Graft versus Host Disease in the Bone Marrow, Liver and Thymus Humanized Mouse Model

Mice bearing a “humanized” immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice). The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc−/−) delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model

Metabolic changes in schizophrenia and human brain evolution.

BACKGROUND: Despite decades of research, the molecular changes responsible for the evolution of human cognitive abilities remain unknown. Comparative evolutionary studies provide detailed information about DNA sequence and mRNA expression differences between humans and other primates but, in the absence of other information, it has proved very difficult to identify molecular pathways relevant to human cognition. RESULTS: Here, we compare changes in gene expression and metabolite concentrations in the human brain and compare them to the changes seen in a disorder known to affect human cognitive abilities, schizophrenia. We find that both genes and metabolites relating to energy metabolism and energy-expensive brain functions are altered in schizophrenia and, at the same time, appear to have changed rapidly during recent human evolution, probably as a result of positive selection. CONCLUSION: Our findings, along with several previous studies, suggest that the evolution of human cognitive abilities was accompanied by adaptive changes in brain metabolism, potentially pushing the human brain to the limit of its metabolic capabilities.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention

Le rôle fondamental de l’observation directe dans la décision de confier une responsabilité professionnelle

Background: Entrustment decisions may be retrospective (based on past experiences with a trainee) or real-time (based on direct observation). We investigated judgments of entrustment based on assessor prior knowledge of candidates and based on systematic direct observation, conducted in an objective structured clinical exam (OSCE). Methods: Sixteen faculty examiners provided 287 retrospective and real-time entrustment ratings of 16 cardiology trainees during OSCE stations in 2019 and 2020. Reliability and validity of these ratings were assessed by comparing correlations across stations as a measure of reliability, differences across postgraduate years as an index of construct validity, correlation to standardized in-training exam (ITE) as a measure of criterion validity, and reclassification of entrustment as a measure of consequential validity. Results: Both retrospective and real-time assessments were highly reliable (all intra-class correlations >0.86). Both increased with year of postgraduate training. Real-time entrustment ratings were significantly correlated with standardized ITE scores; retrospective ratings were not. Real-time ratings explained 37% (2019) and 46% (2020) of variance in examination scores vs. 21% (2019) and 7% (2020) for retrospective ratings. Direct observation resulted in a different level of entrustment compared with retrospective ratings in 44% of cases (p = <0.001). Conclusions: Ratings based on direct observation made unique contributions to entrustment decisions.Contexte : La décision de confier une activité peut être rétrospective (basée sur les expériences antérieures avec un apprenant) ou en temps réel (basée sur l’observation directe). Nous avons étudié les évaluations de niveaux de confiance fondées sur des interactions antérieures des candidats par les évaluateurs et celles fondées sur l’observation directe systématique, dans le cadre d’un examen clinique objectif structuré (ECOS). Méthodes : Seize évaluateurs du corps professoral ont fourni 287 évaluations rétrospectives et en temps réel du niveau de confiance faites lors des stations d’ECOS en 2019 et 2020 concernant 16 stagiaires en cardiologie. La fiabilité et la validité de ces évaluations ont été analysées en comparant les corrélations entre les stations comme mesure de la fiabilité, les différences entre les années d’études postdoctorales comme indice de la validité de construit, la corrélation avec l’examen normalisé en cours de formation (ITE) comme mesure de la validité de critère, et le reclassement des évaluations de la confiance comme mesure de la validité corrélative. Résultats : Les évaluations rétrospectives et en temps réel étaient toutes les deux très fiables (toutes les corrélations intra-classes >0,86). Les deux augmentaient avec le niveau de formation postdoctorale. Les évaluations de la confiance en temps réel étaient significativement corrélées aux scores de l’examen normalisé en cours de formation; les évaluations rétrospectives ne l’étaient pas. Les évaluations en temps réel expliquaient 37 % (2019) et 46 % (2020) de la variance des notes d’examen, contre 21 % (2019) et 7 % (2020) pour les évaluations rétrospectives. L’observation directe a permis de reclasser 44 % des évaluations rétrospectives de la confiance (p=<0,001 dans les deux cas). Conclusion : Les évaluations basées sur l’observation directe contribuent de façon importante à la décision de confier une activité

Immunohistochemical and ultrastructural analysis of the maturing larval zebrafish enteric nervous system reveals the formation of a neuropil pattern

The gastrointestinal tract is constructed with an intrinsic series of interconnected ganglia that span its entire length, called the enteric nervous system (ENS). The ENS exerts critical local reflex control over many essential gut functions; including peristalsis, water balance, hormone secretions and intestinal barrier homeostasis. ENS ganglia exist as a collection of neurons and glia that are arranged in a series of plexuses throughout the gut: the myenteric plexus and submucosal plexus. While it is known that enteric ganglia are derived from a stem cell population called the neural crest, mechanisms that dictate final neuropil plexus organization remain obscure. Recently, the vertebrate animal, zebrafish, has emerged as a useful model to understand ENS development, however knowledge of its developing myenteric plexus architecture was unknown. Here, we examine myenteric plexus of the maturing zebrafish larval fish histologically over time and find that it consists of a series of tight axon layers and long glial cell processes that wrap the circumference of the gut tube to completely encapsulate it, along all levels of the gut. By late larval stages, complexity of the myenteric plexus increases such that a layer of axons is juxtaposed to concentric layers of glial cells. Ultrastructurally, glial cells contain glial filaments and make intimate contacts with one another in long, thread-like projections. Conserved indicators of vesicular axon profiles are readily abundant throughout the larval plexus neuropil. Together, these data extend our understanding of myenteric plexus architecture in maturing zebrafish, thereby enabling functional studies of its formation in the future

Strong cardiovascular prognostic implication of quantitative left atrial contractile function assessed by cardiac magnetic resonance imaging in patients with chronic hypertension

<p>Abstract</p> <p>Background</p> <p>Progressive left ventricular (LV) diastolic dysfunction due to hypertension (HTN) alters left atrial (LA) contractile function in a predictable manner. While increased LA size is a marker of LV diastolic dysfunction and has been shown to be predictive of adverse cardiovascular outcomes, the prognostic significance of altered LA contractile function is unknown.</p> <p>Methods</p> <p>A consecutive group of patients with chronic hypertension but without significant valvular disease or prior MI underwent clinically-indicated CMR for assessment of left ventricular (LV) function, myocardial ischemia, or viability. Calculation of LA volumes used in determining LA emptying functions was performed using the biplane area-length method.</p> <p>Results</p> <p>Two-hundred and ten patients were included in this study. During a median follow-up of 19 months, 48 patients experienced major adverse cardiac events (MACE), including 24 deaths. Decreased LA contractile function (LAEF_Contractile) demonstrated strong unadjusted associations with patient mortality, non-fatal events, and all MACE. For every 10% reduction of LAEF_Contractile, unadjusted hazards to MACE, all-cause mortality, and non-fatal events increased by 1.8, 1.5, and 1.4-folds, respectively. In addition, preservation of the proportional contribution from LA contraction to total diastolic filling (Contractile/Total ratio) was strongly associated with lower MACE and patient mortality. By multivariable analyses, LAEF_Contractilewas the strongest predictor in each of the best overall models of MACE, all-cause mortality, and non-fatal events. Even after adjustment for age, gender, left atrial volume, and LVEF, LAEF_Contractilemaintained strong independent associations with MACE (p < 0.0004), all-cause mortality (p < 0.0004), and non-fatal events (p < 0.0004).</p> <p>Conclusions</p> <p>In hypertensive patients at risk for left ventricular diastolic dysfunction, a decreased contribution of LA contractile function to ventricular filling during diastole is strongly predictive of adverse cardiac events and death.</p

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.Postprint (published version

Ευρετικές προσεγγίσεις του μοναδιάστατου προβλήματος πακετοποίησης

Article 59.1, of the International Code of Nomenclature for Algae, Fungi, and Plants (ICN; Melbourne Code), which addresses the nomenclature of pleomorphic fungi, became effective from 30 July 2011. Since that date, each fungal species can have one nomenclaturally correct name in a particular classification. All other previously used names for this species will be considered as synonyms. The older generic epithet takes priority over the younger name. Any widely used younger names proposed for use, must comply with Art. 57.2 and their usage should be approved by the Nomenclature Committee for Fungi (NCF). In this paper, we list all genera currently accepted by us in Dothideomycetes (belonging to 23 orders and 110 families), including pleomorphic and non-pleomorphic genera. In the case of pleomorphic genera, we follow the rulings of the current ICN and propose single generic names for future usage. The taxonomic placements of 1261 genera are listed as an outline. Protected names and suppressed names for 34 pleomorphic genera are listed separately. Notes and justifications are provided for possible proposed names after the list of genera. Notes are also provided on recent advances in our understanding of asexual and sexual morph linkages in Dothideomycetes. A phylogenetic tree based on four gene analyses supported 23 orders and 75 families, while 35 families still lack molecular data