing. Bioprinted organoids undergo hepatocytic differentiation showing albumin synthesis, liver‐specific enzyme activity, and remarkably acquired native‐like polarization. Organoids embedded within low stiffness gelatins (<2 kPa) are bioprinted into mathematically defined lattices with varying degrees of pore network tortuosity, and cultured under perfusion. These structures act as metabolic biofactories in which liver‐specific ammonia detoxification can be enhanced by the architectural profile of the constructs. This technology opens up new possibilities for regenerative medicine and personalized drug testing.
Plant elicitor peptide 1 fortifies root cell walls and triggers a systemic root-to-shoot immune signaling in Arabidopsis

ABSTRACT Plant immunity is initiated by cell surface-localized receptors upon perception of pathogen-derived microbe or pathogen-associated molecular patterns (MAMPs/PAMPs), damage/danger-associated molecular patterns (DAMPs), and phytocytokines. Different patterns activate highly overlapping immune signaling at the early stage but divergent physiological responses at the late stage. Here, we indicate that plant elicitor peptide 1 (Pep1), a well-known DAMP, induces lignin and callose depositions, two types of late immune responses for strengthening the plant cell wall. Pep1-induced lignin and callose depositions in Arabidopsis root rely on early signaling components for Pep1 perception and signaling propagation. The phytohormone jasmonic acid and ethylene differently regulate the Pep1-regulated cell wall consolidation. Pep1 application in root also triggers a systemic immune signaling in shoot, and reactive oxygen species (ROS) is essential for the signaling communication between root and shoot. Collectively, the study reveals that Pep1 strengthens cell walls in root and triggers a systemic immune signaling from root to shoot.
Prenatal exposure to air pollution is associated with altered brain structure, function, and metabolism in childhood.

BACKGROUND Prenatal exposure to air pollution disrupts cognitive, emotional, and behavioral development. The brain disturbances associated with prenatal air pollution are largely unknown. METHODS In this prospective cohort study, we estimated prenatal exposures to fine particulate matter (PM2.5 ) and polycyclic aromatic hydrocarbons (PAH), and then assessed their associations with measures of brain anatomy, tissue microstructure, neurometabolites, and blood flow in 332 youth, 6-14 years old. We then assessed how those brain disturbances were associated with measures of intelligence, ADHD and anxiety symptoms, and socialization. RESULTS Both exposures were associated with thinning of dorsal parietal cortices and thickening of postero-inferior and mesial wall cortices. They were associated with smaller white matter volumes, reduced organization in white matter of the internal capsule and frontal lobe, higher metabolite concentrations in frontal cortex, reduced cortical blood flow, and greater microstructural organization in subcortical gray matter nuclei. Associations were stronger for PM2.5 in boys and PAH in girls. Youth with low exposure accounted for most significant associations of ADHD, anxiety, socialization, and intelligence measures with cortical thickness and white matter volumes, whereas it appears that high exposures generally disrupted these neurotypical brain-behavior associations, likely because strong exposure-related effects increased the variances of these brain measures. CONCLUSIONS The commonality of effects across exposures suggests PM2.5 and PAH disrupt brain development through one or more common molecular pathways, such as inflammation or oxidative stress. Progressively higher exposures were associated with greater disruptions in local volumes, tissue organization, metabolite concentrations, and blood flow throughout cortical and subcortical brain regions and the white matter pathways interconnecting them. Together these affected regions comprise cortico-striato-thalamo-cortical circuits, which support the regulation of thought, emotion, and behavior.
Genomic and phenotypic analyses of diverse non-clinical Acinetobacter baumannii strains reveals strain-specific virulence and resistance capacity

Acinetobacter baumannii is a critically important pathogen known for its widespread antibiotic resistance and ability to persist in hospital-associated environments. Whilst the majority of A. baumannii infections are hospital-acquired, infections from outside the hospital have been reported with high mortality. Despite this, little is known about the natural environmental reservoir(s) of A. baumannii and the virulence potential underlying non-clinical strains. Here, we report the complete genome sequences of six diverse strains isolated from environments such as river, soil, and industrial sites around the world. Phylogenetic analyses showed that four of these strains were unrelated to representative nosocomial strains and do not share a monophyletic origin, whereas two had sequence types belonging to the global clone lineages GC1 and GC2. Further, the majority of these strains harboured genes linked to virulence and stress protection in nosocomial strains. These genotypic properties correlated well with in vitro virulence phenotypic assays testing resistance to abiotic stresses, serum survival, and capsule formation. Virulence potential was confirmed in vivo, with most environmental strains able to effectively kill Galleria mellonella greater wax moth larvae. Using phenomic arrays and antibiotic resistance profiling, environmental and nosocomial strains were shown to have similar substrate utilisation patterns although environmental strains were distinctly more sensitive to antibiotics. Taken together, these features of environmental A. baumannii strains suggest the existence of a strain-specific distinct gene pools for niche specific adaptation. Furthermore, environmental strains appear to be equally virulent as contemporary nosocomial strains but remain largely antibiotic sensitive.
Pierpont syndrome due to mutation c.1337A>G in TBL1XR1 gene

Department of Paediatrics and Adolescent Medicine, Institute of Biology and Medical Genetics and Department of Radiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic Correspondence to Jiri Zeman, MD, PhD, Department of Paediatrics and Adolescent Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 120 00 Prague 2, Czech Republic Tel: +42
Development and validation of a novel nomogram to predict overall survival of patients with moderate to severe chronic kidney disease

Abstract Introduction The risk of death significantly increased from stage 3 chronic kidney disease (CKD) onward. We aimed to construct a novel nomogram to predict the overall survival (OS) of patients afflicted with CKD from stage 3–5. Methods A total of 882 patients with stage 3–5 CKD were enrolled from the NHANES 2001–2004 survey. Data sets from the 2003–2004 survey population were used to develop a nomogram that would predict the risk of OS. The 2001–2002 survey population was used to validate the nomogram. Least absolute shrinkage and selection operator (Lasso) regression was conducted to screen the significant predictors relative to all-cause death. The multivariate Cox regression based on the screened factors was applied to effectively construct the nomogram. The performance of the nomogram was evaluated according to the C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve with 1000 bootstraps resample. Kaplan–Meier’s curves were used for testing the discrimination of the prediction model. Results Five variables (age, urinary albumin-to-creatinine ratio (UACR), potassium, cystatin C (Cys C), and homocysteine) were screened by the Lasso regression. The nomogram was constructed using these factors, as well as the CKD stage. The included factors (age, CKD stage, UACR, potassium, Cys C, and homocysteine) were all significantly related to the death of CKD patients, according to the multivariate Cox regression analysis. The internal validation showed that this nomogram demonstrates good discrimination and calibration (adjusted C-index: 0.70; AUC of 3-, 5-, and 10-year OS were 0.75, 0.78, and 0.77, respectively). External validation also demonstrated exceedingly similar results (C-index: 0.72, 95% CI: 0.69–0.76; AUC of 3-, 5-, and 10-year OS were 0.76, 0.79, and 0.80, respectively). Conclusions This study effectively constructed a novel nomogram that incorporates CKD stage, age, UACR, potassium, Cys C, and homocysteine, which can be conveniently used to facilitate the individualized prediction of survival probability in patients with stage 3–5 CKD. It displays valuable potential for clinical application.
Identification of novel, cryptic Clostridioides species isolates from environmental samples collected from diverse geographical locations

Clostridioides difficile is a pathogen often associated with hospital-acquired infection or antimicrobial-induced disease; however, increasing evidence indicates infections can result from community or environmental sources. Most genomic sequencing of C. difficile has focused on clinical strains, although evidence is growing that C. difficile spores are widespread in soil and water in the environment. In this study, we sequenced 38 genomes collected from soil and water isolates in Flagstaff (AZ, USA) and Slovenia in an effort targeted towards environmental surveillance of C. difficile . At the average nucleotide identity (ANI) level, the genomes were divergent to C. difficile at a threshold consistent with different species. A phylogenetic analysis of these divergent genomes together with Clostridioides genomes available in public repositories confirmed the presence of three previously described, cryptic Clostridioide s species and added two additional clades. One of the cryptic species (C-III) was almost entirely composed of Arizona and Slovenia genomes, and contained distinct sub-groups from each region (evidenced by SNP and gene-content differences). A comparative genomics analysis identified multiple unique coding sequences per clade, which can serve as markers for subsequent environmental surveys of these cryptic species. Homologues to the C. difficile toxin genes, tcdA and tcdB, were found in cryptic species genomes, although they were not part of the typical pathogenicity locus observed in C. difficile , and in silico PCR suggested that some would not amplify with widely used PCR diagnostic tests. We also identified gene homologues in the binary toxin cluster, including some present on phage and, for what is believed to be the first time, on a plasmid. All isolates were obtained from environmental samples, so the function and disease potential of these toxin homologues is currently unknown. Enzymatic profiles of a subset of cryptic isolates (n=5) demonstrated differences, suggesting that these isolates contain substantial metabolic diversity. Antimicrobial resistance (AMR) was observed across a subset of isolates (n=4), suggesting that AMR mechanisms are intrinsic to the genus, perhaps originating from a shared environmental origin. This study greatly expands our understanding of the genomic diversity of Clostridioides . These results have implications for C. difficile One Health research, for more sensitive C. difficile diagnostics, as well as for understanding the evolutionary history of C. difficile and the development of pathogenesis.
Effectiveness of the ICCMS caries management system for children: a 3-year multicentre randomised controlled trial

Abstract Objective This 3-year multicentre randomised controlled trial compared, in 6-7-year-old Colombian children, the effectiveness of the ICCMS (International Caries Classification and Management System) with a conventional caries-management system (CCMS) in terms of individual caries-risk, caries lesions, and secondarily, oral-health-related knowledge/attitudes/practices, and number of appointments. Material and methods With ethical approval, 240 6–7-year olds from six Colombian clinics were recruited. Trained examiners conducted the following baseline/follow-up assessments: Caries risk (Cariogram-ICCMS); caries severity/activity staging (ICDAS-merged combined radiographic/visual); sealants/fillings/missing teeth, and oral-health-related knowledge, attitudes and practices. Children received their randomly allocated (ICCMS/CCMS) care from dental practitioners. Outcomes: caries-risk control (children); caries-progression control (tooth surfaces); oral-health-related knowledge/attitudes/practices improvement (parents/children), and appointments’ number (children). Descriptive and non-parametric/parametric bivariate analyses were performed. Results Three-year-follow-up: n = 187 (77.9%; ICCMS: n = 92; CCMS: n = 95) disclosed a baseline-to-3-year overall high-caries-risk children decrease (ICCMS: 60.9–0%, p < .001; CCMS: 54.7–5.3%, p < .001) (p > .05). ICCMS versus CCMS showed: fewer tooth-surface caries progression (6.2% vs 7.1%, p = .010) and fewer active-caries lesions (49.8% vs. 59.1%, p < .05); higher proportion of children with ≥2/day fluoride-toothpaste tooth-brushing practice (p < .05); similar mean number of appointments (10.9 ± 5.9 vs. 10.0 ± 3.8, p = .15). Conclusion Both caries-management systems showed similar effectiveness in caries-risk control, with ICCMS more effectively controlling tooth-surface caries progression and improving toothbrushing practices.
Augmenter of liver regeneration protects the kidney against ischemia-reperfusion injury by inhibiting necroptosis

ABSTRACT Necroptosis plays an important role in the pathogenesis of acute kidney injury (AKI), and necroptosis-related interventions may therefore be an important measure for the treatment of AKI. Our previous study has shown that augmenter of liver regeneration (ALR) inhibits renal tubular epithelial cell apoptosis and regulates autophagy; however, the influence of ALR on necroptosis remains unclear. In this study, we investigated the effect of ALR on necroptosis caused by ischemia-reperfusion and the underlying mechanism. In vivo experiments indicated that kidney-specific knockout of ALR aggravated the renal dysfunction and pathological damage induced by ischemia-reperfusion. Simultaneously, the expression of renal necroptosis-associated protein receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), and mixed-lineage kinase domain-like protein (MLKL) significantly increased. In vitro experiments indicated that overexpression of ALR decreased the expression of hypoxia-reoxygenation-induced kidney injury molecules, the inflammation-associated factor tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein. Additionally, the expression of RIP1, RIP3, and MLKL, which are elevated after hypoxia and reoxygenation, was also inhibited by ALR overexpression. Both in vivo and in vitro results indicated that ALR has a protective effect against acute kidney injury caused by ischemia-reperfusion, and the RIP1/RIP3/MLKL pathway should be further verified as a probable necroptosis regulating mechanism. Graphical abstract
Psychometric properties of the Portuguese teacher-version of the Inventory of Callous-Unemotional Traits

Callous unemotional (CU) traits refer to specific deficits in affective experience and interpersonal style, characterized by absence of guilt, constrictive display of emotion and failure to show empathy, callous use of others for one’s own gain. The Inventory of Callous-Unemotional Traits (ICU) was developed to measure CU traits in children and adolescents. The aim of this study was to analyze the factorial structure of the Portuguese version of teacher-report ICU for children in school age and examine psychometric properties such as internal consistency and convergent validity in a community sample. Thirty-six teachers provided behavioral ratings of 100 and 78 children of elementary school, 88 boys and 90 girls, aged between 6 and 10 years old. Confirmatory factor analyses provided further support to a 2-factor structure, comprising the following dimensions: callous and uncaring. This study showed that the ICU seems a reliable an accessible tool that can be used in the Portuguese educational context to evaluate CU traits with low time consumption.