Granzyme K drives a newly-intentified pathway of complement activation.

Granzymes are a family of serine proteases mainly expressed by CD8+ T cells, natural killer cells, and innate-like lymphocytes1,2. Although their major role is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence suggests some granzymes can regulate inflammation by acting on extracellular substrates2. Recently, we found that the majority of tissue CD8+ T cells in rheumatoid arthritis (RA) synovium, inflammatory bowel disease and other inflamed organs express granzyme K (GZMK)3, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2a fragments form a C3 convertase that cleaves C3, allowing further assembly of a C5 convertase that cleaves C5. The resulting convertases trigger every major event in the complement cascade, generating the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in areas with abundant complement activation, and fibroblasts are the major producers of complement C2, C3, and C4 that serve as targets for GZMK-mediated complement activation. Our findings describe a previously unidentified pathway of complement activation that is entirely driven by lymphocyte-derived GZMK and proceeds independently of the classical, lectin, or alternative pathways. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases and infection, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.

Relación entre asimetrías en diferentes pruebas de salto y lesiones musculoesqueléticas en futbolistas profesionales de Colombia / Relation between asymmetries in different jump tests and musculoskeletal injuries in professional football players in Colombia

Objetivo:el objetivo del estudio fue identificar la relación entre los resultados de las pruebas saltabilidad horizontal y vertical con la incidencia las lesiones musculoesqueléticas de miembros inferiores en futbolistas de un club de la liga profesional colombiana. Materiales y métodos:se realizó un estudio analítico, exploratorio, en 30 futbolistas de la nómina profesional del Club Deportivo Atlético Junior F.C. Al inicio de la temporada se evaluaron las características antropométricas, así mismo como la saltabilidad y asimetrías funcionales de las extremidades inferiores a través de pruebas de saltos verticales (CMJ y CMJs) y horizontales (3-Hop Test). El análisis consistió en la comparación los registros de las variables estudiadas entre los futbolistas con (lesionados n=11) y sin lesión (no lesionados n=19) en el transcurso del primer semestre dela temporada 2019. Resultados:en los hallazgos no se encontraron diferencias estadísticas entre los grupos en las características biológicas, antropométricas y de composición corporal (p>0,05). Derivado de los hallazgos en la saltabilidad vertical, no se observaron diferencias significativas en las asimetrías funcionales entre grupos (p>0,05), sin embargo, si se encontraron diferencias en las pruebas de saltabilidad horizontal entre lesionados y no lesionados (p<0,01). Conclusión:de este estudio podemos concluir que, en comparación a los futbolistas profesionales sin lesiones, se encontraron significativamente mayores asimetrías funcionales detectadas a través de la prueba de saltabilidad horizontal en los deportistas con lesión.

Objetives:the goal of the study was to identify the relationship between horizontal and vertical jumping tests with the incidence of lower limb musculoskeletal injuries in soccer players of a professional league club in Colombia. Materials and methods:an analytical, prospective study was carried out on 30 players from the professional roster of Club Deportivo Atlético Junior F.C. At the beginning of the season the anthropometric characteristics and body composition were evaluated, as well as jumping and functional asymmetries of the lower extremities through vertical (CMJ and CMJs) and horizontal (3-Hop-Test) jumping tests. The analysis consisted in comparing the records of the variables studied between the players with (injured n=11) and without injury (not-injured n=19) during the first semester of the 2019 season. Results:no statistical differences were found between the groups in the biological, anthropometric and body composition characteristics (p> 0.05). Derived from the vertical jumping findings, no significant differences were observed in the asymmetries between groups (p> 0.05), however, significant asymmetries were found in the horizontal jumping tests between injured and uninjured players (p <0.01). Conclusion: from this studywe can conclude that unlike uninjured professional soccer players, there were significantly greater functional asymmetries identified through the horizontal jumping test in athletes with injuries

A Two-Cell Model for IL-1ß Release Mediated by Death-Receptor Signaling.

Interleukin-1ß (IL-1ß) is a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. However, many pathogens have evolved strategies to evade inflammasome activation. Here we describe an alternative, two-cell model for IL-1ß release where invariant natural killer T (iNKT) cells use the death receptor pathway to instruct antigen-presenting cells to secrete IL-1ß. Following cognate interactions with TLR-primed bone marrow-derived dendritic cells (BMDCs), iNKT cells rapidly translocate intracellular Fas ligand to the surface to engage Fas on BMDCs. Fas ligation activates a caspase-8-dependent signaling cascade in BMDCs that drives IL-1ß release largely independent of inflammasomes. The apoptotic program initiated by Fas ligation rapidly transitions into a pyroptosis-like form of cell death mediated by gasdermin D. Together, our findings support a two-cell model for IL-1ß secretion that may supersede inflammasome activation when cytosolic triggers fail.

Activation strategies for invariant natural killer T cells.

Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant αß T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling. During infection, experimental evidence suggests that both TCR-driven and cytokine-driven mechanisms contribute to iNKT cell activation. While the relative contributions of these two signaling mechanisms can vary widely depending on the infectious context, both lipid antigens and PAMPs mediate reciprocal activation of iNKT cells and APCs, leading to downstream activation of multiple other immune cell types to promote pathogen clearance. In this review, we discuss the mechanisms involved in iNKT cell activation during infection, focusing on the central contributions of both lipid antigens and PAMP-induced inflammatory cytokines, and highlight in vivo examples of activation during bacterial, viral, and fungal infections.

An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells.

Dendritic cells (DCs) use pattern recognition receptors to detect microorganisms and activate protective immunity. These cells and receptors are thought to operate in an all-or-nothing manner, existing in an immunologically active or inactive state. Here, we report that encounters with microbial products and self-encoded oxidized phospholipids (oxPAPC) induce an enhanced DC activation state, which we call "hyperactive." Hyperactive DCs induce potent adaptive immune responses and are elicited by caspase-11, an enzyme that binds oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. Both lipids induce caspase-11-dependent interleukin-1 release, but only LPS induces pyroptosis. The cells and receptors of the innate immune system can therefore achieve different activation states, which may permit context-dependent responses to infection.

[Spontaneous speech prosody and discourse analysis in schizophrenia and Fronto Temporal Dementia (FTD) patients]. / Valoración de prosodia espontánea afectiva y análisis de discurso en pacientes con esquizofrenia y demencia frontotemporal (DFT) variante lingüística.

UNLABELLED: Patients with schizophrenia and Frontotemporal Dementia (FTD) in their linguistic variants share some language characteristics such as the lexical access difficulties, disordered speech with disruptions, many pauses, interruptions and reformulations. For the schizophrenia patients it reflects a difficulty of affect expression, while for the FTD patients it reflects a linguistic issue. METHODS: This study, through an analysis of a series of cases assessed Clinic both in memory and on the Mental Health Unit of HUSI-PUJ (Hospital Universitario San Ignacio), with additional language assessment (analysis speech and acoustic analysis), present distinctive features of the DFT in its linguistic variants and schizophrenia that will guide the specialist in finding early markers of a differential diagnosis. RESULTS: In patients with FTD language variants, in 100% of cases there is a difficulty understanding linguistic structure of complex type; and important speech fluency problems. In patients with schizophrenia, there are significant alterations in the expression of the suprasegmental elements of speech, as well as disruptions in discourse. CONCLUSIONS: We present how depth language assessment allows to reassess some of the rules for the speech and prosody analysis of patients with dementia and schizophrenia; we suggest how elements of speech are useful in guiding the diagnosis and correlate functional compromise in everyday psychiatrist's practice.

Hypoxia drives transient site-specific copy gain and drug-resistant gene expression.

Copy number heterogeneity is a prominent feature within tumors. The molecular basis for this heterogeneity remains poorly characterized. Here, we demonstrate that hypoxia induces transient site-specific copy gains (TSSGs) in primary, nontransformed, and transformed human cells. Hypoxia-driven copy gains are not dependent on HIF1α or HIF2α; however, they are dependent on the KDM4A histone demethylase and are blocked by inhibition of KDM4A with a small molecule or the natural metabolite succinate. Furthermore, this response is conserved at a syntenic region in zebrafish cells. Regions with site-specific copy gain are also enriched for amplifications in hypoxic primary tumors. These tumors exhibited amplification and overexpression of the drug resistance gene CKS1B, which we recapitulated in hypoxic breast cancer cells. Our results demonstrate that hypoxia provides a biological stimulus to create transient site-specific copy alterations that could result in heterogeneity within tumors and cell populations. These findings have major implications in our understanding of copy number heterogeneity and the emergence of drug resistance genes in cancer.

A coding single-nucleotide polymorphism in lysine demethylase KDM4A associates with increased sensitivity to mTOR inhibitors.

UNLABELLED: SNPs occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence affect cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in subclassifying patients, and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tridemethylase gene KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in patients with non-small cell lung cancer (NSCLC), and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-A482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy. SIGNIFICANCE: This report documents the first coding SNP within a lysine demethylase that associates with worse outcome in patients with NSCLC. We demonstrate that this coding SNP alters the protein turnover and associates with increased mTOR inhibitor sensitivity, which identifies a candidate biomarker for mTOR inhibitor therapy and a therapeutic target for combination therapy.

Valoración de prosodia espontánea afectiva y análisis de discurso en pacientes con esquizofrenia y demencia frontotemporal (DFT) variante lingüística / Spontaneous speech prosody and discourse analysis in schizophrenia and Fronto Temporal Dementia (FTD) patients

La esquizofrenia y la demencia frontotemporal (DFT) variante lingüística comparten características de lenguaje tales como la dificultad para acceder al léxico, la desorganización del discurso con múltiples interrupciones, reformulaciones, pausas y retractaciones. En el caso de los pacientes esquizofrénicos, estas dificultades revelan fallas para expresar el afecto, mientras que en los pacientes con DFT variante lingüística refleja un problema lingüístico. Métodos: El presente estudio, a través de un análisis de una serie de casos valorados tanto en la Clínica de memoria como en la Unidad de Salud Mental del HUSI-PUJ (Hospital Universitario de San Ignacio), con evaluación lingüística adicional (análisis de discurso y análisis acústico), presenta características distintivas de la DFT en sus variantes lingüísticas y la esquizofrenia que permiten guiar al especialista en la búsqueda de marcadores tempranos de un diagnóstico diferencial. Resultados: En el 100%de los pacientes con DFT variante lingüística, hay dificultades para comprender estructuras lingüísticas de tipo complejo e importantes problemas de fluidez del discurso. En los pacientes con esquizofrenia se encuentran importantes alteraciones en la expresión de los elementos suprasegmentales del habla e interrupciones en el discurso. Conclusiones: Se presenta como una evaluación lingüística en profundidad permite revaluar algunas de las modalidades de valoración del discurso y la prosodia de los pacientes con demencia y esquizofrenia; indica que algunos elementos del discurso son útiles para orientar el diagnóstico y correlacionar el deterioro funcional en la cotidianidad de la práctica del psiquiatra.

Patients with schizophrenia and Frontotemporal Dementia (FTD) in their linguistic variants share some language characteristics such as the lexical access difficulties, disordered speech with disruptions, many pauses, interruptions and reformulations. For the schizophrenia patients it reflects a difficulty of affect expression, while for the FTD patients it reflects a linguistic issue. Methods: This study, through an analysis of a series of cases assessed Clinic both in memory and on the Mental Health Unit of HUSI-PUJ (Hospital Universitario San Ignacio), with additional language assessment (analysis speech and acoustic analysis), present distinctive features of the DFT in its linguistic variants and schizophrenia that will guide the specialist in finding early markers of a differential diagnosis. Results: In patients with FTD language variants, in 100% of cases there is a difficulty understanding linguistic structure of complex type; and important speech fluency problems. In patients with schizophrenia, there are significant alterations in the expression of the suprasegmental elements of speech, as well as disruptions in discourse. Conclusions: We present how depth language assessment allows to reassess some of the rules for the speech and prosody analysis of patients with dementia and schizophrenia; we suggest how elements of speech are useful in guiding the diagnosis and correlate functional compromise in everyday psychiatrist's practice.

IκB kinase ß (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.

Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKKß), the critical activating kinase in canonical (NFκB) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKß and K171T IKKß represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKß contributes to lymphomagenesis.

M89V Sialic acid Acetyl Esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal.

Catalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE) have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.

El perfil del médico psiquiatra colombiano / Stereotype of the Colombian Psychiatrist

Objetivo: determinar el perfil del psiquiatra colombiano desde tres aspectos fundamentales: estándares de vida, desarrollo académico y desempeño laboral. Diseño: estudio observacional descriptivo de corte transversal tipo encuesta, realizada entre diciembre 2002 y marzo 2003. Muestra: 234 psiquiatras escogidos de forma aleatoria con una muestra representativa decada región. Resultados: 130 hombres y 46 mujeres. La edad promedio de los psiquiatras encuestados fue de 48,6 años, casados 72,73 por ciento, con un promedio de dos hijos. El 77,27 por ciento pertenece a la Asociación Colombiana de Psiquiatría. El 51,7 por ciento de los psiquiatras ha realizado otros estudios que llevan a título. El número promedio de participaciones en actividades de actualización en los últimos doce meses es de 1,12 para congresos nacionales. Los formatos preferidos para educación continuada incluyen: congresos nacionales y seminarios. La principal área para recibir educación continuada son las psicoterapias. El 74,43 por ciento está de acuerdo con la recertificación del gremio. La entidad preferida para tal actividad es la Asociación Colombiana de Psiquiatría, con un promedio de años propuestos para la recertificación de 4,9 años. El 92,05 por ciento de los psiquiatras está laborando actualmente. En promedio, trabajan 5,23 días, entre nueve y doce horas diarias. Para la mayoría de ellos su práctica está orientada hacia la farmacoterapia y otras terapias biológicas. El 77,84 por ciento de los psiquiatras tiene un ingreso inferior al esperado, el 71 por ciento están satisfechos con su trabajo actual...