Miracle-dz/UniFAR-FTUs huggingface dataset:
Cerebellar abnormalities in the disabled (mdab1–1) mouse

A mouse homolog of the Drosophila Disabled (dab) gene, disabled‐1 (mdab1), encodes an adaptor molecule that functions in neural development. Targeted disruption of the mdab1 gene (mdab1–1 mice) leads to anomalies in the development of the cerebrum, hippocampus, and cerebellum. Here we describe a number of histologic abnormalities in the cerebellum of the mdab1–1 mouse. There is a complete absence of foliation, and most Purkinje cells are clumped in central clusters. However, lamination appears to develop normally in areas where the Purkinje cells and external granular layer are closely apposed. The granular layer forms a thin rind over most of the cerebellar surface, but is subdivided by both transverse and parasagittal boundaries. The Purkinje cells, identified by anti‐zebrin II in the adult or anti‐calbindin in the new born mdab1–1 mutant cerebellum, form a parasagittal banding pattern, similar to but distorted compared with the wild‐type design. The data suggest that the development of the mdab1–1 cerebellum parallels the development of reeler. The reeler gene encodes an extracellular protein (Reelin) that is secreted by the external granular layer. Because Reelin expression is retained in the mdab1–1 mutant mouse, mDab1 p80 may act in a parallel pathway or downstream of Reelin, leading to the transformation of embryonic Purkinje cell clusters into the adult parasagittal bands. J. Comp. Neurol. 402:238–251, 1998. © 1998 Wiley‐Liss, Inc.
Morphology of epithelial cells lining the digestive tract of the giant keyhole limpet, Megathura crenulata (Mollusca; Vetigastropoda)

To understand the digestive functions in the giant keyhole limpet, it is important to know the types of cells present in each region of the gut and their roles in the secretion of digestive enzymes and absorption of nutrients. This study describes the morphology of cells lining the entire gut and identifies sites that may be secreting materials to aid digestion. Previous studies involving electron microscopy and enzyme analysis have focused on the salivary and digestive glands of several gastropods. Studies on the rest of the gut tract typically include only histological descriptions of the epithelia and although several types of cells have been described, they appear very similar. The purpose of this study is to determine if electron microscopy can provide better insights into the functions of cells in these poorly studied regions of the gut. Our ultrastructural observations suggest that only two types of cells, mucus secreting cells and apocrine secretory cells make up the epithelium in the esophagus, style sac, and intestine. These regions account for 85% of the length of the entire digestive tract. Apocrine secretory cells contain pigment granules, bear cilia, and/or microvilli at their apices, and release product into the gut lumen via apocrine secretion. This suggests that the secretory processes involved with digestion are occurring in most regions of the gut and that apocrine secretion is the primary mode by which materials are introduced into the gut lumen. The lips, salivary glands, stomach, and digestive gland lack apocrine secretory cells and the epithelial cells are similar to those described in other gastropods. J. Morphol. 271:1134–1151, 2010. © 2010 Wiley‐Liss, Inc.
Development and implementation of real‐time nucleic acid amplification for the detection of enterovirus infections in comparison to rapid culture of various clinical specimens

Several real‐time PCR and nucleic acid sequence‐based amplification (NASBA) primer pairs and a modified real‐time PCR primer pair for the detection of enteroviruses were compared. The modified real‐time PCR primer pair was evaluated on clinical samples in comparison with cell culture using the MagnaPure LC Isolation instrument for nucleic acid extraction. Six hundred forty samples could be examined both by cell culture and real‐time PCR. Faecal specimens (n = 285), cerebrospinal fluid (n = 210), throat swabs (n = 113), biopsies (n = 1, vesicular fluid (n = 11), and pleural fluid specimens (n = 9) were included. By culture, 26/640 (4%) samples were positive for enterovirus. By real‐time PCR, the number of positive specimens was 50 (7.8%). Of the 210 cerebrospinal fluid samples, three were positive by culture and nine by real‐time PCR. Seventeen and 33 of a total of 285 faecal specimens were positive by culture and real‐time PCR, respectively. In case of discrepant results, the clinical symptoms were in accordance with an infection due to enteroviruses. Genotyping using the VP1 gene correlated with serotyping by neutralization. In contrast, six of the 19 specimens that could be typed both by neutralization and by sequencing using the VP4 domain yielded a different genotype, yet within the same species. Real‐time PCR turned out to be suitable for the detection of enteroviruses in the daily routine setting. In comparison to rapid culture, it offers a rapid, more sensitive, and reliable assay; especially in cerebrospinal fluid, the yield of enteroviruses is much higher. J. Med. Virol. 79:1868–1876, 2007. © Wiley‐Liss, Inc.
Learning Motor Sequences with and without Knowledge of Governing Rules

Objective. To investigate the behavioral and neural effects of rule-based knowledge on motor sequence learning. Methods. The authors developed a novel 2-dimensional variant of the serial reaction time (SRT) task to test the effect of prior, verbalizable rule knowledge on motor learning behavior. To examine neurophysiological effects, they also performed functional magnetic resonance imaging on a small cohort of subjects while performing the same task. Results. Behavioral data demonstrated that instruction on sequence-governing rules enhanced behavioral performance in both learning magnitudes and rates. The neuroimaging data revealed substantially different, but partially overlapping, learning-related activation patterns with and without prior rule instruction. Direct comparison of these 2 conditions revealed significantly different involvement of bilateral superior and anterior prefrontal cortex (Brodmann areas 8 and 10, respectively), right superior temporal cortex (BA 38/21), and left cerebellum. Conclusions. These behavioral findings demonstrate an advantage of teaching governing rules prior to 2D-SRT task performance. While these neuroimaging findings remain to be replicated in a larger cohort of subjects, results suggest that substantially different—though partially overlapping—brain regions subserve learning in these 2 rehabilitation-relevant conditions. Thus, appropriate choice of pretraining may benefit, for example, rehabilitation populations, at least in motor skill acquisition that requires sequencing.
Direct evidence for axonal transport defects in a novel mouse model of mutant spastin‐induced hereditary spastic paraplegia (HSP) and human HSP patients

Mutations in spastin are the most common cause of hereditary spastic paraplegia (HSP) but the mechanisms by which mutant spastin induces disease are not clear. Spastin functions to regulate microtubule organisation, and because of the essential role of microtubules in axonal transport, this has led to the suggestion that defects in axonal transport may underlie at least part of the disease process in HSP. However, as yet there is no direct evidence to support this notion. Here we analysed axonal transport in a novel mouse model of spastin‐induced HSP that involves a pathogenic splice site mutation, which leads to a loss of spastin protein. A mutation located within the same splice site has been previously described in HSP. Spastin mice develop gait abnormalities that correlate with phenotypes seen in HSP patients and also axonal swellings containing cytoskeletal proteins, mitochondria and the amyloid precursor protein (APP). Pathological analyses of human HSP cases caused by spastin mutations revealed the presence of similar axonal swellings. To determine whether mutant spastin influenced axonal transport we quantified transport of two cargoes, mitochondria and APP‐containing membrane bound organelles, in neurons from mutant spastin and control mice, using time‐lapse microscopy. We found that mutant spastin perturbs anterograde transport of both cargoes. In neurons with axonal swellings we found that the mitochondrial axonal transport defects were exacerbated; distal to axonal swellings both anterograde and retrograde transport were severely reduced. These results strongly support a direct role for defective axonal transport in the pathogenesis of HSP because of spastin mutation.
Interferon Gamma-Mediated BoHV-4 Replication Restriction in Bovine Endometrial Stromal Cells Is Host IDO1 Gene Expression Independent and BoHV-4 IE2 Gene Expression Dependent1

ABSTRACT In the present work the interaction between bovine herpesvirus 4 (BoHV-4)-infected bovine endometrial stromal cells (BESCs) and interferon gamma (IFNG) was investigated. Starting from the particular tropism of BoHV-4 toward BESCs, a pure population of these cells, free of CD45-positive cells, was prepared and proven to have a bona fide mesenchymal derivation as shown by vimentin-positive and cytokeratin-negative staining. BESCs expressed functional IFNG receptors (IFNGR) 1 and 2 but not IFNG ligand. BESCs transfected with a new reporter construct made by cloning the bovine indoleamine 2, 3-dioxygenase 1 (IDO1) promoter in front of the luciferase reporter gene responded to exogenous IFNG treatment. Further, IFNG-treated or constitutively secreting IFNG BESCs strongly restricted BoHV-4 replication and consequent cytopathic effect. IDO1 expression in BESCs was tightly induced by IFNG and IDO1 was previously shown to be the mediator for some of the IFNG pathogenostatic effects. However, IDO1 inhibitors and IDO1 constitutive expression could not respectively abrogate or recapitulate IFNG effect on BoHV-4-infected BESCs, whereas BoHV-4 immediate early (IE2) gene expression was transcriptionally depressed by IFNG axis activation independently from IDO1 expression; this was further confirmed by revealing a BoHV-4 IE2 gene promoter area containing potential responsive elements interacting with inhibitory transcription factors induced by IFNG in BESCs. The data achieved in this work highlight at least two issues: first, the role of BESCs as target/effector cells for the IFNG; second, the importance of uterine IFNG integrity to control BoHV-4 infection recrudescence from a persistent/latent state to a chronic disease, endometritis.
Identification of the Vibrio cholerae type 4 prepilin peptidase required for cholera toxin secretion and pilus formation

Cholera toxin secretion is dependent upon the extracellular protein secretion apparatus encoded by the eps gene locus of Vibrio cholerae. Although the eps gene locus encodes several type four prepilin‐like proteins, the peptidase responsible for processing these proteins has not been identified. This report describes the identification of a prepilin peptidase from the V. cholerae genomic database by virtue of its homology with the PilD prepilin peptidase of Pseudomonas aeruginosa. Plasmid disruption or deletion of this peptidase gene in either El Tor or classical V. cholerae O1 biotype strains results in a dramatic decrease in cholera toxin secretion. In the case of the El Tor biotype mutants, surface expression of the type 4 pilus responsible for mannose‐sensitive haemagglutination is abolished. The cloned V. cholerae peptidase processes either EpsI or MshA preproteins when co‐expressed in E. coli. Mutation of the V. cholerae peptidase gene also results in a defect in virulence and decreased levels of OmpU. The V. cholerae peptidase gene sequence shows 80% homology with the Vibrio vulnificus VvpD type 4 prepilin peptidase required for pilus assembly and cytolysin secretion in V. vulnificus. Accordingly, the V. cholerae type 4 prepilin peptidase required for pilus assembly and cholera toxin secretion has been designated VcpD.
Left ventricular diastolic function in type 2 diabetes mellitus and the association with coronary artery calcium score: a cardiac MRI study.

OBJECTIVE The purpose of this study was to compare cardiac MRI-derived parameters of left ventricular (LV) diastolic function between uncomplicated type 2 diabetes mellitus (DM2) and normoglycemic control subjects and to evaluate whether these parameters of LV diastolic function are related to coronary atherosclerosis. SUBJECTS AND METHODS We prospectively studied 41 subjects with DM2 and 21 normoglycemic control subjects (30 women and 32 men; mean age, 57.2 ± 7.1 [SD] years) with no evidence of overt cardiovascular disease. We used cardiac MRI to measure LV volumes, LV peak filling rate (PFR), and transmitral flow and CT to determine coronary artery calcium scores. RESULTS Absolute values of the peak filling rate (PFR) were significantly lower in DM2 patients than in control subjects (mean ± SD, 293.2 ± 51.7 vs 375.7 ± 102.8 mL/s, respectively; p < 0.001). Mitral peak E velocities (mean ± SD, 42.8 ± 10.7 vs 48.8 ± 10.4 cm/s; p = 0.040) and peak E velocity-to-peak A velocity ratios (0.88 ± 0.3 vs 1.1 ± 0.3; p = 0.002) were also lower in DM2 patients compared with control subjects. DM2 patients with coronary artery calcification showed a lower PFR normalized to stroke volume (SV) (mean ± SD, 4.4 ± 1.0 vs 5.3 ± 1.4, respectively; p = 0.038) and lower mitral peak E velocities (40.1 ± 11.3 vs 48.0 ± 7.3 cm/s; p = 0.024) than DM2 patients without coronary calcification. PFR normalized to SV was independently associated with the presence of coronary artery calcification (β = -1.5, p = 0.005). CONCLUSION DM2 decreases cardiovascular MRI-derived parameters of LV diastolic function. Patients with DM2 and coronary atherosclerosis show a more impaired LV diastolic function than patients without coronary atherosclerosis.
3D Elasticity imaging using principal stretches on an open-chest dog heart

Ultrasound strain imaging has demonstrated its ability to quantitatively assess myocardial viability and contractility altered by myocardial ischemia. However, current ultrasound strain imaging methods still use lower dimensional methods to monitor 3D heart motion. Some 3-D tracking algorithms have also been developed recently in different groups. Quantitative analysis using current methods depends on ultrasound probe orientation and selection of a centroid. To address this, 3D elasticity imaging derived using principal stretches independent of the centroid point is used to assess the contractility of myocardial fibers with 3D data from a commercial 3D scanner on an open-chest dog heart. In this study, an open-chest dog was performed according to a Yale institutional animal protocol and 3D radio frequency (RF) volume data were acquired using an commercial 2D phased array (iE33, Philips, Andover, MA) placed in front of the anterior wall of the left-ventricle with a small water stand-off. 3D speckle tracking was applied to estimate 3D displacement with tracking resolution of 1.2 mm in the axial direction and 4.5 mm in azimuthal and zenithal directions. Volume-to-volume tracking results were accumulated referenced to the heart geometry at the end of diastole until the end of systole. Three principal stretches were estimated using eigenvalue decomposition of the derived right Cauchy deformation tensor at each point. Initial results of strains based on principal stretch and the principal direction has successfully demonstrated that heart wall is thickening along the radial direction and shortening along the longitudinal direction during systole. Unlike 1D or 2D methods, 3D speckle tracking can estimate myocardium's three-dimensional motion. Three strains based on the principal stretches were derived from 3D displacements to assess myocardial contractility independent of probe position and the selection of the centroid point.
The HsiB1C1 (TssB-TssC) Complex of the Pseudomonas aeruginosa Type VI Secretion System Forms a Bacteriophage Tail Sheathlike Structure

Background: The type VI secretion system (T6SS) is a bacterial device similar to bacteriophages. Results: Pseudomonas aeruginosa HsiB and HsiC proteins form a T6SS subcomplex, which polymerizes into tubules via the C terminus of HsiC. Conclusion: HsiB and HsiC form a structure with similarity to the bacteriophage tail sheath. Significance: TssB and TssC members of the T6SS form a complex resembling the bacteriophage tail sheath and mimic the gp18 protein. Protein secretion systems in Gram-negative bacteria evolved into a variety of molecular nanomachines. They are related to cell envelope complexes, which are involved in assembly of surface appendages or transport of solutes. They are classified as types, the most recent addition being the type VI secretion system (T6SS). The T6SS displays similarities to bacteriophage tail, which drives DNA injection into bacteria. The Hcp protein is related to the T4 bacteriophage tail tube protein gp19, whereas VgrG proteins structurally resemble the gp27/gp5 puncturing device of the phage. The tube and spike of the phage are pushed through the bacterial envelope upon contraction of a tail sheath composed of gp18. In Vibrio cholerae it was proposed that VipA and VipB assemble into a tail sheathlike structure. Here we confirm these previous data by showing that HsiB1 and HsiC1 of the Pseudomonas aeruginosa H1-T6SS assemble into tubules resulting from stacking of cogwheel-like structures showing predominantly 12-fold symmetry. The internal diameter of the cogwheels is ∼100 Å, which is large enough to accommodate an Hcp tube whose external diameter has been reported to be 85 Å. The N-terminal 212 residues of HsiC1 are sufficient to form a stable complex with HsiB1, but the C terminus of HsiC1 is essential for the formation of the tubelike structure. Bioinformatics analysis suggests that HsiC1 displays similarities to gp18-like proteins in its C-terminal region. In conclusion, we provide further structural and mechanistic insights into the T6SS and show that a phage sheathlike structure is likely to be a conserved element across all T6SSs.
Wait‐list mortality of young patients with Biliary atresia: Competing risk analysis of a eurotransplant registry–based cohort

Liver transplantation (LT) is the standard treatment for biliary atresia (BA) patients with end‐stage liver disease. The prognosis after LT has steadily improved, but overall prognosis of BA patients is also determined by mortality before LT. We aimed to quantify mortality in young BA patients on the Eurotransplant waiting list and to determine the effect of disease severity and age at time of listing on pretransplant mortality. We used a cohort study design, which incorporated data from the Eurotransplant registry. Participants were 711 BA patients who were below 5 years of age from 5 countries and listed for LT between 2001 and 2014. We applied a competing risk analysis to evaluate simultaneously the outcomes death, LT, and still waiting for a suitable organ. We used Cox proportional hazards regression to assess 2‐year mortality. In a subcohort of 416 children, we performed multivariate analyses between 2‐year mortality and disease severity or age, each at listing. Disease severity at listing was quantified by the Model for End‐Stage Liver Disease (MELD) score, which assesses bilirubin, creatinine, albumin, and international normalized ratio as continuous variables. Two‐year wait‐list mortality was 7.9%. Age below 6 months and MELD score above 20 points, each at listing, were strongly and independently associated with 2‐year mortality (each P < 0.001). A total of 21% of infants who fulfilled both criteria did not survive the first 6 months on the waiting list. In conclusion, our findings quantify mortality among young BA patients on the waiting list and the relative importance of risk factors (age and severity of disease at listing). Our results provide both an evidence base to rationally address high mortality in subgroups and a methodology to assess effects of implemented changes, for example, in allocation rules. Liver Transplantation 24 810–819 2018 AASLD.
Test-retest reliability of memory task functional magnetic resonance imaging in Alzheimer disease clinical trials.

OBJECTIVE To examine the feasibility and test-retest reliability of encoding-task functional magnetic resonance imaging (fMRI) in mild Alzheimer disease (AD). DESIGN Randomized, double-blind, placebo-controlled study. SETTING Memory clinical trials unit. PARTICIPANTS We studied 12 patients with mild AD (mean [SEM] Mini-Mental State Examination score, 24.0 [0.7]; mean Clinical Dementia Rating score, 1.0) who had been taking donepezil hydrochloride for more than 6 months from the placebo arm of a larger 24-week study (n = 24, 4 scans on weeks 0, 6, 12, and 24, respectively). INTERVENTIONS Placebo and 3 face-name, paired-associate encoding, block-design blood oxygenation level-dependent fMRI scans in 12 weeks. MAIN OUTCOME MEASURES We performed whole-brain t maps (P < .001, 5 contiguous voxels) and hippocampal regions-of-interest analyses of extent (percentage of active voxels) and magnitude (percentage of signal change) for novel-greater-than-repeated face-name contrasts. We also calculated intraclass correlation coefficients and power estimates for hippocampal regions of interest. RESULTS Task tolerability and data yield were high (95 of 96 scans yielded favorable-quality data). Whole-brain maps were stable. Right and left hippocampal regions-of-interest intraclass correlation coefficients were 0.59 to 0.87 and 0.67 to 0.74, respectively. To detect 25.0% to 50.0% changes in week-0 to week-12 hippocampal activity using left-right extent or right magnitude with 80.0% power (2-sided α = .05) requires 14 to 51 patients. Using left magnitude requires 125 patients because of relatively small signal to variance ratios. CONCLUSIONS Encoding-task fMRI was successfully implemented in a single-site, 24-week, AD randomized controlled trial. Week 0 to 12 whole-brain t maps were stable, and test-retest reliability of hippocampal fMRI measures ranged from moderate to substantial. Right hippocampal magnitude may be the most promising of these candidate measures in a leveraged context. These initial estimates of test-retest reliability and power justify evaluation of encoding-task fMRI as a potential biomarker for signal of effect in exploratory and proof-of-concept trials in mild AD. Validation of these results with larger sample sizes and assessment in multisite studies is warranted.
Instrumented insole system for ambulatory and robotic walking assistance: First advances

Current research highlights the emergent need for the development of wearable, calibrated, and accurate sensory systems for ambulatory human gait analysis. The purpose of this work is to develop a lightweight and calibrated instrumented insole system for the real-time monitoring of gait events in healthy, pathological and robotic-assisted gait. We designed the insole with four force sensing resistors (FSRs) to detect four gait events. We also implemented an electronic interface for the data acquisition and processing and the wireless transmission with the motherboard and the user interface. The validation involved 3 healthy female subjects, which reported that this prototype is flexible, lightweight and comfortable for daily usage. Results showed a maximal error of 6.02±3.02% in the detection of foot flat due to the small sensing area of FSRs placed on the first and fifth metatarsus. Future challenges comprise aesthetic and functional improvements and a more comprehensive validation.