Biology subjects

Calvo, A.

Publications and source records attributed to Calvo, A..

5 recordsLinked to original sources

bioRxiv2025

A Highly Conserved ABC Transporter Mediates Cello-Oligosaccharide Uptake in the Extremely Thermophilic, Lignocellulolytic Bacterium Anaerocellum (f. Caldicellulosiruptor) bescii

Cellulose deconstruction and utilization are key to unlocking renewable fuel and chemical production. Anaerocellum bescii (formerly Caldicellulosiruptor bescii) is an extremely thermophilic cellulolytic bacterium, among the most effective at degrading lignocellulosic biomass due to its arsenal of multi-domain cellulases and hemicellulases. However, little is known about how it transports the assorted sugars released from lignocellulose degradation into the cell for catabolism. Among its twenty-three ATP-Binding Cassette (ABC) sugar transporters, the mechanism for uptake of cello-oligosaccharides released from cellulose degradation remains unclear. Here, we identify an ABC transporter locus (Athe_0595 -- 0598), highly conserved in the genus with two extracellular binding proteins, Athe_0597 and Athe_0598. Biophysical analyses, including Differential Scanning Calorimetry (DSC) and Isothermal Titration Calorimetry (ITC), reveal that Athe_0597, binds cello-oligosaccharides of varying lengths (G2-5), while Athe_0598 is specific to cellobiose (G2). Computational modeling of ligand docking supports these findings and sheds light on the subsite configuration of the substrate binding proteins. To assess its physiological importance, we genetically deleted this transporter locus in A. bescii strain HTAB187, which does not grow on cellulose and grows poorly on cellobiose. Comparison of growth with a msmK deletion strain that cannot consume oligosaccharides shows that HTAB187 can grow on non-cello-oligosaccharides (e.g. maltose) or monosaccharides. Taken together, this study integrates biophysical characterization, structural modeling, and genetic perturbation to elucidate how A. bescii transports cello-oligosaccharides release from cellulose, opening doors for its future use in applied bioprocessing contexts. ImportanceAnaerocellum bescii is the most thermophilic cellulolytic bacterium known, and holds potential for bioprocessing lignocellulosic biomass into renewable fuels. Its diverse ATP-Binding Cassette (ABC) sugar transporters make it a valuable model for studying thermophilic sugar uptake. Here, we identify a single ABC transporter with two substrate binding proteins (Athe_0597 and Athe_0598) responsible for cello-oligosaccharide uptake. Genetic deletion of this transporter impaired growth on cellobiose and eliminated growth on cellulose. This is the first genetic manipulation in A. bescii to modulate transport of a specific sugar. We also characterize the substrate specificity of the substrate binding proteins associated with the locus; one binds various cellodextrins (G2-5), while the other specifically binds cellobiose (G2). Computational modeling reveals how each sugar docks within the binding pocket of these proteins. Understanding the mechanism of cello-oligosaccharide uptake by A. bescii expands opportunities for its metabolic engineering and furthers our understanding of thermophilic sugar transport.

microbiology↗

bioRxiv2024

Lysine deacetylation inhibition reverses TDP-43 mislocalization and in combination with arimoclomol ameliorates neuromuscular pathology

Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA lysine acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivoand how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor {gamma}-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of HDAC inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.

neuroscience↗

bioRxiv2023

Specific configurations of electrical synapses filter sensory information to drive choices in behavior

Synaptic configurations in precisely wired circuits underpin how sensory information is processed by the nervous system, and the emerging animal behavior. This is best understood for chemical synapses, but far less is known about how electrical synaptic configurations modulate, in vivo and in specific neurons, sensory information processing and context-specific behaviors. We discovered that INX-1, a gap junction protein that forms electrical synapses, is required to deploy context-specific behavioral strategies during C. elegans thermotaxis behavior. INX-1 couples two bilaterally symmetric interneurons, and this configuration is required for the integration of sensory information during migration of animals across temperature gradients. In inx-1 mutants, uncoupled interneurons display increased excitability and responses to subthreshold temperature stimuli, resulting in abnormally longer run durations and context-irrelevant tracking of isotherms. Our study uncovers a conserved configuration of electrical synapses that, by increasing neuronal capacitance, enables differential processing of sensory information and the deployment of context-specific behavioral strategies. One-Sentence SummaryCoupling of interneurons by electrical synapses reduces membrane resistance and filters sensory inputs to guide sensory-dependent behavioral choices.

neuroscience↗

bioRxiv2019

White Matter Microstructure and its Relation to Clinical Features of Obsessive-Compulsive Disorder: Findings from the ENIGMA OCD Working Group

ImportanceMicrostructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. ObjectiveTo investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. Design, Setting, and ParticipantsIn this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group. Main Outcomes and MeasuresWe extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohens d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. ResultsAdult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, p<0.0001). In the sagittal stratum only, lower FA was associated with a younger age of onset (z=2.71, p=0.006), longer duration of illness (z=-2.086, p=0.036) and a higher percentage of medicated patients in the cohorts studied (z=-1.98, p=0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to matched controls. Conclusions and RelevanceMicrostructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD. KEY POINTSO_ST_ABSQuestionC_ST_ABSDo patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features? FindingsData from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features. MeaningMicrostructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

neuroscience↗

bioRxiv2017

Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.\n\nSignificance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

neuroscience↗