Miracle-dz/UniFAR-FTUs huggingface dataset:
Muscle Oxygen Supply and Use in Type 1 Diabetes, From Ambient Air to the Mitochondrial Respiratory Chain: Is There a Limiting Step?

OBJECTIVE Long before clinical complications of type 1 diabetes (T1D) develop, oxygen supply and use can be altered during activities of daily life. We examined in patients with uncomplicated T1D all steps of the oxygen pathway, from the lungs to the mitochondria, using an integrative ex vivo (muscle biopsies) and in vivo (during exercise) approach. RESEARCH DESIGN AND METHODS We compared 16 adults with T1D with 16 strictly matched healthy control subjects. We assessed lung diffusion capacity for carbon monoxide and nitric oxide, exercise-induced changes in arterial O2 content (SaO2, PaO2, hemoglobin), muscle blood volume, and O2 extraction (via near-infrared spectroscopy). We analyzed blood samples for metabolic and hormonal vasoactive moieties and factors that are able to shift the O2-hemoglobin dissociation curve. Mitochondrial oxidative capacities were assessed in permeabilized vastus lateralis muscle fibers. RESULTS Lung diffusion capacity and arterial O2 transport were normal in patients with T1D. However, those patients displayed blunted exercise-induced increases in muscle blood volume, despite higher serum insulin, and in O2 extraction, despite higher erythrocyte 2,3-diphosphoglycerate. Although complex I– and complex II–supported mitochondrial respirations were unaltered, complex IV capacity (relative to complex I capacity) was impaired in patients with T1D, and this was even more apparent in those with long-standing diabetes and high HbA1c. O2max was lower in patients with T1D than in the control subjects. CONCLUSIONS Early defects in microvascular delivery of blood to skeletal muscle and in complex IV capacity in the mitochondrial respiratory chain may negatively impact aerobic fitness. These findings are clinically relevant considering the main role of skeletal muscle oxidation in whole-body glucose disposal.
Extensive culturomics of 8 healthy samples enhances metagenomics efficiency

Molecular approaches have long led to the assumption that the human gut microbiota is dominated by uncultivable bacteria. The recent advent of large-scale culturing methods, and in particular that of culturomics have demonstrated that these prokaryotes can in fact be cultured. This is increasing in a dramatic manner the repertoire of commensal microbes inhabiting the human gut. Following eight years of culturomics approach applied on more than 900 samples, we propose herein a remake of the pioneering study applying a dual approach including culturomics and metagenomics on a cohort of 8 healthy specimen. Here we show that culturomics enable a 20% higher richness when compared to molecular approaches by culturing 1 archaeal species and 494 bacterial species of which 19 were new taxa. Species discovered as a part of previous culturomics studies represent 30% of the cultivated isolates, while sequences derived from these new taxa enabled to increase by 22% the bacterial richness retrieved by metagenomics. Overall, 67% of the total reads generated were covered by cultured isolates, significantly reducing the hidden content of sequencing methods compared to the pioneering study. By redefining culture conditions to recover microbes previously considered fastidious, there are greater opportunities than ever to eradicate metagenomics dark matter.
Adaptor protein complexes and disease at a glance

ABSTRACT Adaptor protein (AP) complexes are heterotetramers that select cargo for inclusion into transport vesicles. Five AP complexes (AP-1 to AP-5) have been described, each with a distinct localisation and function. Furthermore, patients with a range of disorders, particularly involving the nervous system, have now been identified with mutations in each of the AP complexes. In many cases this has been correlated with aberrantly localised membrane proteins. In this Cell Science at a Glance article and the accompanying poster, we summarize what is known about the five AP complexes and discuss how this helps to explain the clinical features of the different genetic disorders. Summary: Adaptor protein complexes select cargo for transport between subcellular compartments. Disease-causing mutations identified in each of the five complexes cause certain membrane proteins to be mislocalised.
Fixation-pattern similarity analysis reveals adaptive changes in face-viewing strategies following aversive learning

Animals can effortlessly adapt their behavior by generalizing from past aversive experiences, allowing to avoid harm in novel situations. We studied how visual information was sampled by eye-movements during this process called fear generalization, using faces organized along a circular two-dimensional perceptual continuum. During learning, one face was conditioned to predict a harmful event, whereas the most dissimilar face stayed neutral. This introduced an adversity gradient along one specific dimension, while the other, unspecific dimension was defined solely by perceptual similarity. Aversive learning changed scanning patterns selectively along the adversity-related dimension, but not the orthogonal dimension. This effect was mainly located within the eye region of faces. Our results provide evidence for adaptive changes in viewing strategies of faces following aversive learning. This is compatible with the view that these changes serve to sample information in a way that allows discriminating between safe and adverse for a better threat prediction.
Basic Properties of a New Polymer Gel for 3D-Dosimetry at High Dose-Rates Typical for FFF Irradiation Based on Dithiothreitol and Methacrylic Acid (MAGADIT): Sensitivity, Range, Reproducibility, Accuracy, Dose Rate Effect and Impact of Oxygen Scavenger

The photon induced radical-initiated polymerization in polymer gels can be used for high-resolution tissue equivalent dosimeters in quality control of radiation therapy. The dose (D) distribution in radiation therapy can be measured as a change of the physical measurement parameter T2 using T2-weighted magnetic resonance imaging. The detection by T2 is relying on the local change of the molecular mobility due to local polymerization initiated by radicals generated by the ionizing radiation. The dosimetric signals R2 = 1/T2 of many of the current polymer gels are dose-rate dependent, which reduces the reliability of the gel for clinical use. A novel gel dosimeter, based on methacrylic acid, gelatin and the newly added dithiothreitol (MAGADIT) as an oxygen-scavenger was analyzed for basic properties, such as sensitivity, reproducibility, accuracy and dose-rate dependence. Dithiothreitol features no toxic classification with a difference to THPC and offers a stronger negative redox-potential than ascorbic acid. Polymer gels with three different concentration levels of dithiothreitol were irradiated with a preclinical research X-ray unit and MR-scanned (T2) for quantitative dosimetry after calibration. The polymer gel with the lowest concentration of the oxygen scavenger was about factor 3 more sensitive to dose as compared to the gel with the highest concentration. The dose sensitivity (α = ∆R2/∆D) of MAGADIT gels was significantly dependent on the applied dose rate D˙ (≈48% reduction between D˙ = 0.6 Gy/min and D˙ = 4 Gy/min). However, this undesirable dose-rate effect reduced between 4–8 Gy/min (≈23%) and almost disappeared in the high dose-rate range (8 ≤ D˙≤ 12 Gy/min) used in flattening-filter-free (FFF) irradiations. The dose response varied for different samples within one manufacturing batch within 3%–6% (reproducibility). The accuracy ranged between 3.5% and 7.9%. The impact of the dose rate on the spatial integrity is demonstrated in the example of a linear accelerator (LINAC) small sized 5 × 10 mm2 10 MV photon field. For MAGADIT the maximum shift in the flanks in this field is limited to about 0.8 mm at a FFF dose rate of 15 Gy/min. Dose rate sensitive polymer gels likely perform better at high dose rates; MAGADIT exhibits a slightly improved performance compared to the reference normoxic polymer gel methacrylic and ascorbic acid in gelatin initiated by copper (MAGIC) using ascorbic acid.
Parental Socialization, School Adjustment and Cyber-Aggression among Adolescents

The objective of the present study is to analyse the relationships between parental socialization styles—indulgent, authoritarian, authoritative and negligent, school adjustment (social integration, academic competence and family involvement) and cyber-aggression (direct and indirect) in adolescents. Participating in this study were 1304 Spanish students of both sexes (53.1% girls), aged between 12 and 18 years (M = 13.87, SD = 1.33). Multivariate analyses of variance were performed. The results showed significant relationships between parental socialization styles, school adjustment and cyber-aggression. It was observed that adolescents from indulgent and authoritative families showed greater academic competence and greater family involvement. Additionally, the children from authoritarian families displayed greater involvement in direct and indirect cyber-aggression behaviours. The results obtained and their implications are discussed in the final section.
Frequency and format of clinical trial results dissemination to patients: a survey of authors of trials indexed in PubMed

Objective Dissemination of research findings is central to research integrity and promoting discussion of new knowledge and its potential for translation into practice and policy. We investigated the frequency and format of dissemination to trial participants and patient groups. Design Survey of authors of clinical trials indexed in PubMed in 2014–2015. Results Questionnaire emailed to 19 321 authors; 3127 responses received (16%). Of these 3127 trials, 2690 had human participants and 1818 enrolled individual patients. Among the 1818, 498 authors (27%) reported having disseminated results to participants, 238 (13%) planned to do so, 600 (33%) did not plan to, 176 (10%) were unsure and 306 (17%) indicated ‘other’ or did not answer. Of the 498 authors who had disseminated, 198 (40%) shared academic reports, 252 (51%) shared lay reports, 111 (22%) shared both and 164 (33%) provided individualised study results. Of the 1818 trials, 577 authors (32%) shared/planned to share results with patients outside their trial by direct contact with charities/patient groups, 401 (22%) via patient communities, 845 (46%) via presentations at conferences with patient representation, 494 (27%) via mainstream media and 708 (39%) by online lay summaries. Relatively few of the 1818 authors reported dissemination was suggested by institutional bodies: 314 (17%) of funders reportedly suggested dissemination to trial participants, 252 (14%) to patient groups; 333 (18%) of ethical review boards reportedly suggested dissemination to trial participants, 148 (8%) to patient groups. Authors described many barriers to dissemination. Conclusion Fewer than half the respondents had disseminated to participants (or planned to) and only half of those who had disseminated shared lay reports. Motivation to disseminate results to participants appears to arise within research teams rather than being incentivised by institutional bodies. Multiple factors need to be considered and various steps taken to facilitate wide dissemination of research to participants.
Using Methacryl-Polyhedral Oligomeric Silsesquioxane as the Thermal Stabilizer and Plasticizer in Poly(vinyl chloride) Nanocomposites

In this study, we investigated the influence of methacryl-functionalized polyhedral oligomeric silsesquioxane (MA-POSS) nanoparticles as a plasticizer and thermal stabilizer for a poly(vinyl chloride) (PVC) homopolymer and for a poly(vinyl chloride)/dissononyl cyclohexane-1,2-dicarboxylate (PVC/DINCH) binary blend system. The PVC and the PVC/DINCH blend both became flexible, with decreases in their glass transition temperatures and increases in their thermal decomposition temperatures, upon an increase in MA-POSS content, the result of hydrogen bonding between the C=O groups of MA-POSS and the H–CCl units of the PVC, as determined using infrared spectroscopy. Furthermore, the first thermal decomposition temperature of the pure PVC, due to the emission of HCl, increased from 290 to 306 °C, that is, the MA-POSS nanoparticles had a retarding effect on the decomposition of the PVC matrix. In tensile tests, all the PVC/DINCH/MA-POSS ternary blends were transparent and displayed flexibility, but their modulus and tensile strength both decreased, while their elongation properties increased, upon an increase in MA-POSS concentration, both before and after thermal annealing. In contrast, the elongation decreased, but the modulus and tensile strength increased, after thermal annealing at 100 °C for 7 days.
Corticobasal ganglia projecting neurons are required for juvenile vocal learning but not for adult vocal plasticity in songbirds

Significance We addressed the question, “How do corticobasal ganglia projecting neurons contribute to vocal learning? ” We performed specific ablation of the vocal cortical neurons projecting to the basal ganglia, HVC(X) neurons in a songbird, which generate temporally precise firing during singing. Specific ablation of HVC(X) neurons in juveniles caused deficits in learning the tutor song’s acoustics and less consistency of song sequence. In contrast, adult HVC(X) neuron ablation did not affect the degree of vocal fluctuations or cause alteration in song structure by auditory feedback inhibition. These results support the hypothesis that HVC(X) neurons are a neural substrate for transferring temporal signals, but not for regulating vocal fluctuations or conveying auditory feedback, to the basal ganglia for vocal learning and maintenance. Birdsong, like human speech, consists of a sequence of temporally precise movements acquired through vocal learning. The learning of such sequential vocalizations depends on the neural function of the motor cortex and basal ganglia. However, it is unknown how the connections between cortical and basal ganglia components contribute to vocal motor skill learning, as mammalian motor cortices serve multiple types of motor action and most experimentally tractable animals do not exhibit vocal learning. Here, we leveraged the zebra finch, a songbird, as an animal model to explore the function of the connectivity between cortex-like (HVC) and basal ganglia (area X), connected by HVC(X) projection neurons with temporally precise firing during singing. By specifically ablating HVC(X) neurons, juvenile zebra finches failed to copy tutored syllable acoustics and developed temporally unstable songs with less sequence consistency. In contrast, HVC(X)-ablated adults did not alter their learned song structure, but generated acoustic fluctuations and responded to auditory feedback disruption by the introduction of song deterioration, as did normal adults. These results indicate that the corticobasal ganglia input is important for learning the acoustic and temporal aspects of song structure, but not for generating vocal fluctuations that contribute to the maintenance of an already learned vocal pattern.
Group-specific archaeological signatures of stone tool use in wild macaques

Stone tools in the prehistoric record are the most abundant source of evidence for understanding early hominin technological and cultural variation. The field of primate archaeology is well placed to improve our scientific knowledge by using the tool behaviours of living primates as models to test hypotheses related to the adoption of tools by early stone-age hominins. Previously we have shown that diversity in stone tool behaviour between neighbouring groups of long-tailed macaques (Macaca-fascicularis) could be explained by ecological and environmental circumstances (Luncz et al., 2017b). Here however, we report archaeological evidence, which shows that the selection and reuse of tools cannot entirely be explained by ecological diversity. These results suggest that tool-use may develop differently within species of old-world monkeys, and that the evidence of material culture can differ within the same timeframe at local geographic scales and in spite of shared environmental and ecological settings.
Barrier Lyapunov Function-Based Adaptive Fault-Tolerant Control for a Class of Strict-Feedback Stochastic Nonlinear Systems

This article investigates the adaptive fuzzy fault-tolerant control problem for a class of strict-feedback stochastic nonlinear systems with quantized input signal. A hysteretic quantizer is utilized to avoid chattering caused by quantized input signals. The fuzzy-logic systems are utilized to approximate the unknown nonlinear functions and also to construct the fuzzy state observer, which is used to estimate the immeasurable state vector. The actuator faults considered in this article are loss of effectiveness and lock-in-place faults. By using the Lyapunov stability theory, the closed-loop stochastic nonlinear system is guaranteed to be stable in probability, and all the signals of the closed-loop system are bounded in probability in the presence of quantized input and actuator faults. Finally, a simulation example is given to verify the validity of the proposed control strategy.
Global selective sweep of a highly inbred genome of the cattle parasite Neospora caninum

Significance The parasite Neospora caninum has a worldwide distribution and causes fetal loss in livestock. It is transmitted in cows vertically (from mother to fetus), and in some herds nearly all cattle are infected. We genotyped Neospora strains isolated from an array of infected hosts (dogs, cattle, deer, horse, rhinoceros) and observed a single, highly inbred genome that has swept globally. At first glance, data support vertical transmission as a primary mode for the expansion of the parasite genome; however, genome-level analyses identified large introgression blocks of a distinct ancestry that has recombined into the genome, consistent with a unisexual expansion model. The successful genome appears to have piggy-backed on the expansion of European cattle breeds that have been exported globally. Neospora caninum, a cyst-forming apicomplexan parasite, is a leading cause of neuromuscular diseases in dogs as well as fetal abortion in cattle worldwide. The importance of the domestic and sylvatic life cycles of Neospora, and the role of vertical transmission in the expansion and transmission of infection in cattle, is not sufficiently understood. To elucidate the population genomics of Neospora, we genotyped 50 isolates collected worldwide from a wide range of hosts using 19 linked and unlinked genetic markers. Phylogenetic analysis and genetic distance indices resolved a single genotype of N. caninum. Whole-genome sequencing of 7 isolates from 2 different continents identified high linkage disequilibrium, significant structural variation, but only limited polymorphism genome-wide, with only 5,766 biallelic single nucleotide polymorphisms (SNPs) total. Greater than half of these SNPs (∼3,000) clustered into 6 distinct haploblocks and each block possessed limited allelic diversity (with only 4 to 6 haplotypes resolved at each cluster). Importantly, the alleles at each haploblock had independently segregated across the strains sequenced, supporting a unisexual expansion model that is mosaic at 6 genomic blocks. Integrating seroprevalence data from African cattle, our data support a global selective sweep of a highly inbred livestock pathogen that originated within European dairy stock and expanded transcontinentally via unisexual mating and vertical transmission very recently, likely the result of human activities, including recurrent migration, domestication, and breed development of bovid and canid hosts within similar proximities.
Nanomechanical properties of steric zipper globular structures

Significance The increase in life expectancy has nowadays positioned neurodegenerative diseases as a leading cause of death. Neurodegeneration is related to early amyloid protein aggregation; however, in the lack of an aggregation mechanism, neurodegenerative diseases still remain neither cured nor prevented. In a fundamental study of amyloid early aggregation, we have characterized the nanomechanical properties of steric zippers, the shortest amyloid sequences that yet bear high propensity to form fibers. We have found that steric zippers form unprecedented globular structures on route to fiber formation that exhibit a characteristic nanomechanical fingerprint. Approaching amyloid fiber formation from a basic physical perspective, this study sheds light on the internal structure of amyloid precursor chains, providing insight into the design of antiamyloid drugs. The term amyloid defines a group of proteins that aggregate into plaques or fibers. Amyloid fibers gained their fame mostly due to their relation with neurodegenerative diseases in humans. However, secreted by lower organisms, such as bacteria and fungi, amyloid fibers play a functional role: for example, when they serve as cement in the extracellular matrix of biofilms. Originating either in humans or in microorganisms, the sequence of amyloid proteins is decorated with hexapeptides with high propensity to form fibers, known as steric zippers. We have found that steric zippers form globular structures on route to making fibers and exhibit a characteristic force–distance (F-D) fingerprint when pulled with an atomic force microscope (AFM) tip. Particularly, the F-D pulling curves showed force plateau steps, suggesting that the globular structures were composed of chains that were unwound like a yarn ball. Force plateau analysis showed that the F-D characteristic parameters were sequence sensitive, representing differences in the packing of the hexapeptides within the globules. These unprecedented findings show that steric zippers exhibit a characteristic nanomechanical signature in solution in addition to previously observed characteristic crystallographic structure. Getting to the fundamental interactions that govern the unzipping of full-length amyloid fibers may initiate the development of antiamyloid methods that target the physical in addition to the structural properties of steric zippers.
Teachers’ mindsets in medical education: A pilot survey of clinical supervisors

Abstract Purpose: Current medical education models maintain that competencies such as professionalism and communication can be taught; however, some argue that certain attributes that make up these competencies, such as empathy, are fixed. Teachers’ implicit theories, or mindsets (beliefs about the fixed versus learnable nature of human attributes) have been shown to impact their teaching and assessment practices; but little work has explored mindsets in medical education. We examined clinical supervisors’ mindsets of two cognitive attributes (intelligence and clinical reasoning) and two affective attributes (moral character and empathy). Methods: Clinical supervisors (n = 40) from three specialities completed a survey designed to measure mindsets using two existing instruments for intelligence and moral character and 18 new items for clinical reasoning and empathy. Participants completed the survey twice for test-retest reliability (n = 25). Results: New items had satisfactory psychometric properties. Clinical supervisors’ mindsets were mixed. Only 8% of participants saw clinical reasoning as fixed while more saw empathy (45%), intelligence (53%), and moral character (53%) as fixed – running counter to current educational models that characterize these attributes as learnable. Conclusion: This study provides evidence supporting the use of these new tools to measure mindsets that may help to better understand the impact of mindsets on medical education.