Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

Exploring host genetic polymorphisms involved in SARS-CoV infection autcomes: implications for personalized medicine in COVID-19

Objective. To systematically explore genetic polymorphisms associated with the clinical outcomes in SARS-CoV infection in humans. Methods. This comprehensive literature search comprised available English papers published in PubMed/Medline and SCOPUS databases following the PRISMA-P guidelines and PICO/AXIS criteria. Results. Twenty-nine polymorphisms located in 21 genes were identified as associated with SARS-CoV susceptibility/resistance, disease severity, and clinical outcomes predominantly in Asian populations. Thus, genes implicated in key pathophysiological processes such as the mechanisms related to the entry of the virus into the cell and the antiviral immune/inflammatory responses were identified. Conclusions. Although caution must be taken, the results of this systematic review suggest that multiple genetic polymorphisms are associated with SARS-CoV infection features by affecting virus pathogenesis and host immune response, which could have important applications for the study and understanding of genetics in SARS-CoV-2/COVID-19 and for personalized translational clinical practice depending on the population studied and associated environments

Polymorphic appetite effects on waist circumference depend on rs3749474 CLOCK gene variant

Chronobiological aspects controlled by CLOCK genes may influence obesity incidence. Although there are studies that show an association between the expression of these genes and energy intake, waist circumference or abdominal obesity phenotypes, interactions with appetite have been insufficiently investigated in relation to chrononutrition. The objective was to identify interactions between CLOCK genetic variants involved in appetite status. A total of 442 subjects (329 women, 113 men; aged 18 to 65 years) were recruited. Anthropometric, dietary and lifestyle data were collected by trained nutritionists. Participants were classified according to their appetite feelings with a Likert scale. Multiple linear regression models were used to examine associations of the type genotype x appetite status on adiposity-related variables. p values were corrected by the Bonferroni method. A significant influence was found concerning the effects of appetite on waist circumference with respect to rs3749474 CLOCK polymorphism (p < 0.001). An additive model analysis (adjusted by age, gender, exercise and energy intake) showed that risk allele carriers, increased the waist circumference around 14 cm (β = 14.1, CI = 6.3–22.0) by each increment in the level of appetite. The effects of appetite on waist circumference may be partly modulated by the rs3749474 CLOCK polymorphism

The Brazilian Tunable Filter Imager for the SOAR telescope

This paper presents a new Tunable Filter Instrument for the SOAR telescope. The Brazilian Tunable Filter Imager (BTFI) is a versatile, new technology, tunable optical imager to be used in seeing-limited mode and at higher spatial fidelity using the SAM Ground-Layer Adaptive Optics facility at the SOAR telescope. The instrument opens important new science capabilities for the SOAR community, from studies of the centers of nearby galaxies and the insterstellar medium to statistical cosmological investigations. The BTFI takes advantage of three new technologies. The imaging Bragg Tunable Filter concept utilizes Volume Phase Holographic Gratings in a double-pass configuration, as a tunable filter, while a new Fabry-Perot (FP) concept involves technologies which allow a single FP etalon to act over a large range of interference orders and spectral resolutions. Both technologies will be in the same instrument. Spectral resolutions spanning the range between 25 and 30,000 can be achieved through the use of iBTF at low resolution and scanning FPs beyond R ~2,000. The third new technologies in BTFI is the use of EMCCDs for rapid and cyclically wavelength scanning thus mitigating the damaging effect of atmospheric variability through data acquisition. An additional important feature of the instrument is that it has two optical channels which allow for the simultaneous recording of the narrow-band, filtered image with the remaining (complementary) broad-band light. This avoids the uncertainties inherent in tunable filter imaging using a single detector. The system was designed to supply tunable filter imaging with a field-of-view of 3 arcmin on a side, sampled at 0.12" for direct Nasmyth seeing-limited area spectroscopy and for SAM's visitor instrument port for GLAO-fed area spectroscopy. The instrument has seen first light, as a SOAR visitor instrument. It is now in comissioning phase.Comment: accepted in PAS

Estrategias de guía e ingredientes dietéticos de precisión para enfermedades crónicas en población pre-sénior y sénior

El envejecimiento de la población supone un importante reto, económico y cualitativo, para el sistema de salud orientándolo hacia una atención de tipo preventivo, en la que la nutrición de precisión (NP) y la prescripción de hábitos saludables adquieren relevancia capital. El fin de la NP es procurar una nutrición adaptada a cada individuo, entendiendo que la prevención o el tratamiento de trastornos crónicos (obesidad, diabetes, enfermedad cardiovascular, etc.) deben abordarse de un modo integral, considerando información personal y clínica relevante, edad y características feno- y genotípicas. La elaboración de la presente guía surge de la necesidad de desarrollar modelos nutricionales de precisión que permitan la individualización del tratamiento nutricional, con énfasis en el adulto mayor. Las necesidades nutricionales, las recomendaciones dietéticas y los ingredientes para una NP en las personas pre-sénior y sénior quedan resumidas en realizar al menos 3 comidas diarias, reducir las calorías totales, optar por una alimentación variada y equilibrada con alimentos frescos y de alta densidad nutricional, incorporar verduras, legumbres y pescado, consumir productos lácteos y fibra, preferir carnes blancas en lugar de rojas, evitar frituras, embutidos y alimentos procesados, moderar el consumo de sal, café y alcohol, e hidratarse adecuadamente.The aging of the population underlines an important challenge for the health system not only from sanitary and economic reasons but also by quality perspectives concerning preventive care, where precision nutrition (PN) and the prescription or advice on healthy habits becomes relevant. PN focuses on provide nutrition adapted to each individual, understanding that the prevention or treatment of chronic disorders (obesity, diabetes, cardiovascular disease, etc.) must be addressed in a comprehensive way, considering not only relevant personal and clinical information, but also healthy aging and phenotypical and genotypical features. This guide was prepared due to the need to develop precision nutritional models that allow individualized nutritional treatment for each subject and physiopathological particularities with emphasis on the elderly. Therefore, the requirements of the Spanish pre-senior and senior populations, dietary recommendations and precision foods are reviewed in this document: have at least three daily meals, reduce total calories, choose a varied and balanced diet with fresh foods and high nutritional density, add vegetables, legumes and fish, consume dairy products and fiber, prefer white meat instead of red, avoid fried foods, sausages and processed foods, moderate the consumption of salt, coffee and alcohol, and get hydrated

Screening for neurocognitive impairment, depression, and anxiety in HIV-infected patients in Western Europe and Canada

CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV-positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients ≥18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART-experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART-experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response

Real-Time PCR in HIV/Trypanosoma cruzi Coinfection with and without Chagas Disease Reactivation: Association with HIV Viral Load and CD4+ Level

Chagas disease is endemic in Latin America and is caused by the flagellate protozoan T. cruzi. The acute phase is asymptomatic in the majority of the cases and rarely causes inflammation of the heart or the central nervous system. Most infected patients progress to a chronic phase, characterized by cardiac or digestive involvement when not asymptomatic. However, when patients are also exposed to an immunosuppressant (such as chemotherapy), neoplasia, or other infections such as HIV, T. cruzi infection may develop into a severe disease (Chagas disease reactivation) involving the heart and central nervous system. The current microscopic methods for diagnosing Chagas disease reactivation are not sensitive enough to prevent the high rate of death observed in these cases. Therefore, we propose a quantitative method to monitor blood levels of the parasite, which will allow therapy to be administered as early as possible, even if the patient has not yet presented symptoms