Miracle-dz/UniFAR-FTUs huggingface dataset:
Echocardiographic reference ranges for normal non-invasive myocardial work indices: results from the EACVI NORRE study.

AIMS To obtain the normal ranges for 2D echocardiographic (2DE) indices of myocardial work (MW) from a large group of healthy volunteers over a wide range of ages and gender. METHODS AND RESULTS A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from left ventricle (LV) pressure-strain loops. Peak LV systolic pressure was non-invasively derived from brachial artery cuff pressure. The lowest values of MW indices in men and women were 1270 mmHg% and 1310 mmHg% for GWI, 1650 mmHg% and 1544 mmHg% for GCW, and 90% and 91% for GWE, respectively. The highest value for GWW was 238 mmHg% in men and 239 mmHg% in women. Men had significant lower values of GWE and higher values of GWW. GWI and GCW significantly increased with age in women. CONCLUSION The NORRE study provides useful 2DE reference ranges for novel indices of non-invasive MW.
Recurrent connections between CA2 pyramidal cells

Recurrent excitatory synapses are shown theoretically to play roles in memory storage and associative learning, and such recurrent synapses are well described to occur in the CA3 region of the hippocampus. Here, we report that the CA2 region also contains recurrent excitatory monosynaptic couplings. Using dual whole-cell patch-clamp recordings from CA2 pyramidal cells in mouse hippocampal slices under differential interference contrast microscopic controls, we evaluated monosynaptic excitatory connections. Unitary excitatory postsynaptic potentials occurred in 1.4% of 502 cell pairs. These connected pairs were located preferentially in the superficial layer and proximal part (CA2b) of the CA2 region. These results indicate that recurrent excitatory circuits are dense in the CA2 region as well as in the CA3 region.
Heterogeneity in studies of p16 in cervical lesions in different Malaysian institutions: Time to consider collaborative study.

INTRODUCTION Clinical decision making becomes difficult when clinical and methodological heterogeneity does not permit synthesis of results of multiple small studies. AIM For studies done in Malaysia, to identity the sample sizes and heterogeneity present in the various studies which used p16 in evaluating lesions of the cervix. To evaluate if it would be possible for a single study to answer the various questions posed by the original authors. To highlight areas where the design features of future studies can be optimised. MATERIALS AND METHODS Various databases were searched using synonyms for p16 AND cervix AND Malaysia. These were assessed for broad conformity to a Diagnostic Test Accuracy format. Methodological and clinical heterogeneity indicators were extracted into standardised fields. RESULTS There were 5 studies eligible for inclusion. Each sought to study different aspects of the disease such as diagnostic grade stratification and pathogenesis. The study type broadly conformed to a Diagnostic Test Accuracy format. The study design used was either consecutive or non-consecutive. Sample size ranged from 75 to 201. Clinical heterogeneity was present in the choice of controls with some using normal and some using inflamed tissue. Methodological heterogeneity in applying the reference test, index test and different antibody clones were present. CONCLUSION There was both clinical and methodological heterogeneity making synthesis of studies difficult. It is possible to design a study which would be able to answer all the questions posed by the original authors with internal validity while at the same time increasing sample size.
A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.
An Alternative Platform for Protein Expression Using an Innate Whole Expression Module from Metagenomic DNA

Many integrated gene clusters beyond a single genetic element are commonly trapped as the result of promoter traps in (meta)genomic DNA libraries. Generally, a single element, which is mainly the promoter, is deduced from the resulting gene clusters and employed to construct a new expression vector. However, expression patterns of target proteins under the incorporated promoter are often inconsistent with those shown in clones harboring plasmids with gene clusters. These results suggest that the integrated set of gene clusters with diverse cis- and trans-acting elements is evolutionarily tuned as a complete set for gene expression, and is an expression module with all the components for the expression of a nested open reading frame (ORF). This possibility is further supported by truncation and/or serial deletion analysis of this module in which the expression of the nested ORF is highly fluctuated or reduced frequently, despite being supported by plentiful cis-acting elements in the spanning regions around the ORF such as the promoter, ribosome binding site (RBS), terminator, and 3′-/5′-UTRs for gene expression. Here, we examined whether an innate module with a naturally overexpressed gene could be considered as a scaffold for an expression system. For a proof-of-principle study, we mined a complete expression module with an innately overexpressed ORF in E. coli from a metagenomics DNA library, and incorporated it into a vector that had no regulatory element for expressing the insert. We obtained successful expression of several inserts such as MBP, GFPuv, β-glucosidase, and esterase using this simple construct without tuning and codon optimization of the target insert.
Hypertrophic Cardiomyopathy in Patients with Atrial Fibrillation: Prevalence and Associated Stroke Risks in a Nationwide Cohort Study

Abstract Background There have been no prior nationwide reports on the prevalence of hypertrophic cardiomyopathy (HCM) among patients suffering from atrial fibrillation (AF). It is also unclear how much stroke risk is attributable to HCM compared with other stroke risks in patients with AF. This study assessed the prevalence of HCM among non-valvular AF (NVAF) patients and to assess the magnitude of increase in stroke risk in NVAF patients with HCM, compared with those without HCM. Patients and Methods From the Korean National Health Insurance Service database from January 1, 2005 to December 31, 2016, we analysed 979,784 patients with prevalent NVAF aged 18 years or older. Results The overall HCM prevalence in NVAF patients was 1.1%. Although HCM in these patients is an absolute indication for oral anticoagulant (OAC) prescription, only 1,622 (15.3%) patients were receiving OAC at the time of AF diagnosis. Among OAC-naïve patients with NVAF, compared with those without HCM, those with HCM had the increased risk of ischaemic stroke/systemic embolism with clinical variable adjusted hazard ratio of 1.55 (95% confidential interval, 1.48–1.63; p < 0.001). Ischaemic stroke/systemic embolism rate of NVAF patients with HCM without any non-gender CHA2DS2-VASc stroke risk factors was 4.02 per 100 person-years, and approached to that of NVAF patients without HCM with CHA2DS2-VASc score of 3 (4.07 per 100 person-years). Conclusion Among all NVAF patients, 1.1% of patient has HCM. The risk of stroke in NVAF with HCM without any CHA2DS2-VASc stroke risk factors was similar to that of those patients without HCM with CHA2DS2-VASc score of 3. Despite this, the actual use of OACs among NVAF patients with HCM was sub-optimal, relative to their high stroke risk.
Respiratory Dysfunction in Craniovertebral Junction Pathology: A Pulmonary Function Test Correlation

Introduction: Respiratory dysfunction in craniovertebral junction (CVJ) pathology can be due to (1) direct compression of neural tissue, or (2) weakness of muscles of respiration. Majority of the times, this impairment is clinically occult. The outcome of a patient with CVJ anomaly is also dependent upon his/her respiratory function. Objective: To assess the respiratory function following relief of compression in the early postoperative (within first week of surgery) and late postoperative period (3 months or more after surgery) and to compare with preoperative status using pulmonary function tests (PFTs). Materials and methods: Twenty-five patients with CVJ pathology underwent bedside evaluation with single breath count (SBC) and respiratory system examination. Spirometry was performed in the preoperative phase and immediate postoperative phase and on follow-up (3 months), and the results were compared and analyzed between the preoperative and postoperative phases and also were compared with healthy, ageand sex-matched controls. Descriptive statistical analysis was carried out using Student’s t-test. Wilcoxon signed rank test was used to find the significance of study parameters between preand postintervention in each group. Statistical software Statistical Package for the Social Sciences (SPSS) version 15.0, Stata 8.0, MedCalc 9.0. 1, and Systat 11.0 were used for the analysis of the data. Results: Twenty-five patients underwent preoperative and early postoperative and late postoperative evaluation. Majority were in their second and third decades of life. Males were predominant (76%). Atlantoaxial dislocation (AAD) was the most common pathology. All parameters, viz., forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), ratio between FEV1 and FVC (FEV1:FVC), forced expiratory flow, maximal voluntary ventilation (MVV), and peak expiratory flow rate (PEFR) showed significant compromise in the preoperative period compared with normative data, and improvement in all these values occurred in late postoperative period only. JOSS
The Minds of God(s) and Humans: Differences in Mind Perception in Fiji and North America

Abstract Previous research suggests that how people conceive of minds depends on the culture in which they live, both in determining how they interact with other human minds and how they infer the unseen minds of gods. We use exploratory factor analysis to compare how people from different societies with distinct models of human minds and different religious traditions perceive the minds of humans and gods. In two North American samples (American adults, N = 186; Canadian students, N = 202), we replicated a previously found two‐factor agency/experience structure for both human and divine minds, but in Fijian samples (Indigenous iTaukei Fijians, N = 77; Fijians of Indian descent, N = 214; total N = 679) we found a three‐factor structure, with the additional containing items related to social relationships. Further, Fijians’ responses revealed a different three‐factor structure for human minds and gods’ minds. We used these factors as dimensions in the conception of minds to predict (a) expectations about human and divine tendencies towards punishment and reward; and (b) conception of gods as more embodied (an extension of experience) or more able to know people's thoughts (an extension of agency). We found variation in how these factors predict conceptions of agents across groups, indicating further theory is needed to explain how culturally generated concepts of mind lead to other sorts of social inferences. We conclude that mind perception is shaped by culturally defined social expectations and recommend further work in different cultural contexts to examine the interplay between culture and social cognition.
Crack paths under mixed mode (I + III) or (I + II + III) loadings

Des experiences de fracture et de fatigue que nous avons realisees en mode mixte (I + III) et (I + II + III) ont montre que le front de fissure se propage en tournant progressivement autour de la direction de propagation, tendant ainsi vers une situation de mode I pur. Il en resulte que l'angle de branchement de l'extension est variable le long du front initial. L'objectif de cette note est la determination de la valeur de cet angle de branchement le long du front, dans le cadre de la mecanique lineaire de la rupture fragile. Les valeurs obtenues sont comparees aux valeurs experimentales.
Where is the “where” in the brain? A meta‐analysis of neuroimaging studies on spatial cognition

Spatial representations are processed in the service of several different cognitive functions. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta‐analysis to identify: (a) the shared neural activations among spatial functions to reveal the “core” network of spatial processing; (b) the specific neural activations associated with each of these functions. Following PRISMA guidelines, a total of 133 fMRI and PET studies were included in the meta‐analysis. The overall analysis showed that the core network of spatial processing comprises regions that are symmetrically distributed on both hemispheres and that include dorsal frontoparietal regions, presupplementary motor area, anterior insula, and frontal operculum. The specific analyses revealed the brain regions that are selectively recruited for each spatial function, such as the right temporoparietal junction for shift of spatial attention, the right parahippocampal gyrus, and the retrosplenial cortex for navigation and spatial long‐term memory. The findings are integrated within a systematic review of the neuroimaging literature and a new neurocognitive model of spatial cognition is proposed.
Effect of Rosuvastatin in Preventing Chemotherapy-Induced Cardiotoxicity in Women With Breast Cancer: A Randomized, Single-Blind, Placebo-Controlled Trial

Objective: Chemotherapy-induced cardiotoxicity is a major and leading cause of death in breast cancer survivors. It can present decades after chemotherapy and can manifest in different ways; some chemotherapeutic agents have a powerful dose-dependent relationship with cardiotoxicity. The aim of this study was to investigate the effect of rosuvastatin on preventing chemotherapy-induced cardiotoxicity in patients with breast cancer. Methods: Our study was a randomized, single-blind, placebo-controlled trial that involved 89 women with newly diagnosed breast cancer who were scheduled to receive chemotherapy. Patients were randomly assigned to receive rosuvastatin or a placebo in a 1:1 ratio for 6 months. Echocardiography, using 2-dimensional (2D) Doppler, tissue Doppler, and speckle-tracking methods, was used to determine the absolute changes in the left ventricular systolic ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left atrial (LA) diameter, transmitral Doppler early diastolic velocity (E wave), tissue Doppler early diastolic (e′) and peak systolic (s′) mitral annular velocities, E/e′ ratio, and global longitudinal systolic strain. Results: The LVEF was significantly reduced in the placebo group at the end of the study when compared with the baseline value. However, there was no significant difference in the LVEF in the intervention group (intergroup P = .012). Furthermore, compared with the intervention group at the end of the study, there was a significant increase in the 4- and 2-chamber LVESV, LA diameter, and E/e′ ratio in the placebo group (intergroup P = .019, P = .024, P < .001, and P = .021, respectively) and a significant decrease in the e′ and s′ velocities in the placebo group (intergroup P < .001 and P < .006, respectively). Conclusions: The present study showed that the prophylactic use of rosuvastatin may prevent the development of chemotherapy-induced cardiotoxicity.
ADHD risk genes involved in dopamine signaling and metabolism are associated with reduced estimated life expectancy at young adult follow‐up in hyperactive and control children

ADHD is associated with an elevated risk of mortality and reduced estimated life expectancy (ELE) by adulthood. Reduced life expectancy is substantially related to the trait of behavioral disinhibition; a correlate of both ADHD and of several dopamine genes related to dopamine signaling and metabolism. We therefore hypothesized that several ADHD risk genes related to dopamine might also be predictive of reduced ELE. Using a longitudinal study of 131 hyperactive children and 71 control cases followed to young adulthood, we examined whether several polymorphisms involving DRD4, DAT1, and DBH were related to ELE. The homozygous 9/9 allele of DAT1 and the heterozygous allele of DBH TaqI were associated with 5‐ and 2‐year reductions, respectively, in total ELE. They did not operate on ELE through any relationships to ADHD specifically or behavioral disinhibition more generally. Instead, they showed links to alcohol use (DBH), reduced education, smoking, and reduced exercise (DAT1) employed in the computation of ELE. We conclude that polymorphisms of two dopamine genes are linked to reductions in ELE independently of their association with ADHD.
Mouse Parabrachial Neurons Signal a Relationship between Bitter Taste and Nociceptive Stimuli

Taste and somatosensation both mediate protective behaviors. Bitter taste guides avoidance of ingestion of toxins while pain sensations, such as noxious heat, signal adverse conditions to ward off harm. Although brain pathways for taste and somatosensation are typically studied independently, prior data suggest that they intersect, potentially reflecting their common protective role. To investigate this, we applied electrophysiologic and optogenetic techniques in anesthetized mice of both sexes to evaluate relationships between oral somatosensory and taste activity in the parabrachial nucleus (PbN), implicated for roles in gustation and pain. Spikes were recorded from taste-active PbN neurons tested with oral delivery of thermal and chemesthetic stimuli, including agonists of nocisensitive transient receptor potential (TRP) ion channels on somatosensory fibers. Gustatory neurons were also tested to follow electrical pulse stimulation of an oral somatosensory region of the spinal trigeminal subnucleus caudalis (Vc), which projects to the PbN. Neurons composed classic taste groups, including sodium, electrolyte, appetitive, or bitter cells. Across groups, most neurons spiked to Vc pulse stimulation, implying that trigeminal projections reach PbN gustatory neurons. Among such cells, a subpopulation responsive to the bitter taste stimuli quinine and cycloheximide, and aversive concentrations of sodium, cofired to agonists of nocisensitive TRP channels, including capsaicin, mustard oil, and noxious heat. Such neurons populated the lateral PbN. Further, nociceptive activity in PbN bitter taste neurons was suppressed during optogenetic-assisted inhibition of the Vc, implying convergent trigeminal input contributed to such activity. Our results reveal a novel role for PbN gustatory cells in cross-system signaling related to protection. SIGNIFICANCE STATEMENT Prior data suggest that gustatory and trigeminal neural pathways intersect and overlap in the parabrachial area. However, no study has directly examined such overlap and why it may exist. Here we found that parabrachial gustatory neurons can receive afferent projections from trigeminal nuclei and fire to oral nociceptive stimuli that excite somatosensory receptors and fibers. Activation to aversive nociceptive stimuli in gustatory cells was associated with responding to behaviorally avoided bitter tastants. We were further able to show that silencing trigeminal projections inhibited nociceptive activity in parabrachial bitter taste neurons. Our results imply that in the parabrachial area, there is predictable overlap between taste and somatosensory processing related to protective coding and that classically defined taste neurons contribute to this process.
Functional characterization of the ZEB2 regulatory landscape

Zinc finger E-box-binding homeobox 2 (ZEB2) is a key developmental regulator of the central nervous system (CNS). Although the transcriptional regulation of ZEB2 is essential for CNS development, the elements that regulate ZEB2 expression have yet to be identified. Here, we identified a proximal regulatory region of ZEB2 and characterized transcriptional enhancers during neuronal development. Using chromatin immunoprecipitation sequencing for active (H3K27ac) and repressed (H3K27me3) chromatin regions in human neuronal progenitors, combined with an in vivo zebrafish enhancer assay, we functionally characterized 18 candidate enhancers in the ZEB2 locus. Eight enhancers drove expression patterns that were specific to distinct mid/hindbrain regions (ZEB2#e3 and 5), trigeminal-like ganglia (ZEB2#e6 and 7), notochord (ZEB2#e2, 4 and 12) and whole brain (ZEB2#e14). We further dissected the minimal sequences that drive enhancer-specific activity in the mid/hindbrain and notochord. Using a reporter assay in human cells, we showed an increased activity of the minimal notochord enhancer ZEB2#e2 in response to AP-1 and DLX1/2 expressions, while repressed activity of this enhancer was seen in response to ZEB2 and TFAP2 expressions. We showed that Dlx1 but not Zeb2 and Tfap2 occupies Zeb2#e2 enhancer sequence in the mouse notochord at embryonic day 11.5. Using CRISPR/Cas9 genome editing, we deleted the ZEB2#e2 region, leading to reduction of ZEB2 expression in human cells. We thus characterized distal transcriptional enhancers and trans-acting elements that govern regulation of ZEB2 expression during neuronal development. These findings pave the path toward future analysis of the role of ZEB2 regulatory elements in neurodevelopmental disorders, such as Mowat-Wilson syndrome.