SerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of peripheral heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. Yet, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. A genome-wide analysis of gene expression in cultures of primary HGPS fibroblasts identified SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1), as central gene that propels a cell-autonomous pathogenic signaling from the altered nuclear lamina. Indeed, siRNA-mediated downregulation and pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by the correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector and target for therapeutic interventions in HGPS pathogenesis

Structural basis of human kinesin-8 function and inhibition

Kinesin motors play diverse roles in mitosis and are targets for anti-mitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality – microtubule-based stepping and regulation of microtubule dynamics. We investigated the mechanism of Kif18A and its inhibition by the small molecule BTB-1. The Kif18A motor domain drives ATP-dependent plus-end microtubule gliding, and undergoes conformational changes consistent with canonical mechanisms of plus-end directed motility. The Kif18A motor domain also depolymerises microtubule plus and minus ends. BTB-1 inhibits both microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modelling, identified an allosteric BTB-1 binding site near loop5, where it blocks the ATP-dependent conformational changes we characterised. Strikingly, BTB-1 binding is close to that of well-characterised Kif11 inhibitors that block tight microtubule binding, whereas BTB-1 traps Kif18A on the microtubule. Our work highlights a general mechanism of kinesin inhibition in which small molecule binding near loop5 prevents a range of conformational changes, blocking motor function

Galactose inhibition of the constitutive transport of hexoses in Saccharomyces cerevisiae

The relationship between the pathways of glucose and galactose utilization in Saccharomyces cerevisiae has been studied. Galactose (which is transported and phosphorylated by inducible systems) is a strong inhibitor of the utilization of glucose, fructose and mannose (which have the same constitutive transport and phosphorylation systems). Conversely, all these three hexoses inhibit the utilization of galactose, though with poor efficiency. These cross-inhibitions only occur in yeast adapted to galactose or in galactose-constitutive mutants. The efficiency of galactose as inhibitor is even greater than the efficiencies of each of the other three hexoses to inhibit the utilization of each other. Phosphorylation is not involved in the inhibition and transport of sugars is the affected step. The cross-inhibitions between galactose and either glucose, fructose or mannose do not implicate utilization of one hexose at the expense of the other, as it occurs in the mutual interactions between the latter three sugars. it seems that, by growing the yeast in galactose, a protein component is synthesized, or alternatively modified, that once bound to either galactose or any one of the other three hexoses (glucose, fructose or mannose), cross-interacts respectively with the constitutive or the inducible transport systems, impairing their function.This work was supported by a grant (PB87-0206) from the DGICYT, Promoción General del Conocimiento.Peer Reviewe

Metastatic mixed gestational trophoblastic tumour of the uterus: A case report

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Demographic and clinical characteristics of patients with SARS-CoV-2 infection

Objetivo: La pandemia por la infección SARS-CoV-2 ha tenido un fuerte impacto internacional y nacional. La Unidad de Cuidados Intensivos del Hospital R.A. Calderón Guardia ha recibido pacientes críticos con COVID-19 desde marzo 2020. El propósito de este estudio es describir las principales características clínicas y de evolución de esta población. Métodos: Se trata de un estudio observacional descriptivo, que abarcó un periodo de 7 meses de marzo a septiembre de 2020. La información se tomó de 2 bases de datos de la UCI, una de las cuales se diseñó para tal fin. Resultados: Se recolectó la información de 120 pacientes, de los cuales 91 (76%) eran hombres con una edad promedio general de 60 años. La letalidad promedio fue similar para hombres y mujeres, situándose en 52%. Se trató de una población fundamentalmente con sobrepeso u obesidad con un índice de masa corporal promedio de 31,3. Ochenta y un pacientes (67,5%) requirieron de ventilación mecánica asistida y 72 pacientes (60%) desarrollaron insuficiencia renal aguda. La ventilación mecánica aumentó el riesgo de fallecer en 14,7 veces y la lesión renal lo incrementó en 10, 6 veces. Aproximadamente la mitad de los pacientes desarrolló al menos una infección nosocomial. Conclusión: La infección severa por SARS-CoV-2 tiene una carga de morbi-mortalidad alta y se asocia con frecuencia a mayores requerimientos ventilatorios y a falla renal. Estas dos últimas condiciones aumentan de forma importante el riesgo de fallecimiento.Background: The SARS-CoV-2 pandemic has had a strong international and national impact. The Intensive Care Unit of the Dr. R.A. Calderón Guardia Hospital has received critically ill patients with COVID-19 since March 2020. The purpose of this study was to describe the main clinical and evolution characteristics of this population. Methods: This is a descriptive, observational study covering a 7-month period from March to September 2020. Information was taken from 2 ICU databases, one of which was designed for this purpose. Results: Information was collected from 120 patients, 91 (76%) male with a mean age of 60 years, mean mortality was similar for men and women standing at 52%. The population was primarily overweight or obese with an average body mass index of 31.3. Eighty-one patients (67.5%) required mechanical ventilation and 72 patients (60%) developed acute renal failure. Mechanical ventilation increased the risk of death by 14.7 times and renal injury by 10.6 times. Approximately half of the patients developed at least one nosocomial infection. Conclusion: Severe SARS-CoV-2 infection has a high morbidity and mortality burden and is frequently associated with increased ventilatory requirements and renal failure. The latter two conditions significantly increase the risk of death.UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicin

Low endemicity and low pathogenicity of rotaviruses among rural children in Costa Rica

Artículo científico -- Universidad de Costa Rica. Instituto de Investigaciones en Salud. 1985Rotaviruses were prospectively studied in 51 rural Costa Rican children from birth to two years. Samples of feces were collected weekly over a 33-month period. Rotavirus was detected in 45 (1.04%) of 4,317 fecal specimens; 39 infections were documented (an incidence of 0.5 infection per child-year), only five of which were associated with diarrhea (a pathogenicity of 12.8%). Secretory antibody in fecal extracts, detected in six of 39 infections, was short lived and did not protect against reinfection. Serum antibody was present in 69.6% of two-year-old children, but was not detected in 18.8% with documented infections. On the other hand, serum antibody was present in six of 14 children in whom rotavirus was not detected, thus increasing the overall incidence to 0.6 infection per child-year. The combination of prolonged breast-feeding, exposure to a lower infecting dose (compared with urban children), and a higher standard of hygiene than expected may explain the low incidence and low pathogenicity of rotavirus among these rural children.Universidad de Costa Rica. Instituto de Investigaciones en Salud.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

HiTSEE KNIME: a visualization tool for hit selection and analysis in high-throughput screening experiments for the KNIME platform

We present HiTSEE (High-Throughput Screening Exploration Environment), a visualization tool for the analysis of large chemical screens used to examine biochemical processes. The tool supports the investigation of structure-activity relationships (SAR analysis) and, through a flexible interaction mechanism, the navigation of large chemical spaces. Our approach is based on the projection of one or a few molecules of interest and the expansion around their neighborhood and allows for the exploration of large chemical libraries without the need to create an all encompassing overview of the whole library. We describe the requirements we collected during our collaboration with biologists and chemists, the design rationale behind the tool, and two case studies on different datasets. The described integration (HiTSEE KNIME) into the KNIME platform allows additional flexibility in adopting our approach to a wide range of different biochemical problems and enables other research groups to use HiTSEE

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes