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

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

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

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

Begutachtung von Artikeln bei der GMS Zeitschrift für Medizinische Ausbildung

Introduction:Evidence based medicine is not the ideal way to assess and evaluate treatment success, failure and outcomes. Modern technology makes it possible to register a multitude of information. Advances in the venous field are fast and require a more efficient way to allow selection based on outcomes and quality. Registries are theoretically contain the data needed to investigate venous treatments and instruments. Materials and methods:A literature review was performed and twenty-five articles were selected for review. Results:Current registries fail to perform as needed and do not deliver the needed information. Separate frameworks and applications are available, but up until now no centralized and combined effort has been made to create a true all encompassing European venous registry. Conclusions:A European venous registry containing standardized variables regarding all aspects of venous disease is needed to truly investigate and improve our care. An intuitive and integrated EHR application can facilitate the gathering of data needed to create such a registry. A number of rules apply though

An overview of the most commonly used venous quality of life and clinical outcome measurements

Background: Modern medicine should no longer rely solely on technical success to evaluate treatments. The treatment of venous disease has seen many new developments, insights, and treatment modalities. Combining clinical scores with quality of life (QoL) outcome measurements is becoming the new norm for evaluation of treatments. Many different outcome assessment instruments are currently available, indicating a lack of consensus. Methods: We set out to find the most reliable and comprehensive scoring instrument for clinical and QoL measurement in venous disease. In this review, we focus on the eight most widely used instruments. For clinical assessment, these are the Clinical, Etiologic, Anatomic, and Pathologic (CEAP) classification, Villalta scale, and Venous Clinical Severity Score (VCSS); for generic QoL, the 36-Item Short Form Health Survey (SF-36) and EQ-5D questionnaires; and for disease specific QoL, the Aberdeen Varicose Vein Questionnaire (AVVQ), Chronic Venous Insufficiency Questionnaire (CIVIQ), and VEnous INsufficiency Epidemiological and Economic Study on Quality of Life/Symptoms (VEINES-QOL/Sym) questionnaire. Each instrument is reviewed. Conclusions: For the accurate evaluation of treatment outcomes, socioeconomic, QoL, and clinical aspects must be assessed. None of the available disease-specific instruments is suited to use in uniform outcome measurement for the whole spectrum of venous disease. A new combined QoL and clinical instrument is needed to validly assess and compare the outcomes of venous treatments. The VEINES-QOL/Sym is currently the most valid instrument to assess disease-specific QoL

Short-term follow-up of Quality-of-Life in interventionally treated patients with post-thrombotic syndrome after deep venous occlusion

Introduction Treatment of deep venous occlusive disease is gaining popularity, although the results and outcomes of various techniques are yet to be fully studied. Quality-of-Life (QoL) improvement is a valid and important outcome in medicine, but no specific QoL instruments for deep venous pathology exist up until now. We assessed the short term QoL effects of treated patients with post thrombotic syndrome after deep venous occlusion. Materials and methods Patients with proven venous occlusive disease referred to the outpatient clinic of our department of Venous Surgery in the Maastricht University Medical Centre were included. After inclusion, patients were treated by PTA and stenting and when indicated an endophlebectomy was performed and an AV fistula was made. QoL was assessed with the disease specific VEINES-QOL/Sym and the generic SF-36 questionnaires preoperatively at baseline and postoperatively at 3 and 12 months. Results 61 patients completed the 3 month follow-up period and 28 patients the 12 month follow-up period. VEINES-QOL and Sym scores improved after 3 months: 17.5 points for QOL (p= Conclusions Treating deep venous occlusive disease leads to short-term improvement of both disease specific QoL as well as generic QoL scores. Larger long-term follow-up studies are needed to corroborate these results