Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity

<p>Abstract</p> <p>Context</p> <p>Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed.</p> <p>Objective</p> <p>To investigate the possibility of the existence of a crosstalk between the <it>CALPAIN 10 </it>homologue <it>CALPAIN 5 </it>and nuclear receptors of the peroxisome proliferator-activated receptors family.</p> <p>Design</p> <p>Cross-sectional, genetic association study and gene-gene interaction analysis.</p> <p>Subjects</p> <p>The study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30) and 1228 non obese subjects.</p> <p>Results</p> <p>In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (<it>PPARD</it>) gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027). In addition, we have found a significant interaction between <it>CAPN5 </it>and <it>PPARD </it>genes (p = 0.038) that reduces the risk for obesity in a 55%.</p> <p>Conclusion</p> <p>Our results suggest that <it>CAPN5 </it>and <it>PPARD </it>gene products may also interact in vivo.</p

A component-based approximation for trend detection of intense rainfall in the Spanish Mediterranean coast

Rainfall behavior is a fundamental issue in areas with scarce and irregular amounts, such as the Spanish Mediterranean region. We identified 12 spatial patterns that characterized 899 torrential precipitation events (≥150 mm in 24 h) that occurred in the 3,537 rainy precipitation series in the period 1950–2020. Three of these components––eastern and ESE––showed positive and significant trends in their accumulated volumes. We then characterized the mean synoptic causes of the 10 most intense events in each component at both mean sea-level pressure and 500 hPa geopotential height, and also the integrated water-vapor transport between 1,000 and 300 hPa. We found a clear spatial distribution of the pluviometric effects related to unstable atmospheric situations (such as troughs and cut-off lows), and also to SW–SE advection fluxes that brought moist air from the Western Mediterranean. In particular, torrential rainfall in the Balearic Islands related more to E–NE advections than to southeastern ones. We also determined that the major parts of these components occurred in early autumn, especially in September and October. We expect these findings to help our understanding of the processes leading to catastrophic situations along the Spanish Mediterranean coast and to lead to improvements in early alert systems and management plans.The authors want to thank the Proyecto UTA-Mayor N° 5807–22 from the Universidad de Tarapacá, Chile. MLC, JMV, PS and OMR want to thank the Climatology Group (2017SGR1362, Catalan Government). RSN is partially supported by the Universidad Autónoma de Madrid (UAM) and the Comunidad de Madrid through project SI3-PJI-2021-00398, the Natural Hazards and Global Change research group from UAM, and the Government of Aragón through the “Program of research groups” (group H09_20R, “Climate, Water, Global Change, and Natural Systems”). JJM and MJE participation has been funded by the Spanish Ministerio de Ciencia e Innovación through the research project PID2020-118797RB-I00 (MCIN/AEI/10.13039/501100011033) and by Generalitat Valenciana through the research project PROMETEO/2021/016 (Conselleria d’Innovació, Universitats, Ciència i Societat Digital)

A novel strategy based on genomics and specific PCR reveals how a multidrug resistant Mycobacterium tuberculosis strain became prevalent in Equatorial Guinea 15 years after its emergence.

OBJECTIVE: Molecular epidemiology techniques in tuberculosis (TB) can identify high-risk strains that are actively transmitted. We aimed to implement a novel strategy to optimize the identification and control of multidrug-resistant (MDR) TB in a specific population. METHODS: We developed a strain-specific PCR tailored from whole genome sequencing (WGS) data to track a specific MDR prevalent strain in Equatorial Guinea (EG-MDR). RESULTS: The PCR was applied prospectively on remnants of GeneXpert reaction mixtures owing to the lack of culture facilities in Equatorial Guinea. In 147 (93%) of 158 cases, we were able to differentiate between infection by the EG-MDR strain or by any other strain and found that 44% of all rifampicin-resistant TB cases were infected by EG-MDR. We also analysed 93 isolates obtained from Equatorial Guinea 15 years ago, before MDR-TB had become the problem it is today. We found that two of the scarce historical MDR cases were infected by EG-MDR. WGS revealed low variability-six single nucleotide polymorphisms acquired by this strain over 15 years-likely because of the lack in the country of a specific program to treat MDR-TB. CONCLUSIONS: Our novel strategy, which integrated WGS analysis and strain-specific PCRs, represents a low-cost, rapid and transferable strategy that allowed a prospective efficient survey and fast historical analysis of MDR-TB in a population

Detection of Minority Variants and Mixed Infections in Mycobacterium tuberculosis by Direct Whole-Genome Sequencing on Noncultured Specimens Using a Specific-DNA Capture Strategy

Detection of mixed Mycobacterium tuberculosis (MTB) infections is essential, particularly when resistance mutations are present in minority bacterial populations that may affect patients' disease evolution and treatment. Whole-genome sequencing (WGS) has extended the amount of key information available for the diagnosis of MTB infection, including the identification of mixed infections. Having genomic information at diagnosis for early intervention requires carrying out WGS directly on the clinical samples. However, few studies have been successful with this approach due to the low representation of MTB DNA in sputa. In this study, we evaluated the ability of a strategy based on specific MTB DNA enrichment by using a newly designed capture platform (MycoCap) to detect minority variants and mixed infections by WGS on controlled mixtures of MTB DNAs in a simulated sputum genetic background. A pilot study was carried out with 12 samples containing 98% of a DNA pool from sputa of patients without MTB infection and 2% of MTB DNA mixtures at different proportions. Our strategy allowed us to generate sequences with a quality equivalent to those obtained from culture: 62.5× depth coverage and 95% breadth coverage (for at least 20× reads). Assessment of minority variant detection was carried out by manual analysis and allowed us to identify heterozygous positions up to a 95:5 ratio. The strategy also automatically distinguished mixed infections up to a 90:10 proportion. Our strategy efficiently captures MTB DNA in a nonspecific genetic background, allows detection of minority variants and mixed infections, and is a promising tool for performing WGS directly on clinical samples. IMPORTANCE We present a new strategy to identify mixed infections and minority variants in Mycobacterium tuberculosis by whole-genome sequencing. The objective of the strategy is the direct detection in patient sputum; in this way, minority populations of resistant strains can be identified at the time of diagnosis, facilitating identification of the most appropriate treatment for the patient from the first moment. For this, a platform for capturing M. tuberculosis-specific DNA was designed to enrich the clinical sample and obtain quality sequences

Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach.This work was supported by grants from Fundación Leticia Castillejo Castillo and Ministerio de Economía y Competitividad (grant SAF2012-30862 to RSP and grant CTQ2011-24434 to FAJ). RSP Research Institute, and the work carried out in his laboratory receive support from the European Community through the regional development funding program (FEDER). JGC received funding from the Regional Ministry of Education and Science of Castilla–La Mancha (FPI-JCCM) and from Fundación Leticia Castillejo Castillo. MCC and RSP have a contract from the INCRECYT progra

Exploiting the potential of autophagy in cisplatin therapy: a new strategy to overcome resistance

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

This study was supported by the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181)—co-financed by the European Development Regional Fund “A way to achieve Europe” and by Consejería de Sanidad de la Comunidad de Madrid (CÍVICO study 2020/0082). R.L.G. and O.C.M. hold a research contract “Rio Hortega” (CM19/00120 and CM19/00092, respectively) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. MCL holds a predoctoral fellowship (FPU19/06393) from the Spanish Ministry of Science and Innovation.An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.Depto. de MedicinaFac. de MedicinaTRUEUnión EuropeaMinisterio de Ciencia e Innovación (España)Comunidad de MadridInstituto de Salud Carlos IIIpu