Miracle-dz/UniFAR-FTUs huggingface dataset:
Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease

Objective To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)–PET, in familial autosomal-dominant Alzheimer disease (ADAD). Methods The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11C-DED-PET. Results Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness. Conclusions Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
Sickle Cell Disease: Metabolomic Profiles of Vaso-Occlusive Crisis in Plasma and Erythrocytes

The metabolomic profile of vaso-occlusive crisis, compared to the basal state of sickle cell disease, has never been reported to our knowledge. Using a standardized targeted metabolomic approach, performed on plasma and erythrocyte fractions, we compared these two states of the disease in the same group of 40 patients. Among the 188 metabolites analyzed, 153 were accurately measured in plasma and 143 in red blood cells. Supervised paired partial least squares discriminant analysis (pPLS-DA) showed good predictive performance for test sets with median area under the receiver operating characteristic (AUROC) curves of 99% and mean p-values of 0.0005 and 0.0002 in plasma and erythrocytes, respectively. A total of 63 metabolites allowed discrimination between the two groups in the plasma, whereas 61 allowed discrimination in the erythrocytes. Overall, this signature points to altered arginine and nitric oxide metabolism, pain pathophysiology, hypoxia and energetic crisis, and membrane remodeling of red blood cells. It also revealed the alteration of metabolite concentrations that had not been previously associated with sickle cell disease. Our results demonstrate that the vaso-occlusive crisis has a specific metabolomic signature, distinct from that observed at steady state, which may be potentially helpful for finding predictive biomarkers for this acute life-threatening episode.
Leucine-Enriched Essential Amino Acids Improve Recovery from Post-Exercise Muscle Damage Independent of Increases in Integrated Myofibrillar Protein Synthesis in Young Men

Background: Leucine-enriched essential amino acids (LEAAs) acutely enhance post-exercise myofibrillar protein synthesis (MyoPS), which has been suggested to be important for muscle repair and recovery. However, the ability of LEAAs to concurrently enhance MyoPS and muscle damage recovery in free-living humans has not been studied. Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, twenty recreationally active males consuming a controlled diet (1.2 g/kg/d of protein) were supplemented thrice daily with 4 g of LEAAs (containing 1.6 g leucine) or isocaloric placebo for four days following an acute bout of lower-body resistance exercise (RE). MyoPS at rest and integrated over 96 h of recovery was measured by D2O. Isometric and isokinetic torque, muscle soreness, Z-band streaming, muscle heat shock protein (HSP) 25 and 72, plasma creatine kinase (CK), and plasma interleukin-6 (IL-6) were measured over 96 h post-RE to assess various direct and indirect markers of muscle damage. Results: Integrated MyoPS increased ~72% over 96 h after RE (p < 0.05), with no differences between groups (p = 0.98). Isometric, isokinetic, and total peak torque decreased ~21% by 48 h after RE (p < 0.05), whereas total peak torque was ~10% greater overall during recovery in LEAAs compared to placebo (p < 0.05). There were moderate to large effects for peak torque in favour of LEAAs. Muscle soreness increased during recovery with no statistical differences between groups but small to moderate effects in favour of LEAAs that correlated with changes in peak torque. Plasma CK, plasma IL-6, and muscle HSP25 increased after RE (p < 0.05) but were not significantly different between groups (p ≥ 0.13). Consistent with a trend toward attenuated Z-band streaming in LEAAs (p = 0.07), muscle HSP72 expression was lower (p < 0.05) during recovery in LEAAs compared with placebo. There were no correlations between MyoPS and any measures of muscle damage (p ≥ 0.37). Conclusion: Collectively, our data suggest that LEAAs moderately attenuated muscle damage without concomitant increases in integrated MyoPS in the days following an acute bout of resistance exercise in free-living recreationally active men.
Long-term outcomes of bariatric surgery in patients with diabetes

ABSTRACT Introduction: Initially seen as a weight-loss operation, bariatric surgery is now recognized as a metabolic procedure with a critical role in the management of type 2 diabetes mellitus (T2DM). Early improvement in glucose metabolism is a remarkable effect of surgery; however, what deserves equal thought are implications for long-term diabetes control and relapse. Evidence suggests the metabolic effects of surgery fatigue and a proportion of patients will experience relapse of T2DM, with or without weight regain. Herein, we discuss the evidence examining the durability of these effects and approaches to improve long-term control. Areas covered: PubMed, Embase, CENTRAL, and Medline were searched for trials looking at outcomes for patients with obesity and T2DM undergoing bariatric surgery between January 2000 andDecember 2019. Additional studies were found by searching publications from related journals and references. Export opinion: Bariatric surgery is a safe and effective treatment for T2DM and obesity however the response to surgery, like any other treatment is variable. Some patients will experience a relapse of diabetes in the long term. Recent developments in pharmacotherapy present an opportunity to augment or sustain what can be achieved with surgery. Combinational treatment may dramatically change the way both diseases are managed.
Insights into the Diversification and Evolution of R2R3-MYB Transcription Factors in Plants1

Gene duplications within a specific subfamily led to the expansion of one of the largest transcription factor families in land plants. As one of the largest families of transcription factors (TFs) in plants, R2R3-MYB proteins play crucial roles in regulating a series of plant-specific biological processes. Although the diversity of plant R2R3-MYB TFs has been studied previously, the processes and mechanisms underlying the expansion of these proteins remain unclear. Here, we performed evolutionary analyses of plant R2R3-MYB TFs with dense coverage of streptophyte algae and embryophytes. Our analyses revealed that ancestral land plants exhibited 10 subfamilies of R2R3-MYB proteins, among which orthologs of seven subfamilies were present in chlorophytes and charophycean algae. We found that asymmetric gene duplication events in different subfamilies account for the expansion of R2R3-MYB proteins in embryophytes. We further discovered that the largest subfamily of R2R3-MYBs in land plants, subfamily VIII, emerged in the common ancestor of Zygnematophyceae and embryophytes. During plant terrestrialization, six duplication events gave rise to seven clades of subfamily VIII. Subsequently, this TF subfamily showed a tendency for expansion in bryophytes, lycophytes, and ferns and extensively diversified in ancestral gymnosperms and angiosperms in clades VIII-A-1, VIII-D, and VIII-E. In contrast to subfamily VIII, other subfamilies of R2R3-MYB TFs have remained less expanded across embryophytes. The findings regarding phylogenetic analyses, auxiliary motifs, and DNA-binding specificities provide insight into the evolutionary history of plant R2R3-MYB TFs and shed light on the mechanisms underlying the extensive expansion and subsequent sub- and neofunctionalization of these proteins.
Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model

To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2–0.6%) for 5–6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies.
Diffuse Axonal Injury in the Rat Brain: Axonal Injury and Oligodendrocyte Activity Following Rotational Injury

Traumatic brain injury (TBI) commonly results in primary diffuse axonal injury (DAI) and associated secondary injuries that evolve through a cascade of pathological mechanisms. We aim at assessing how myelin and oligodendrocytes react to head angular-acceleration-induced TBI in a previously described model. This model induces axonal injuries visible by amyloid precursor protein (APP) expression, predominantly in the corpus callosum and its borders. Brain tissue from a total of 27 adult rats was collected at 24 h, 72 h and 7 d post-injury. Coronal sections were prepared for immunohistochemistry and RNAscope® to investigate DAI and myelin changes (APP, MBP, Rip), oligodendrocyte lineage cell loss (Olig2), oligodendrocyte progenitor cells (OPCs) (NG2, PDGFRa) and neuronal stress (HSP70, ATF3). Oligodendrocytes and OPCs numbers (expressed as percentage of positive cells out of total number of cells) were measured in areas with high APP expression. Results showed non-statistically significant trends with a decrease in oligodendrocyte lineage cells and an increase in OPCs. Levels of myelination were mostly unaltered, although Rip expression differed significantly between sham and injured animals in the frontal brain. Neuronal stress markers were induced at the dorsal cortex and habenular nuclei. We conclude that rotational injury induces DAI and neuronal stress in specific areas. We noticed indications of oligodendrocyte death and regeneration without statistically significant changes at the timepoints measured, despite indications of axonal injuries and neuronal stress. This might suggest that oligodendrocytes are robust enough to withstand this kind of trauma, knowledge important for the understanding of thresholds for cell injury and post-traumatic recovery potential.
Grazing Cow Behavior’s Association with Mild and Moderate Lameness

Simple Summary Diseases of cow hooves usually affect how a cow walks (gait), and cows with sufficiently abnormal gait are classified as lame. In addition to altered gait, there are also reports of differences in behavior, such as lying time. To aid heat detection, cow behavior is regularly measured on farms using cow-attached accelerometers. Using these and similar measures of cow behavior to detect lameness has been investigated with mixed results. The strongest reported lameness–behavior associations have been with lying time and activity measures. Most of these and other associations have been reported previously with zero-grazing cows. Here, we looked to see if 14 different behavior measures were associated with mild and moderate lameness in grazing animals. Four trials were performed with two breeds of cows across two farms with data from 63 cows aggregated together in total. Measures of activity and standing/laying events were weakly associated with lameness. The usefulness of these measures for lameness detection with grazing animals may thus be limited. Abstract Accelerometer-based mobility scoring has focused on cow behaviors such as lying and walking. Accuracy levels as high as 91% have been previously reported. However, there has been limited replication of results. Here, measures previously identified as indicative of mobility, such as lying bouts and walking time, were examined. On a research farm and a commercial farm, 63 grazing cows’ behavior was monitored in four trials (16, 16, 16, and 15 cows) using leg-worn accelerometers. Seventeen good mobility (score 0), 23 imperfect mobility (score 1), and 22 mildly impaired mobility (score 2) cows were monitored. Only modest associations with activity, standing, and lying events were found. Thus, behavior monitoring appears to be insufficient to discern mildly and moderately impaired mobility of grazing cows.
The Author’s Contributions to Echocardiography Literature (Part I—1978–1990)

The author has undertaken multiple echocardiographic studies during his academic career; most of these were published in peer-reviewed journals. These studies include an evaluation of the role of echocardiography in the estimation of left-to-right shunt in isolated ventricular septal defects, an examination of the utility of contrast echocardiography in the diagnosis of anomalous connection of the right superior vena cava to the left atrium, a description of pitfalls in M-mode echocardiographic assessment of the aortic root in left ventricular hypoplasia syndromes, reviews of echocardiographic evaluation of left ventricular function, study of the role of contrast echocardiography in the evaluation of hypoxemia following open heart surgery, a quantification of left ventricular muscle mass by m-mode echocardiography in children, an examination of race and sex related differences in echocardiographic measurements in children, study of cardiac size and function in patients with sickle cell disease, an examination of afterload reduction in the management of primary myocardial disease, study of the utility of echo-Doppler studies in the evaluation of the results of balloon pulmonary valvuloplasty, study of the usefulness of Doppler in the prediction of pressure gradients in valvar pulmonary stenosis, a review of Doppler echocardiography in noninvasive diagnoses of heart disease, echo-Doppler studies of the evaluation of the results of balloon angioplasty of aortic coarctation, study of the value of Doppler in the prediction of pressure gradients across coarctation of the aorta, and a characterization of foramen ovale and transatrial Doppler velocity patterns in the normal fetus.
Regional Emergence of Candida auris in Chicago and Lessons Learned from Intensive Follow-Up at One Ventilator-Capable Skilled Nursing Facility.

BACKGROUND Since the identification of the first two Candida auris cases in Chicago, Illinois, in 2016, ongoing spread has been documented in the Chicago area. We describe C. auris emergence in high-acuity long-term healthcare facilities and present a case-study of public health response to C. auris and carbapenemase-producing organisms (CPOs) at one ventilator-capable skilled nursing facility (vSNF A). METHODS We performed point prevalence surveys (PPSs) to identify patients colonized with C. auris, infection control (IC) assessments, and provided ongoing support for IC improvements in Illinois acute and long-term care facilities during August 2016-December 2018. During 2018, we initiated a focused effort at vSNF A, and conducted seven C. auris PPSs; during four PPSs, we also performed CPO screening and environmental sampling. RESULTS During August 2016-December 2018 in Illinois, 490 individuals were found to be colonized or infected with C. auris. PPSs identified highest prevalence of C. auris colonization in vSNF settings (prevalence 23-71%). IC assessments in multiple vSNFs identified common challenges in core IC practices. Repeat PPSs at vSNF A in 2018 identified increasing C. auris prevalence from 43% to 71%. Most residents screened during multiple PPSs remained persistently colonized with C. auris. Among 191 environmental samples collected, 39% were positive for C. auris, including samples from bedrails, windowsills, and shared patient-care items. CONCLUSIONS High burden in vSNFs along with persistent colonization of residents and environmental contamination point to the need for prioritizing IC interventions to control spread of C. auris and CPOs.
The Curious World of Carnivorous Plants

Plants that trap and eat animals have inspired awe since before the days of Darwin. Lured into the danger zone by optical, tactile, and olfactory strategies, the prey succumb to ingenious traps and face their doom. But unlike plants that temporarily catch insects for pollination, the true carnivores go considerably further: they digest them for the nutrients they need to survive in extremely inhospitable sites on land and in water. This exquisite, thoroughly up-to-date book, copiously illustrated with closeup photography, provides the first comprehensive listing of some 630 known carnivorous plant species, described in fascinating detail, with identification history, physiology, ecology, and an extensive bibliography. It is an essential reference for hobbyist, naturalist, and collector alike.
Deep Multi-Scale Fusion Neural Network for Multi-Class Arrhythmia Detection

Automated electrocardiogram (ECG) analysis for arrhythmia detection plays a critical role in early prevention and diagnosis of cardiovascular diseases. Extracting powerful features from raw ECG signals for fine-grained diseases classification is still a challenging problem today due to variable abnormal rhythms and noise distribution. For ECG analysis, the previous research works depend mostly on heartbeat or single scale signal segments, which ignores underlying complementary information of different scales. In this paper, we formulate a novel end-to-end Deep Multi-Scale Fusion convolutional neural network (DMSFNet) architecture for multi-class arrhythmia detection. Our proposed approach can effectively capture abnormal patterns of diseases and suppress noise interference by multi-scale feature extraction and cross-scale information complementarity of ECG signals. The proposed method implements feature extraction for signal segments with different sizes by integrating multiple convolution kernels with different receptive fields. Meanwhile, joint optimization strategy with multiple losses of different scales is designed, which not only learns scale-specific features, but also realizes cumulatively multi-scale complementary feature learning during the learning process. In our work, we demonstrate our DMSFNet on two open datasets (CPSC_2018 and PhysioNet/CinC_2017) and deliver the state-of-art performance on them. Among them, CPSC_2018 is a 12-lead ECG dataset and CinC_2017 is a single-lead dataset. For these two datasets, we achieve the F1 score $\text{82.8}\%$ and $\text{84.1}\%$ which are higher than previous state-of-art approaches respectively. The results demonstrate that our end-to-end DMSFNet has outstanding performance for feature extraction from a broad range of distinct arrhythmias and elegant generalization ability for effectively handling ECG signals with different leads.
Protease propeptide structures, mechanisms of activation, and functions

Abstract Proteases are a diverse group of hydrolytic enzymes, ranging from single-domain catalytic molecules to sophisticated multi-functional macromolecules. Human proteases are divided into five mechanistic classes: aspartate, cysteine, metallo, serine and threonine proteases, based on the catalytic mechanism of hydrolysis. As a protective mechanism against uncontrolled proteolysis, proteases are often produced and secreted as inactive precursors, called zymogens, containing inhibitory N-terminal propeptides. Protease propeptide structures vary considerably in length, ranging from dipeptides and propeptides of about 10 amino acids to complex multifunctional prodomains with hundreds of residues. Interestingly, sequence analysis of the different protease domains has demonstrated that propeptide sequences present higher heterogeneity compared with their catalytic domains. Therefore, we suggest that protease inhibition targeting propeptides might be more specific and have less off-target effects than classical inhibitors. The roles of propeptides, besides keeping protease latency, include correct folding of proteases, compartmentalization, liganding, and functional modulation. Changes in the propeptide sequence, thus, have a tremendous impact on the cognate enzymes. Small modifications of the propeptide sequences modulate the activity of the enzymes, which may be useful as a therapeutic strategy. This review provides an overview of known human proteases, with a focus on the role of their propeptides. We review propeptide functions, activation mechanisms, and possible therapeutic applications.
The limits and challenges of antiobesity pharmacotherapy.

Introduction: Pharmacotherapy is a useful adjunct when patients with obesity are unable to achieve adequate benefit from lifestyle interventions.Areas covered: This review covers the history of antiobesity drugs, efficacy, and risks of currently approved drugs, limits of their usefulness in clinical practice, gaps in knowledge, methodological limitations of clinical trials, and reasons for underutilization.Expert opinion: In randomized controlled trials, currently approved antiobesity drugs have yielded an average weight loss ranging from approximately 3% to 9% relative to placebo at 1 year. Inadequate inclusion of racial and ethnic minorities and men, and high dropout rates in clinical trials limit generalizability of these findings to clinical practice. Weight loss achieved with antiobesity drugs is generally associated with lowered glycemia, but improvements in blood pressure and lipid measures tend to be marginal. There is limited evidence for sustained weight loss beyond 1 year and for safety and efficacy of antiobesity drugs in children and adolescents, and in post-bariatric surgery patients. None have demonstrated reduction in major adverse cardiovascular events or other significant disease outcomes. Limited health insurance coverage and negative perceptions of physicians have hindered the utilization of antiobesity drugs.