Oxidative stress mediates epigenetic modifications and the expression of miRNAs and genes related to apoptosis in diabetic retinopathy patients

Producción CientíficaKnowledge on the underlying mechanisms and molecular targets for managing the ocular complications of type 2 diabetes mellitus (T2DM) remains incomplete. Diabetic retinopathy (DR) is a major cause of irreversible visual disability worldwide. By using ophthalmological and molecular-genetic approaches, we gathered specific information to build a data network for deciphering the crosslink of oxidative stress (OS) and apoptosis (AP) processes, as well as to identify potential epigenetic modifications related to noncoding RNAs in the eyes of patients with T2DM. A total of 120 participants were recruited, being classified into two groups: individuals with T2MD (T2MDG, n = 67), divided into a group of individuals with (+DR, n = 49) and without (−DR, n = 18) DR, and a control group (CG, n = 53). Analyses of compiled data reflected significantly higher plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and significantly lower total antioxidant capacity (TAC) in the +DR patients compared with the −DR and the CG groups. Furthermore, the plasma caspase-3 (CAS3), highly involved in apoptosis (AP), showed significantly higher values in the +DR group than in the −DR patients. The microRNAs (miR) hsa-miR 10a-5p and hsa-miR 15b-5p, as well as the genes BCL2L2 and TP53 involved in these pathways, were identified in relation to DR clinical changes. Our data suggest an interaction between OS and the above players in DR pathogenesis. Furthermore, potential miRNA-regulated target genes were identified in relation to DR. In this concern, we may raise new diagnostic and therapeutic challenges that hold the potential to significantly improve managing the diabetic eye.Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias (REI), Fondo Europeo de Desarrollo Regional (FEDER), NextGenerationEU - (grant RD21/0002/0032)Comunidad Valenciana, Fundación para el Fomento de la Salud y la Investigación Biomédica (FISABIO) - (Project MACBIO/2022-2023: UGP-21-216

A transcriptomic snapshot of early molecular communication between Pasteuria penetrans and Meloidogyne incognita

© The Author(s). 2018Background: Southern root-knot nematode Meloidogyne incognita (Kofoid and White, 1919), Chitwood, 1949 is a key pest of agricultural crops. Pasteuria penetrans is a hyperparasitic bacterium capable of suppressing the nematode reproduction, and represents a typical coevolved pathogen-hyperparasite system. Attachment of Pasteuria endospores to the cuticle of second-stage nematode juveniles is the first and pivotal step in the bacterial infection. RNA-Seq was used to understand the early transcriptional response of the root-knot nematode at 8 h post Pasteuria endospore attachment. Results: A total of 52,485 transcripts were assembled from the high quality (HQ) reads, out of which 582 transcripts were found differentially expressed in the Pasteuria endospore encumbered J2 s, of which 229 were up-regulated and 353 were down-regulated. Pasteuria infection caused a suppression of the protein synthesis machinery of the nematode. Several of the differentially expressed transcripts were putatively involved in nematode innate immunity, signaling, stress responses, endospore attachment process and post-attachment behavioral modification of the juveniles. The expression profiles of fifteen selected transcripts were validated to be true by the qRT PCR. RNAi based silencing of transcripts coding for fructose bisphosphate aldolase and glucosyl transferase caused a reduction in endospore attachment as compared to the controls, whereas, silencing of aspartic protease and ubiquitin coding transcripts resulted in higher incidence of endospore attachment on the nematode cuticle. Conclusions: Here we provide evidence of an early transcriptional response by the nematode upon infection by Pasteuria prior to root invasion. We found that adhesion of Pasteuria endospores to the cuticle induced a down-regulated protein response in the nematode. In addition, we show that fructose bisphosphate aldolase, glucosyl transferase, aspartic protease and ubiquitin coding transcripts are involved in modulating the endospore attachment on the nematode cuticle. Our results add new and significant information to the existing knowledge on early molecular interaction between M. incognita and P. penetrans.Peer reviewedFinal Published versio

A lower bound on intergalactic magnetic fields from time variability of 1ES 0229+200 from MAGIC and Fermi/LAT observations

V. A. Acciari et al.[Context] Extended and delayed emission around distant TeV sources induced by the effects of propagation of γ ray s through the intergalactic medium can be used for the measurement of the intergalactic magnetic field (IGMF).[Aims] We search for delayed GeV emission from the hard-spectrum TeV γ-ray emitting blazar 1ES 0229+200, with the goal of detecting or constraining the IGMF-dependent secondary flux generated during the propagation of TeV γ rays through the intergalactic medium.[Methods] We analysed the most recent MAGIC observations over a 5 year time span, and complemented them with historic data of the H.E.S.S. and VERITAS telescopes, along with a 12-year-long exposure of the Fermi/LAT telescope. We used them to trace source evolution in the GeV–TeV band over a decade and a half. We used Monte Carlo simulations to predict the delayed secondary γ-ray flux, modulated by the source variability, as revealed by TeV-band observations. We then compared these predictions for various assumed IGMF strengths to all available measurements of the γ-ray flux evolution.[Results] We find that the source flux in the energy range above 200 GeV experiences variations around its average on the 14-year time span of observations. No evidence for the flux variability is found in the 1 − 100 GeV energy range accessible to Fermi/LAT. The non-detection of variability due to delayed emission from electromagnetic cascade developing in the intergalactic medium imposes a lower bound of B > 1.8 × 10−17 G for the long-correlation-length IGMF and B > 10−14 G for an IGMF of cosmological origin. Though weaker than the one previously derived from the analysis of Fermi/LAT data, this bound is more robust, being based on a conservative intrinsic source spectrum estimate and accounting for the details of source variability in the TeV energy band. We discuss implications of this bound for cosmological magnetic fields that might explain the baryon asymmetry of the Universe.The financial support of the German BMBF, MPG and HGF; the Italian INFN and INAF; the Swiss National Fund SNF; the ERDF under the Spanish Ministerio de Ciencia e Innovación (MICINN) (PID2019-104114RB-C31, PID2019-104114RB-C32, PID2019-104114RB-C33, PID2019-105510GB-C31,PID2019-107847RB-C41, PID2019-107847RB-C42, PID2019-107847RB-C44, PID2019-107988GB-C22); the Indian Department of Atomic Energy; the Japanese ICRR, the University of Tokyo, JSPS, and MEXT; the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-400/18.12.2020 and the Academy of Finland grant nr. 320045 is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia “Severo Ochoa” (SEV-2016-0588, SEV-2017-0709, CEX2019-000920-S), the Unidad de Excelencia “María de Maeztu” (CEX2019-000918-M, MDM-2015-0509-18-2) and by the CERCA program of the Generalitat de Catalunya; by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project uniri-prirod-18-48; by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3; the Polish National Research Centre grant UMO-2016/22/M/ST9/00382; and by the Brazilian MCTIC, CNPq and FAPERJ.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2019-000920-S).With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2019-000918-M).Peer reviewe

Agroforestry creates carbon sinks whilst enhancing the environment in agricultural landscapes in Europe

Agroforestry, relative to conventional agriculture, contributes significantly to carbon sequestration, increases a range of regulating ecosystem services, and enhances biodiversity. Using a transdisciplinary approach, we combined scientific and technical knowledge to evaluate nine environmental pressures in terms of ecosystem services in European farmland and assessed the carbon storage potential of suitable agroforestry systems, proposed by regional experts. First, regions with potential environmental pressures were identified with respect to soil health (soil erosion by water and wind, low soil organic carbon), water quality (water pollution by nitrates, salinization by irrigation), areas affected by climate change (rising temperature), and by underprovision in biodiversity (pollination and pest control pressures, loss of soil biodiversity). The maps were overlaid to identify areas where several pressures accumulate. In total, 94.4% of farmlands suffer from at least one environmental pressure, pastures being less affected than arable lands. Regional hotspots were located in north-western France, Denmark, Central Spain, north and south-western Italy, Greece, and eastern Romania. The 10% of the area with the highest number of accumulated pressures were defined as Priority Areas, where the implementation of agroforestry could be particularly effective. In a second step, European agroforestry experts were asked to propose agroforestry practices suitable for the Priority Areas they were familiar with, and identified 64 different systems covering a wide range of practices. These ranged from hedgerows on field boundaries to fast growing coppices or scattered single tree systems. Third, for each proposed system, the carbon storage potential was assessed based on data from the literature and the results were scaled-up to the Priority Areas. As expected, given the wide range of agroforestry practices identified, the carbon sequestration potentials ranged between 0.09 and 7.29 t C ha−1 a−1. Implementing agroforestry on the Priority Areas could lead to a sequestration of 2.1 to 63.9 million t C a−1 (7.78 and 234.85

Nutrient supply does play a role on the structure of marine picophytoplankton communities

Conference communicationThe Margalef´s mandala (1978) is a simplified bottom-up control model that explains how mixing and nutrient concentration determine the composition of marine phytoplankton communities. Due to the difficulties of measuring turbulence in the field, previous attempts to verify this model have applied different proxies for nutrient supply, and very often used interchangeably the terms mixing and stratification. Moreover, because the mandala was conceived before the discovery of smaller phytoplankton groups (picoplankton <2 µm), it describes only the succession of vegetative phases of microplankton. In order to test the applicability of the classical mandala to picoplankton groups, we used a multidisciplinary approach including specifically designed field observations supported by remote sensing, database analyses, and modeling and laboratory chemostat experiments. Simultaneous estimates of nitrate diffusive fluxes, derived from microturbulence observations, and picoplankton abundance collected in more than 200 stations, spanning widely different hydrographic regimes, showed that the contribution of eukaryotes to picoautotrophic biomass increases with nutrient supply, whereas that of picocyanobacteria shows the opposite trend. These findings were supported by laboratory and modeling chemostat experiments that reproduced the competitive dynamics between picoeukaryote sand picocyanobacteria as a function of changing nutrient supply. Our results indicate that nutrient supply controls the distribution of picoplankton functional groups in the ocean, further supporting the model proposed by Margalef.Spanish Governmen

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Adjuvant dabrafenib and trametinib for patients with resected BRAF-mutated melanoma: DESCRIBE-AD real-world retrospective observational study

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF-V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF-mutated melanoma patients aged & GE;18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations

Polymorphisms within inflammatory genes and colorectal cancer

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). RESULTS: There was no statistically significant association between the SNPs investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size

Adaptive and Phase Selective Spike Timing Dependent Plasticity in Synaptically Coupled Neuronal Oscillators

We consider and analyze the influence of spike-timing dependent plasticity (STDP) on homeostatic states in synaptically coupled neuronal oscillators. In contrast to conventional models of STDP in which spike-timing affects weights of synaptic connections, we consider a model of STDP in which the time lags between pre- and/or post-synaptic spikes change internal state of pre- and/or post-synaptic neurons respectively. The analysis reveals that STDP processes of this type, modeled by a single ordinary differential equation, may ensure efficient, yet coarse, phase-locking of spikes in the system to a given reference phase. Precision of the phase locking, i.e. the amplitude of relative phase deviations from the reference, depends on the values of natural frequencies of oscillators and, additionally, on parameters of the STDP law. These deviations can be optimized by appropriate tuning of gains (i.e. sensitivity to spike-timing mismatches) of the STDP mechanism. However, as we demonstrate, such deviations can not be made arbitrarily small neither by mere tuning of STDP gains nor by adjusting synaptic weights. Thus if accurate phase-locking in the system is required then an additional tuning mechanism is generally needed. We found that adding a very simple adaptation dynamics in the form of slow fluctuations of the base line in the STDP mechanism enables accurate phase tuning in the system with arbitrary high precision. Adaptation operating at a slow time scale may be associated with extracellular matter such as matrix and glia. Thus the findings may suggest a possible role of the latter in regulating synaptic transmission in neuronal circuits

Common Variation in ISL1 Confers Genetic Susceptibility for Human Congenital Heart Disease

Congenital heart disease (CHD) is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant–common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations