Cooperativity-Dependent Folding of Single-Stranded DNA

The folding of biological macromolecules is a fundamental process of which we lack a full comprehension. Mostly studied in proteins and RNA, single-stranded DNA (ssDNA) also folds, at physiological salt conditions, by forming nonspecific secondary structures that are difficult to characterize with biophysical techniques. Here, we present a helix-coil model for secondary-structure formation, where ssDNA bases are organized in two different types of domains (compact and free). The model contains two parameters: the energy gain per base in a compact domain, ε , and the cooperativity related to the interfacial energy between different domains, γ . We test the ability of the model to quantify the formation of secondary structure in ssDNA molecules mechanically stretched with optical tweezers. The model reproduces the experimental force-extension curves in ssDNA of different molecular lengths and varying sodium and magnesium concentrations. Salt-correction effects for the energy of compact domains and the interfacial energy are found to be compatible with those of DNA hybridization. The model also predicts the folding free energy and the average size of domains at zero force, finding good agreement with secondary-structure predictions by mfold. We envision the model could be further extended to investigate native folding in RNA and protein

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis

Altres ajuts: Fundación Tatiana Pérez de Guzman el Bueno; SynCogDis Network (SAF2014-52624-REDT, SAF2017-90664-REDT); Human Frontiers Science Program (HFSP RGP0022/2013); Fondo Europeo de Desarrollo Regional (FEDER).Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis

Impaired decision-making and brain shrinkage in alcoholism

Alcohol-dependent individuals usually favor instant gratification of alcohol use and ignore its long-term negative consequences, reflecting impaired decision-making. According to the somatic marker hypothesis, decision-making abilities are subtended by an extended brain network. As chronic alcohol consumption is known to be associated with brain shrinkage in this network, the present study investigated relationships between brain shrinkage and decision-making impairments in alcohol-dependent individuals early in abstinence using voxel-based morphometry. Thirty patients performed the Iowa Gambling Task and underwent a magnetic resonance imaging investigation (1.5T). Decision-making performances and brain data were compared with those of age-matched healthy controls. In the alcoholic group, a multiple regression analysis was conducted with two predictors (gray matter [GM] volume and decision-making measure) and two covariates (number of withdrawals and duration of alcoholism). Compared with controls, alcoholics had impaired decision-making and widespread reduced gray matter volume, especially in regions involved in decision-making. The regression analysis revealed links between high GM volume in the ventromedial prefrontal cortex, dorsal anterior cingulate cortex and right hippocampal formation, and high decision-making scores (P<0.001, uncorrected). Decision-making deficits in alcoholism may result from impairment of both emotional and cognitive networks

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis

OBJECTIVE: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). METHODS: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. RESULTS: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31). CONCLUSIONS: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions

When Music and Long-Term Memory Interact: Effects of Musical Expertise on Functional and Structural Plasticity in the Hippocampus

The development of musical skills by musicians results in specific structural and functional modifications in the brain. Surprisingly, no functional magnetic resonance imaging (fMRI) study has investigated the impact of musical training on brain function during long-term memory retrieval, a faculty particularly important in music. Thus, using fMRI, we examined for the first time this process during a musical familiarity task (i.e., semantic memory for music). Musical expertise induced supplementary activations in the hippocampus, medial frontal gyrus, and superior temporal areas on both sides, suggesting a constant interaction between episodic and semantic memory during this task in musicians. In addition, a voxel-based morphometry (VBM) investigation was performed within these areas and revealed that gray matter density of the hippocampus was higher in musicians than in nonmusicians. Our data indicate that musical expertise critically modifies long-term memory processes and induces structural and functional plasticity in the hippocampus

Parental breeding age effects on descendants' longevity interact over 2 generations in matrilines and patrilines

Individuals within populations vary enormously in mortality risk and longevity, but the causes of this variation remain poorly understood. A potentially important and phylogenetically widespread source of such variation is maternal age at breeding, which typically has negative effects on offspring longevity. Here, we show that paternal age can affect offspring longevity as strongly as maternal age does and that breeding age effects can interact over 2 generations in both matrilines and patrilines. We manipulated maternal and paternal ages at breeding over 2 generations in the neriid fly Telostylinus angusticollis. To determine whether breeding age effects can be modulated by the environment, we also manipulated larval diet and male competitive environment in the first generation. We found separate and interactive effects of parental and grand-parental ages at breeding on descendants' mortality rate and life span in both matrilines and patrilines. These breeding age effects were not modulated by grand-parental larval diet quality or competitive environment. Our findings suggest that variation in maternal and paternal ages at breeding could contribute substantially to intrapopulation variation in mortality and longevity

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.This work was supported by grants from MICINN (RTI2018-098581-B-I00 to L.M.P.), Fundación Tatiana Pérez de Guzman el Bueno, and the SynCogDis Network (SAF2014-52624-REDT and SAF2017- 90664-REDT to L.M.P. and A. Bayes). Collaboration between L.M.d.l.P. and Y.H. was supported by Human Frontiers Science Program (HFSP) grant RGP0022/2013. J.P.L.-A. was supported by grants from MICIU co-financed by ERDF (RYC-2015-18056 and RTI2018-102260-B-I00) and Severo Ochoa grant SEV-2017-0723. R.R.-V. and A. Bayes were supported by MINECO BFU2015-69717-P and RTI2018-097037-B-100 and a Marie Curie career integration grant (ref. 304111). A.V.M. was supported by MICINN (SAF2017- 85717-R) and Fundación Alicia Koplowitz. A. Barco was supported by grants SAF2017-87928-R from MICINN co-financed by ERDF and RGP0039/2017 from the Human Frontiers Science Program Organization. The Instituto de Neurociencias is a ‘‘Centre of Excellence Severo Ochoa.’’ D.G.-D. and C.M.N. hold PhD fellowships from MICINN (BES-2013-064171 and BES2016-076281, respectively).Peer reviewe

Interplay between n-3 and n-6 long-chain polyunsaturated fatty acids and the endocannabinoid system in brain protection and repair.

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFA) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) have shown beneficial effects on learning and memory, neuroinflammatory processes and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-archidonoylglycerol (2-AG) are the most widely studied endocannabinoids, and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair