Biology subjects

Gomez, R.

Publications and source records attributed to Gomez, R..

24 records · Page 2Linked to original sources

bioRxiv2020

Synaptic plasticity of somatosensory neurons is determined by functional coupling between NMDA receptors and BK channels

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) are crucial mediators of synaptic plasticity due to their ability to act as coincidence detectors of presynaptic and postsynaptic neuronal activity. However, NMDARs exist within the molecular context of a variety of postsynaptic signaling proteins, which can fine-tune their function. Here we describe a novel form of NMDAR suppression by large-conductance Ca2+- and voltage-gated K+ (BK) channels in the basal dendrites of a subset of barrel cortex layer 5 pyramidal neurons. We show that NMDAR activation increases intracellular Ca2+ in the vicinity of BK channels, thus activating K+ efflux and strong negative feedback inhibition. We further show that neurons exhibiting such NMDAR-BK coupling serve as high-pass filters for incoming synaptic inputs, precluding the induction of spike-timing-dependent plasticity. Together, these data suggest that NMDAR-localized BK channels regulate synaptic integration and provide input-specific synaptic diversity to a thalamocortical circuit.

neuroscience↗

bioRxiv2020

Integrating cyanobacterial flavodiiron proteins within the chloroplast photosynthetic electron transport chain maintains carbohydrate turnover and enhances drought stress tolerance in barley

Chloroplasts, the sites of photosynthesis in higher plants, have evolved several means to tolerate short episodes of drought stress through biosynthesis of diverse metabolites essential for plant function, but these become ineffective when the duration of the stress is prolonged. Cyanobacteria are the closest bacterial homologs of plastids with two photosystems to perform photosynthesis and to evolve oxygen as a byproduct. The presence of Flv genes encoding flavodiiron proteins has been shown to enhance stress tolerance in cyanobacteria. Here, the products of Synechocystis genes Flv1 and Flv3 were expressed in chloroplasts of barley in an attempt to support the growth of plants exposed to drought. The heterologous expression of both Flv1 and Flv3 accelerated days to heading, increased biomass, promoted the number of spikes and grains per plant, and improved grain yield of barley plants exposed to drought. Improved growth correlated with enhanced availability of soluble sugars, a higher turnover of amino acids and the accumulation of lower levels of proline in the leaf. Flv1 and Flv3 maintained the energy status of the leaves in the stressed plants by converting sucrose to glucose and fructose, immediate precursors for energy production to support plant growth under drought. The results suggest that sugars and amino acids play a fundamental role in the maintenance of the energy status and metabolic activity to ensure growth and survival under stress conditions, that is, water limitation in this particular case. Engineering chloroplasts by introducing Flv genes, therefore, has the potential to improve plant productivity wherever drought stress represents a significant production constraint.

plant biology↗

bioRxiv2020

Redundancy Circuits of the Commissural Pathways in Human and Rhesus Macaque Brains

It has been hypothesized that the human brain has traded redundancy for efficiency, but the structural existence has not been identified to examine this claim. Here, we report three redundancy circuits of the commissural pathways in primate brains, namely the orbitofrontal, temporal, and occipital redundancy circuits of the anterior commissure and corpus callosum. Each redundancy circuit has two distinctly separated routes connecting a common pair of cortical regions. We mapped their trajectories in human and rhesus macaque brains using individual and population-averaged tractography. The dissection results confirmed the existence of these redundancy circuits connecting the orbitofrontal lobe, amygdala, and visual cortex. The volume analysis showed a significant reduction in the orbitofrontal and occipital redundancy circuits of the human brain, whereas the temporal redundancy circuit had a substantial organizational difference between the human and rhesus macaque. Our overall findings suggest that the human brain is more efficient in the commissural pathway, as shown by the significantly reduced volume of the anterior commissure which serves as the backup connections for the corpus callosum. This reduction of the redundancy circuit may explain why humans are more vulnerable to psychiatric brain disorders stemming from the corpus callosum compared to non-human primates. SignificanceWe report and describe the connection routes of three redundancy circuits of the commissural pathways in human and rhesus macaque brains and compare their volumes. Our tractography and dissection studies confirmed that the human brain has smaller redundancy circuits. This is the first time such redundancy circuits of the commissural pathways have been identified, and their differences quantified in human and rhesus macaque to verify the redundancy-efficiency tradeoff hypothesis. The findings provide new insight into the topological organization of the human brain and may help understand the circuit mechanism of brain disorders involving these pathways.

neuroscience↗

bioRxiv2020

Providing an additional electron sink by the introduction of cyanobacterial flavodiirons enhances the growth of Arabidopsis thaliana in varying light

The ability of plants to maintain photosynthesis in a dynamically changing environment is of central importance for their growth. As their photosynthetic machinery typically cannot adapt rapidly to fluctuations in the intensity of radiation, the level of photosynthetic efficiency is not always optimal. Cyanobacteria, algae, non-vascular plants (mosses and liverworts) and gymnosperms all produce flavodiirons (Flvs), a class of proteins not represented in the angiosperms; these proteins act to mitigate the photoinhibition of photosystem I. Here, genes specifying two cyanobacterial Flvs have been expressed in the chloroplasts of Arabidopsis thaliana in an attempt to improve the robustness of Photosystem I (PSI). The expression of Flv1 and Flv3 together shown to enhance the efficiency of the utilization of light and to boost the plants capacity to accumulate biomass. Based on an assessment of the chlorophyll fluorescence in the transgenic plants, the implication was that photosynthetic activity (including electron transport flow and non-photochemical quenching during a dark-to-light transition) was initiated earlier in the transgenic than in wild type plants. The improved photosynthetic performance of the transgenics was accompanied by an increased production of ATP, an acceleration of carbohydrate metabolism and a more pronounced partitioning of sucrose into starch. The indications are that Flvs are able to establish an efficient electron sink downstream of PSI, thereby ensuring that the photosynthetic electron transport chain remains in a more oxidized state. The expression of Flvs in a plant acts to both protect photosynthesis and to control the ATP/NADPH ratio; together, their presence is beneficial for the plants growth potential.

biochemistry↗

bioRxiv2019

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

SummaryRegulation of transcription occurs in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a key role in lineage specification. We sought to characterise DNA methylation changes during chondrogenesis of mesenchymal stem cells (MSCs) in order to further our understanding of epigenetic regulation in chondrocytes. The consequences of which has potential to improve cartilage generation for tissue engineering purposes and also to provide context for observed methylation changes in cartilage diseases such as osteoarthritis. We identified significant DNA hypomethylation during chondrogenesis including changes at many key cartilage gene loci. Importantly characterisation of significant CpG loci indicated their predominant localisation to enhancer regions. Comparison with adult cartilage and other tissue methylation profiles identified chondrocyte-specific regulatory regions. Taken together we have associated methylation at many CpGs with the chondrocyte phenotype.\n\nAbstractRegulation of transcription is determined in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a role in lineage specification. Multipotent mesenchymal stem cell (MSC) differentiation into chondrocytes not only serves as a model for chondrocyte development but also provides an important source of cartilage for tissue engineering purposes. We sought to characterise DNA methylation changes during chondrogenesis to further understanding of epigenetic regulation but to also provide context for the changes identified during disease.\n\nDNA cytosine methylation changes during human MSC differentiation into chondrocytes were measured by Infinium 450K methylation array. Methylation changes at gene loci were contrasted with gene expression changes. Chromatin states of significant methylation loci were interpreted by intersection with chondrogenesis histone modification ChlP-seq data. Chondrogenic and cartilage specific hypomethylation was utilised in order to identify a chondrocyte methylome. Articular cartilage and tissue panel DNA methylation was compared and alterations during osteoarthritis cartilage disease classified.\n\nSignificant DNA hypomethylation was identified following chondrogenic differentiation of MSCs including changes at many key cartilage gene loci. Highly upregulated genes during chondrogenesis were more likely to exhibit a reduction in DNA methylation. Characterisation of significant CpG loci indicated their predominant localisation in CpG poor regions which importantly are most likely to correspond to enhancer regions. Methylation level at certain CpGs following chondrogenesis corresponds to the level found in adult cartilage.\n\nTaken together, considerable demethylation changes to the epigenetic landscape occur during MSC chondrogenesis especially at sites marked by enhancer modifications. Comparison with other tissues, including healthy and OA cartilage, associates CpGs to the chondrocyte phenotype and provides context for changes in disease.

genomics↗

bioRxiv2018

Multiple sclerosis-associated changes in the composition and immune functions of spore-forming bacteria

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa and show that their presence correlates with impaired differentiation of IL-10 secreting, regulatory T lymphocytes in-vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of pro-inflammatory, IFN{gamma}+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control derived spore-forming bacteria were able to induce immunoregulatory responses.\n\nOur analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth.\n\nImportanceDespite the rapid emergence of microbiome related studies in human diseases, few go beyond a simple description of relative taxa levels in a select group of patients. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of both complete microbial communities and individual taxa, revealing novel functional associations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is associated with impaired immunomodulatory responses in vitro.

immunology↗