A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.Funding: This work was supported by grants from the Spanish Ministry of Science and Technology (grant BFU2017-86378-P) (to FdlC), Fondo Investigaciones Sanitarias (PI18/01304) (to JC), Gilead Fellowship programme 2018 (to JC)

Towards a new seismic hazard assessment in Spain

Seismic hazard is an evolving science that is fed by geological and seismological studies. As new data and models arise, the revision of hazard maps is compelling. Additionally, understanding the nature and the sources of the uncertainties involved in seismic hazard analyses is essential in order to reduce them. In this context, Spain is not an exception and a move towards a reassessment of the national hazard maps is pertinent. Several hazard-controlling factors needing to be updated and eventually revaluated are identified in this work in progress. The first one concerns the seismic catalogue. It must be homogenised, incorporating data from neighbouring countries and correlating magnitude scales for different regions and recording periods. A second factor refers to seismicity characterization by zoning and zoneless models: Neotectonic, seismological and other geological data that justify the development of a new zoning model for Spain and adjacent areas are disclosed. Revaluation of seismic areas that are traditionally considered as stable but show evidence of seismic activity at present and during Quaternary times needs to be considered. The interest of developing a neotectonic characterization of active faults is advanced. For zoneless models, the different elements that define the continuous spatial variation of the activity rate density have to be examined. For a zoneless model based on kernel functions, these elements would be the specific type of kernel function, the bandwidth and the reference years. A third factor requiring a modern analysis refers to the implementation of different strong motion prediction models. These include models based on local data and developed with data from other regions. Special attention is paid to the application of the next generation attenuation models originally developed for western North America to Spain. Criteria for selecting different models must be clearly and thoughtfully enumerated. The final goal of this work is to assess the variability of seismic hazard results to the new data and models that are becoming available. Such information will be of indubitable interest for forthcoming versions of the seismic code, national annexes of Eurocode 8 and research projects fomented by the Spanish Nuclear Security Counci

Identification and Functional Testing of Novel Interacting Protein Partners for the Stress Sensors Wsc1p and Mid2p of \u3cem\u3eSaccharomyces cerevisiae\u3c/em\u3e

Wsc1p and Mid2p are transmembrane signaling proteins of cell wall stress in the budding yeast Saccharomyces cerevisiae. When an environmental stress compromises cell wall integrity, they activate a cell response through the Cell Wall Integrity (CWI) pathway. Studies have shown that the cytoplasmic domain of Wsc1p initiates the CWI signaling cascade by interacting with Rom2p, a Rho1-GDP-GTP exchange factor. Binding of Rom2p to the cytoplasmic tail of Wsc1p requires dephosphorylation of specific serine residues but the mechanism by which the sensor is dephosphorylated and how it subsequently interacts with Rom2p remains unclear. We hypothesize that Wsc1p and Mid2p must be physically associated with interacting proteins other than Rom2p that facilitate its interaction and regulate the activation of CWI pathway. To address this, a cDNA plasmid library of yeast proteins was expressed in bait strains bearing membrane yeast two-hybrid (MYTH) reporter modules of Wsc1p and Mid2p, and their interacting preys were recovered and sequenced. 14 previously unreported interactors were confirmed for Wsc1p and 29 for Mid2p. The interactors’ functionality were assessed by cell growth assays and CWI pathway activation by western blot analysis of Slt2p/Mpk1p phosphorylation in null mutants of each interactor under defined stress conditions. The susceptibility of these strains to different stresses were tested against antifungal agents and chemicals. This study reports important novel protein interactions of Wsc1p and Mid2p that are associated with the cellular response to oxidative stress induced by Hydrogen Peroxide and cell wall stress induced by Caspofungin

Toward the Discovery of Biological Functions Associated with the Mechanosensor Mtl1p of \u3ci\u3eSaccharomyces cerevisiae\u3c/i\u3e via Integrative Multi-OMICs Analysis

Functional analysis of the Mtl1 protein in Saccharomyces cerevisiae has revealed that this transmembrane sensor endows yeast cells with resistance to oxidative stress through a signaling mechanism called the cell wall integrity pathway (CWI). We observed upregulation of multiple heat shock proteins (HSPs), proteins associated with the formation of stress granules, and the phosphatase subunit of trehalose 6-phosphate synthase which suggests that mtl1Δ strains undergo intrinsic activation of a non-lethal heat stress response. Furthermore, quantitative global proteomic analysis conducted on TMT-labeled proteins combined with metabolome analysis revealed that mtl1Δ strains exhibit decreased levels of metabolites of carboxylic acid metabolism, decreased expression of anabolic enzymes and increased expression of catabolic enzymes involved in the metabolism of amino acids, with enhanced expression of mitochondrial respirasome proteins. These observations support the idea that Mtl1 protein controls the suppression of a non-lethal heat stress response under normal conditions while it plays an important role in metabolic regulatory mechanisms linked to TORC1 signaling that are required to maintain cellular homeostasis and optimal mitochondrial function

Changes in the Frontotemporal Cortex and Cognitive Correlates in First-Episode Psychosis

Background: Loss of cortical volume in frontotemporal regions has been reported in patients with schizophrenia and their relatives. Cortical area and thickness are determined by different genetic processes, and measuring these parameters separately may clarify disturbances in corticogenesis relevant to schizophrenia. Our study also explored clinical and cognitive correlates of these parameters.Methods: Thirty-seven patients with first-episode psychosis (34 schizophrenia, 3 schizoaffective disorder) and 38 healthy control subjects matched for age and sex took part in the study. Imaging was performed on an magnetic resonance imaging 1.5-T scanner. Area and thickness of the frontotemporal cortex were measured using a surface-based morphometry method (Freesurfer). All subjects underwent neuropsychologic testing that included measures of premorbid and current IQ, working and verbal memory, and executive function.Results: Reductions in cortical area, more marked in the temporal cortex, were present in patients. Overall frontotemporal cortical thickness did not differ between groups, although regional thinning of the right superior temporal region was observed in patients. There was a significant association of both premorbid IQ and IQ at disease onset with area, but not thickness, of the frontotemporal cortex, and working memory span was associated with area of the frontal cortex. These associations remained significant when only patients with schizophrenia were considered.Conclusions: Our results suggest an early disruption of corticogenesis in schizophrenia, although the effect of subsequent environmental factors cannot be excluded. In addition, cortical abnormalities are subject to regional variations and differ from those present in neurodegenerative diseases

Beneficial effects of essential oils from the mediterranean diet on gut microbiota and their metabolites in ischemic heart disease and type-2 diabetes mellitus

[Abstract] Ischemic heart disease (IHD) and type-2 diabetes mellitus (T2DM) remain major health problems worldwide and commonly coexist in individuals. Gut microbial metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), have been linked to cardiovascular and metabolic diseases. Previous studies have reported dysbiosis in the gut microbiota of these patients and the prebiotic effects of some components of the Mediterranean diet. Essential oil emulsions of savory (Satureja hortensis), parsley (Petroselinum crispum) and rosemary (Rosmarinus officinalis) were assessed as nutraceuticals and prebiotics in IHD and T2DM. Humanized mice harboring gut microbiota derived from that of patients with IHD and T2DM were supplemented with L-carnitine and orally treated with essential oil emulsions for 40 days. We assessed the effects on gut microbiota composition and abundance, microbial metabolites and plasma markers of cardiovascular disease, inflammation and oxidative stress. Our results showed that essential oil emulsions in mice supplemented with L-carnitine have prebiotic effects on beneficial commensal bacteria, mainly Lactobacillus genus. There was a decrease in plasma TMAO and an increase in fecal SCFAs levels in mice treated with parsley and rosemary essential oils. Thrombomodulin levels were increased in mice treated with savory and parsley essential oils. While mice treated with parsley and rosemary essential oils showed a decrease in plasma cytokines (INFɣ, TNFα, IL-12p70 and IL-22); savory essential oil was associated with increased levels of chemokines (CXCL1, CCL2 and CCL11). Finally, there was a decrease in protein carbonyls and pentosidine according to the essential oil emulsion. These results suggest that changes in the gut microbiota induced by essential oils of parsley, savory and rosemary as prebiotics could differentially regulate cardiovascular and metabolic factors, which highlights the potential of these nutraceuticals for reducing IHD risk in patients affected by T2DM.Junta de Andalucía; PI-0170-2018Instituto de Salud Carlos III; PT20/00101Junta de Andalucía; RH-0078-2021Instituto de Salud Carlos III; CPII19/00022Instituto de Salud Carlos III; FI20/0022

Inverse kinematics of a 6 DoF human upper limb using ANFIS and ANN for anticipatory actuation in ADL-based physical Neurorehabilitation

Objective: This research is focused in the creation and validation of a solution to the inverse kinematics problem for a 6 degrees of freedom human upper limb. This system is intended to work within a realtime dysfunctional motion prediction system that allows anticipatory actuation in physical Neurorehabilitation under the assisted-as-needed paradigm. For this purpose, a multilayer perceptron-based and an ANFIS-based solution to the inverse kinematics problem are evaluated. Materials and methods: Both the multilayer perceptron-based and the ANFIS-based inverse kinematics methods have been trained with three-dimensional Cartesian positions corresponding to the end-effector of healthy human upper limbs that execute two different activities of the daily life: "serving water from a jar" and "picking up a bottle". Validation of the proposed methodologies has been performed by a 10 fold cross-validation procedure. Results: Once trained, the systems are able to map 3D positions of the end-effector to the corresponding healthy biomechanical configurations. A high mean correlation coefficient and a low root mean squared error have been found for both the multilayer perceptron and ANFIS-based methods. Conclusions: The obtained results indicate that both systems effectively solve the inverse kinematics problem, but, due to its low computational load, crucial in real-time applications, along with its high performance, a multilayer perceptron-based solution, consisting in 3 input neurons, 1 hidden layer with 3 neurons and 6 output neurons has been considered the most appropriated for the target application

The rise and fall of methanotrophy following a deepwater oil-well blowout

The blowout of the Macondo oil well in the Gulf of Mexico in April 2010 injected up to 500,000 tonnes of natural gas, mainly methane, into the deep sea1. Most of the methane released was thought to have been consumed by marine microbes between July and August 20102, 3. Here, we report spatially extensive measurements of methane concentrations and oxidation rates in the nine months following the spill. We show that although gas-rich deepwater plumes were a short-lived feature, water column concentrations of methane remained above background levels throughout the rest of the year. Rates of microbial methane oxidation peaked in the deepwater plumes in May and early June, coincident with a rapid rise in the abundance of known and new methane-oxidizing microbes. At this time, rates of methane oxidation reached up to 5,900 nmol l−1 d−1—the highest rates documented in the global pelagic ocean before the blowout4. Rates of methane oxidation fell to less than 50 nmol l−1 d−1 in late June, and continued to decline throughout the remainder of the year. We suggest the precipitous drop in methane consumption in late June, despite the persistence of methane in the water column, underscores the important role that physiological and environmental factors play in constraining the activity of methane-oxidizing bacteria in the Gulf of Mexico