Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion

The Hedgehog signalling pathway is crucial for development, adult stem cell maintenance, cell migration and axon guidance in a wide range of organisms. During development, the Hh morphogen directs tissue patterning according to a concentration gradient. Lipid modifications on Hh are needed to achieve graded distribution, leading to debate about how Hh is transported to target cells despite being membrane-tethered. Cytonemes in the region of Hh signalling have been shown to be essential for gradient formation, but the carrier of the morphogen is yet to be defined. Here we show that Hh and its co-receptor Ihog are in exovesicles transported via cytonemes. These exovesicles present protein markers and other features of exosomes. Moreover, the cell machinery for exosome formation is necessary for normal Hh secretion and graded signalling. We propose Hh transport via exosomes along cytonemes as a significant mechanism for the restricted distribution of a lipid-modified morphogen.PostprintPeer reviewe

Towards a new classification of galaxies: principal component analysis of CALIFA circular velocity curves

We present a galaxy classification system for 238 (E1-Sdm) CALIFA (Calar Alto Legacy Integral Field Area) galaxies based on the shapes and amplitudes of their circular velocity curves (CVCs). We infer the CVCs from the de-projected surface brightness of the galaxies, after scaling by a constant mass-to-light ratio based on stellar dynamics - solving axisymmetric Jeans equations via fitting the second velocity moment $V_{\mathrm{rms}}=\sqrt{V^2+\sigma^2}$ of the stellar kinematics. We use principal component analysis (PCA) applied to the CVC shapes to find characteristic features and use a $k$-means classifier to separate circular curves into classes. This objective classification method identifies four different classes, which we name slow-rising (SR), flat (FL), round-peaked (RP) and sharp-peaked (SP) circular curves. SR are typical for low-mass, late-type (Sb-Sdm), young, faint, metal-poor and disc-dominated galaxies. SP are typical for high-mass, early-type (E1-E7), old, bright, metal-rich and bulge-dominated galaxies. FL and RP appear presented by galaxies with intermediate mass, age, luminosity, metallicity, bulge-to-disk ratio and morphologies (E4-S0a, Sa-Sbc). The discrepancy mass factor, $f_d=1-M_{*}/M_{dyn}$, have the largest value for SR and SP classes ($\sim$ 74 per cent and $\sim$ 71 per cent, respectively) in contrast to the FL and RP classes (with $\sim$ 59 per cent and $\sim$ 61 per cent, respectively). Circular curve classification presents an alternative to typical morphological classification and appears more tightly linked to galaxy evolution.Comment: Accepted for publication in MNRAS (Minor changes), 123 pages, 19 figures, 87 Tables (containing the basic properties of the 238 E1-Sdm galaxies; the five main Principal Component Eigenvectors; the five main Principal Components - PC_i; the Multi-Gaussian Expansion models - MGEs; the circular velocity curve models and their uncertainties

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Generations UNAB No.4

Esta cuarta edición de la revista Generaciones UNAB, gira en torno a la celebración de los 40 años de inicio de labores de la Facultad de Derecho, cuyo primeros 25 graduados obtuvieron su título en 1978; así como a la celebración de los primeros 30 años de inicio de labores de la Facultad de Comunicación Social que graduó a sus primeros 17 estudiantes en 1987. Hoy, cuatro y tres décadas después del inicio de labores respectivamente, y atendiendo al compromiso institucional con la región, ña Universidad ha permitido que Santander, Colombia y el mundo cuenten con 3.104 abogados y 1.647 comunicadores sociales que se destacan por su compromiso con la sociedad, su trabajo en equipo, ética y valores en el ejercicio profesional.Editorial; Por Marcela Peralta Bautista…03 Columnista invitado, Facultades bien dirigidas; Por Alfonso Gómez Gómez…06 40 años de la Facultad de Derecho…08 Cuatro décadas formando futuro; Por José Manuel Arias Carrizosa…09 Una facultad de libertadores; Por Jaime Gutiérrez Rivero…10 Defendiendo la libertad del conocimiento; Por Sergio Rangel Consuegra…11 La cara humana del derecho; Por Jorge González Aranda…13 La decanatura marcó mi vida; Por Gabriel Burgos Mantilla…14 La unión hace la fuerza; Por Jorge Castillo Rugeles…16 Mis estudiantes son lo más importante; Por Rodolfo Mantilla Jácome…18 La hermenéutica jurídica como sello diferenciador; Por Juan Carlos Acuña Gutiérrez...20 Equipo de trabajo y apoyo directivo; Por Jorge Eduardo Lamo Gómez…22 30 años de la Facultad de Comunicación Social…25 Haciendo el sueño realidad; Por Carlos H. Gómez…26 Un compromiso de vida; Por Maria Isabel León Carreño…28 Construir debatiendo; Por Rodrigo Velasco Ortiz…30 La importancia de potenciar capacidades; Por Luz Amalia Camacho Velásquez...32 Una propuesta académica única; Por Iván Darío Montoya Osorio…34 Graduados Destacando…37 Docente en la Facultad de Derecho UNAB…38 Comunicación Social-Periodista de la UNAB; Por Sonia Díaz…39 Emprendedores UNAB “Apps.com”; Por Marcela Peralta Bautista…40 Instigación “Trata de personas”; Por Lya Fernández de Mantilla, Johana Marcela Reyes…42 Encuentros…45This fourth edition of the magazine Generaciones UNAB, revolves around the celebration of 40 years of beginning of work of the Faculty of Law, whose first 25 graduates obtained their degree in 1978; as well as the celebration of the first 30 years of beginning of work of the Faculty of Social Communication that graduated its first 17 students in 1987. Today, four and three decades after the start of work respectively, and in response to the institutional commitment to the region, ña University has allowed Santander, Colombia and the world to have 3,104 lawyers and 1,647 social communicators who stand out for their commitment to society , their teamwork, ethics and values ​​in professional practice

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

MAGIC and H.E.S.S. detect VHE gamma rays from the blazar OT081 for the first time: a deep multiwavelength study

https://pos.sissa.it/395/815/pdfPublished versio

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health