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Background: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. Results: The aim of the present study was to analyze the long-term evolution of methylation patterns in a subset of metabolically healthy subjects in order to search for epigenetic markers that could predict the progression to an unhealthy state. Twenty-six CpG sites were significantly differentially methylated, both at baseline and 11-year follow-up. These sites were related to 19 genes or pseudogenes, a more in-depth analysis of the methylation sites of these genes showed that CYP2E1 had 50% of the collected CpG sites differently methylated between stable metabolically healthy obesity (MHO) and unstable MHO, followed by HLA-DRB1 (33%), ZBTB45 (16%), HOOK3 (14%), PLCZ1 (14%), SLC1A1 (12%), MUC2 (12%), ZFPM2 (12.5%) and HLA-DQB2 (8%). Pathway analysis of the selected 26 CpG sites showed enrichment in pathways linked to th1 and th2 activation, antigen presentation, allograft rejection signals and metabolic processes. Higher methylation levels in the cg20707527 (ZFPM2) could have a protective effect against the progression to unstable MHO (OR: 0.21, 95%CI (0.067–0.667), p &lt, 0.0001), whilst higher methylation levels in cg11445109 (CYP2E1) would increase the progression to MUO, OR: 2.72, 95%CI (1.094–6.796), p &lt, 0.0014, respectively). Conclusions: DNA methylation status is associated with the stability/worsening of MHO phenotype. Two potential biomarkers of the transition to an unhealthy state were identified and deserve further investigation (cg20707527 and cg11445109). Moreover, the described differences in methylation could alter immune system-related pathways, highlighting these pathways as therapeutic targets to prevent metabolic deterioration in MHO patients.

We assessed the structure–function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p p 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p r = 0.33, p

Axial spondyloarthritis (axSpA) is a chronic rheumatic disease characterized by the presence of inflammatory back pain. In patients with chronic low back pain, the lumbar flexion relaxation phenomenon measured by surface electromyography (sEMG) differs from that in healthy individuals. However, sEMG activity in axSpA patients has not been studied. The purpose of this study was to analyze the flexion relaxation phenomenon in axSpA patients. A study evaluating 39 axSpA patients and 35 healthy controls was conducted. sEMG activity at the erector spinae muscles was measured during lumbar full flexion movements. sEMG activity was compared between axSpA patients and the controls, as well as between active (BASDAI ≥ 4) and non-active (BASDAI &lt, 4) patients. The reliability (using intraclass correlation coefficients (ICC)), criterion validity and discriminant validity using the area Under the curve (AUC) for the inverse flexion/relaxation ratio (1/FRR) were evaluated. Significant differences (p &lt, 0.05) were observed between axSpA patients and the control group in lumbar electric activity, especially during flexion, relaxation, and extension and in FRR and 1/FRR (0.66 ± 0.39 vs. 0.25 ± 0.19, respectively). In addition, significant differences were found between active and non-active but also between non-active and healthy subjects. The sEMG showed good reliability (ICC &gt, 0.8 for 1/FRR) and criterion validity. ROC analysis showed good discriminant validity for axSpA patients (AUC = 0.835) vs. the control group using 1/FRR. An abnormal flexion/relaxation phenomenon exists in axSpA patients compared with controls. sEMG could be an additional objective tool in the evaluation of patient function and disease activity status.

This work was supported by the research project Stance4Health (contract no. 816303) from the European Commission (Research Executive Agency)., The sequence data are available in the European Nucleotide Archive (ENA) under accession number PRJEB14013 (https:// www.ebi.ac.uk/ena/browser/view/PRJEB41013)., This paper will form part of the doctoral thesis of SM, conducted within the context of the “Nutrition and Food Sciences Programme” at the University of Granada, The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2021.625782/ full#supplementary-material, Food and food bioactive components are major drivers of modulation of the human gut microbiota. Tannin extracts consist of a mix of bioactive compounds, which are already exploited in the food industry for their chemical and sensorial properties. The aim of our study was to explore the viability of associations between tannin wood extracts of different origin and food as gut microbiota modulators. 16S rRNA amplicon next-generation sequencing (NGS) was used to test the effects on the gut microbiota of tannin extracts from quebracho, chestnut, and tara associated with commercial food products with different composition in macronutrients. The different tannin-enriched and non-enriched foods were submitted to in vitro digestion and fermentation by the gut microbiota of healthy subjects. The profile of the short chain fatty acids (SCFAs) produced by the microbiota was also investigated. The presence of tannin extracts in food promoted an increase of the relative abundance of the genus Akkermansia, recognized as a marker of a healthy gut, and of various members of the Lachnospiraceae and Ruminococcaceae families, involved in SCFA production. The enrichment of foods with tannin extracts had a booster effect on the production of SCFAs, without altering the profile given by the foods alone. These preliminary results suggest a positive modulation of the gut microbiota with potential benefits for human health through the enrichment of foods with tannin extracts., European Commission European Commission Joint Research Centre 816303

Five agarose types (D1LE, D2LE, LM, MS8 and D5) were evaluated in tissue engineering and compared for the first time using an array of analysis methods. Acellular and cellular constructs were generated from 0.3–3%, and their biomechanical properties, in vivo biocompatibility (as determined by LIVE/DEAD, WST-1 and DNA release, with n = 6 per sample) and in vivo biocompatibility (by hematological and biochemical analyses and histology, with n = 4 animals per agarose type) were analyzed. Results revealed that the biomechanical properties of each hydrogel were related to the agarose concentration (p < 0.001). Regarding the agarose type, the highest (p < 0.001) Young modulus, stress at fracture and break load were D1LE, D2LE and D5, whereas the strain at fracture was higher in D5 and MS8 at 3% (p < 0.05). All agaroses showed high biocompatibility on human skin cells, especially in indirect contact, with a correlation with agarose concentration (p = 0.0074 for LIVE/DEAD and p = 0.0014 for WST-1) and type, although cell function tended to decrease in direct contact with highly concentrated agaroses. All agaroses were safe in vivo, with no systemic effects as determined by hematological and biochemical analysis and histology of major organs. Locally, implants were partially encapsulated and a pro-regenerative response with abundant M2- type macrophages was found. In summary, we may state that all these agarose types can be safely used in tissue engineering and that the biomechanical properties and biocompatibility were strongly associated to the agarose concentration in the hydrogel and partially associated to the agarose type. These results open the door to the generation of specific agarose-based hydrogels for definite clinical applications such as the human skin, cornea or oral mucosa., Hispanagar SA, Burgos, Spain, through CDTI, Ministry of Science and Innovation, Spain, Programa Operativo Plurirregional de Crecimiento Inteligente (CRIN) IDI-20180052, ISCIII thorough AES AC17/00013, Junta de Andalucía PE-0395-2019, Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+i) from Ministerio de Ciencia, Innovación y Universidades (Instituto de Salud Carlos III) FIS PI17/0391, Fondo Europeo de Desarrollo Regional ERDF-FEDER, European Union PI20/0317

This research was funded by FEDER and Foundation for Science and Technology (FCT), grant number POCI-01-0145-FEDER-028159 and POCI-01-0145-FEDER-030782); by Fondo de Investigaciones Sanitarias (Madrid, Spain), grant number ISCIII-FEDER PI20/01845, ISCIII-FEDER PI12/02688, and ISCIII-FEDER PI17/02276. B.S.M. was funded by FCT, grant number DL 57/2016. A.C.A. was funded by FCT, grant number POCI-01-0145-FEDER-028159. C.C. was funded by FCT, grant number CEECIND/04058/2018. A.C. was funded by FCT, grant number CEECIND/03628/2017., The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical reasons., Simple Summary Acute myeloid leukemia (AML) is a hematological neoplasm with a very poor survival rate. To date, diagnostic tools to monitor individuals at higher risk of developing AML are scarce. Single nucleotide polymorphisms (SNPs) have emerged as good candidates for disease prevention. AML is characterized by altered autophagy, a vital mechanism to remove and recycle unnecessary or dysfunctional cellular components. ATG10 is one of the autophagy core genes involved in the autophagosome formation. We hypothesize that SNPs located in regulatory regions of the ATG10 gene could predispose individuals to AML development. We therefore genotyped three SNPs within the ATG10 locus. We identified the ATG10(rs3734114) as a potential risk factor for developing AML, whereas the ATG10(rs1864182) was associated with decreased risk. These findings highlight ATG10 as a key regulator of susceptibility to AML. Furthermore, we believe that ATG10 SNPs could be exploited in the clinical setting as an AML prevention strategy. Acute myeloid leukemia (AML) is the most common acute leukemia, characterized by a heterogeneous genetic landscape contributing, among others, to the occurrence of metabolic reprogramming. Autophagy, a key player on metabolism, plays an essential role in AML. Here, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene, central for the autophagosome formation. We screened a multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs: rs1864182T>G, rs1864183C>T and rs3734114T>C. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells from a cohort of 46 healthy individuals. Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10(rs1864182G) allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10(rs3734114C) allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10(rs1864182G) allele had decreased autophagy when compared to homozygous major allele carriers. Our results uncover the potential of screening for ATG10 genetic variants in AML prevention strategies, in particular for subjects carrying other AML risk factors such as elderly individuals with clonal hematopoiesis of indeterminate potential., European Commission, Portuguese Foundation for Science and Technology European Commission POCI-01-0145-FEDER-028159 POCI-01-0145-FEDER-030782, Instituto de Salud Carlos III ISCIII-FEDER PI20/01845 ISCIII-FEDER PI12/02688 ISCIII-FEDER PI17/02276, Portuguese Foundation for Science and Technology European Commission POCI-01-0145-FEDER-028159 DL 57/2016 CEECIND/04058/2018 CEECIND/03628/2017

We would like to extend our gratitude to the all the patients and the healthy volunteers who participated in the study, as well as the University of Granada, Biomedicine PhD program. This work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461., Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC., Roche Spain, University of Granada (DdMP), Spanish Government REF FPU14/05461

Recent studies have linked changes in peripheral chemokine concentrations to the presence of both addictive behaviors and psychiatric disorders. The present study further explore this link by analyzing the potential association of psychiatry comorbidity with alterations in the concentrations of circulating plasma chemokine in patients of both sexes diagnosed with alcohol use disorders (AUD). To this end, 85 abstinent subjects with AUD from an outpatient setting and 55 healthy subjects were evaluated for substance and mental disorders. Plasma samples were obtained to quantify chemokine concentrations [C-C motif (CC), C-X-C motif (CXC), and C-X3-C motif (CX3C) chemokines]. Abstinent AUD patients displayed a high prevalence of comorbid mental disorders (72%) and other substance use disorders (45%). Plasma concentrations of chemokines CXCL12/stromal cell-derived factor-1 (p