Biology subjects

Seshadri, S.

Publications and source records attributed to Seshadri, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Bioactive Spermidine-Crosslinked DNA Hydrogel for rapid homeostasis and accelerated wound healing

Damage to the skin by trauma, burns, or surgical procedures often results in uncontrolled bleeding, which remains a leading cause of preventable death following injury, yet most conventional hemostatic materials are engineered solely to arrest bleeding and often adhere strongly to the wound bed, causing pain, rebleeding, and disruption of newly formed tissue upon removal. Here, we report a DNA hydrogel that structurally mimics neutrophil extracellular traps (NETs) and is crosslinked using a bioactive small molecule with potent autophagy-inducing, cardioprotective, anti-inflammatory, antioxidant, and mitochondria-protective properties, integrating rapid hemostasis with active support for tissue regeneration in a single biomaterial. The DNA network provides an intrinsically biocompatible, biodegradable scaffold capable of recruiting platelets and erythrocytes to achieve rapid clot formation, while the bioactive crosslinker is released as the network degrades, delivering a sustained cytoprotective and anti-inflammatory stimulus directly at the wound site. The hydrogel was characterised physiochemically and evaluated for cytocompatibility, hemolytic potential, hemostatic efficacy, and wound-healing performance in a murine model. Results demonstrate that the bioactive-crosslinked DNA hydrogel achieves rapid, effective hemostasis, while accelerating wound closure and supporting regenerative tissue remodelling. This dual-function platform offers a promising strategy for next-generation wound-care biomaterials that unite immediate bleeding control with accelerated, natural tissue healing.

bioengineering↗

bioRxiv2025

Programmable DNA-Silk fibroin hydrogel scaffold with temporal mechanical reinforcement for mesenchymal stem cells differentiation and accelerated wound healing in a full-thickness skin defect mice model

DNA-based hydrogels have attracted significant attention in biomedical applications due to their programmability, biocompatibility, and tunable functionalities. However, their clinical translation is hindered by high synthesis costs, limited mechanical strength, poor stability, and complex synthesis protocols. In this work, we present a novel DNA-silk fibroin hybrid hydrogel that overcomes these limitations by combining the unique biofunctionality of DNA with the superior mechanical and chemical properties of silk fibroin. Salmon-derived DNA, an abundant and low-cost source, was incorporated with silk fibroin to form hybrid networks via a simple, scalable process. Silk fibroin served as a robust scaffold, enhancing mechanical strength, controlling degradability, and improving structural stability, while the entangled DNA-silk network reduced rapid DNA degradation. The resulting hybrid hydrogel demonstrated temporal mechanical reinforcement and prolonged stability, with in vitro studies demonstrating that the developed hybrid hydrogel enhanced the chondrogenic and osteogenic differentiation of Infrapatellar Fat Pad Mesenchymal Stem Cells (IFP-MSCs). Additionally, hemostatic and in vivo studies demonstrated the potential of DNA-silk fibroin hydrogel as a promising biomaterial for rapid hemostasis and accelerated wound healing. Overall, the developed DNA-silk fibroin hybrid hydrogel offers strong potential for mesenchymal tissue engineering, hemostatic adjuvant and wound healing.

bioengineering↗

bioRxiv2025

Altered Gut Microbiota Mediates the Association between APOE Genotype and Amyloid-β Accumulation in Middle-Aged Adults

ImportanceThe apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimers disease (AD), yet the mechanisms linking APOE to amyloid-{beta} (A{beta}) pathology remain incompletely understood. Emerging evidence suggests that the gut microbiome may modulate neurodegeneration; however, its role as a mediator in the APOE-A{beta} relationship remains unclear. ObjectiveTo evaluate whether specific microbial taxa mediate APOE-related effects on brain A{beta} burden in an established population-based study of middle-aged adults. Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Framingham Heart Study cohort. Data were collected at the third examination visit (n = 227, %Female = 58, mean age = 56.5 {+/-} 8.3), between 2016 and 2019. ExposuresGut bacterial DNA was sequenced using 16S rRNA, and amplicon sequence variants (ASVs) were agglomerated at various taxonomic levels (14 phyla, 70 families, and [~]140 genera). APOE genotypes were derived from blood DNA using PCR and restriction isotyping. Predicted microbial functional potential was based on KEGG Orthologs. Main Outcomes and MeasuresOverall and regional measures of cerebral amyloid-{beta} deposition were assessed using carbon-11 Pittsburgh (PiB) Compound-B PET scans. The global PiB deposition served as the primary outcome for "overall" amyloid burden. Regional amyloid deposition values were analyzed as secondary outcomes. ResultsA higher A{beta} burden was significantly associated with the depletion of protective genera (e.g., Faecalibacterium {beta} [95%CI],-0.35 [-0.40,-0.30]; Ruminococcus-0.25 [-0.27,-0.23]; Butyricicoccus-0.27 [-0.32,-0.22]) and the enrichment of pro-inflammatory taxa (e.g., Alistipes 0.07 [0.06, 0.08], Bacteroides 0.10 [0.07, 0.13]) and Barnesiella (0.18 [0.16, 0.20]). These associations were more pronounced in APOE {varepsilon}4 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that Ruminococcus, Butyricicoccus, Clostridium, and Christensenellaceae collectively mediated [~]0.3-0.4% of the effect of APOE {varepsilon}4 on global A{beta} burden. Functional profiling revealed a reduced abundance of microbial genes involved in key metabolic pathways among individuals with higher A{beta} levels. Conclusion and RelevanceGut microbiome composition partially mediates the relationship between APOE {varepsilon}4 and cerebral amyloid burden. These findings support a gut-brain axis mechanism in AD and suggest that microbiome-targeted interventions may mitigate APOE-related risk.

neuroscience↗

bioRxiv2025

Advancing Fair and Explainable Machine Learning for Neuroimaging Dementia Pattern Classification in Multi-Ethnic Populations

Dementia, a degenerative disease affecting millions globally, is projected to triple by 2050. Early and precise diagnosis is essential for effective treatment and improved quality of life. However, current diagnostic approaches frequently demonstrate inconsistent precision and impartiality, particularly among diverse cultural groups. This study investigates performance discrepancies in dementia classification among White American, African American, and Hispanic populations. We reveal significant cross-group bias, particularly when models trained on one group are tested on another. To address this, we introduce a novel combination of few-shot learning and domain alignment to improve model adaptability across underrepresented populations. Our results show that these techniques substantially reduce inter-group performance gaps, especially between White American and Hispanic cohorts. This finding highlights the crucial need for fairness-aware strategies and the inclusion of diverse populations in training data to ensure accurate and equitable dementia diagnoses.

neuroscience↗

bioRxiv2025

Functional alignment of protein language models via reinforcement learning

Protein language models (pLMs) enable generative design of novel protein sequences but remain fundamentally misaligned with protein engineering goals, as they lack explicit understanding of function and often fail to improve properties beyond those found in nature. We introduce Reinforcement Learning from eXperimental Feedback (RLXF), a general framework that aligns protein language models with experimentally measured functional objectives, drawing inspiration from the methods used to align large language models like ChatGPT. Applied across five diverse protein families, RLXF improves generation of high-functioning variants beyond pre-trained baselines. We demonstrate this with CreiLOV, an oxygen-independent fluorescent protein, where RLXF-aligned models generate sequences with significantly enhanced fluorescence, including the most fluorescent CreiLOV variants reported to date. Our results indicate that RLXF-aligned models effectively integrate the evolutionary knowledge encoded in pre-trained pLMs with experimental observations, improving the success rate of generated sequences and enabling the discovery of synergistic mutation combinations that are difficult to identify through zero-shot or evolutionary approaches. RLXF provides a scalable and accessible approach to steer generative models toward desired biochemical properties, enabling function-driven protein design beyond the limits of natural evolution.

bioengineering↗

bioRxiv2025

Adherence to Lifes Essential 8 Enhances Gut Microbiota Diversity and Cognitive Performance

Emerging evidence suggests a complex interplay among cardiovascular health, gut microbiome composition, and cognitive function. Lifes Essential 8 (LE8), developed by the American Heart Association, includes vital metrics of cardiovascular health, such as diet, physical activity, nicotine exposure, sleep health, body mass index (BMI), blood glucose, blood lipids, and blood pressure. In this study, we analyzed data from 781 participants in the Framingham Heart Study (FHS) to explore the relationship between LE8 adherence, gut microbiota, and cognitive performance. Participants with greater adherence to LE8 demonstrated significantly increased gut microbial diversity (-diversity: Chao1, p = 0.0014; Shannon, p = 0.0071) and distinct microbial compositions ({beta}-diversity: PERMANOVA p = 1e-4). Higher adherence to LE8 was related to an increased abundance of genera Barnesiella and Ruminococcus, while a reduced abundance of Clostridium was associated with higher LE8 adherence. Greater gut microbial diversity (-diversity: Chao1, p = 0.0012; Shannon, p = 0.0066), and beneficial genera like Oscillospira correlated with better global cognitive scores (GCS). Taxonomic overlap analyses revealed microbial taxa that simultaneously influence both LE8 adherence and cognitive outcomes. Mediation analyses indicated that specific taxa, including Barnesiella and Lentisphaerae, mediated the link between LE8 adherence and cognitive performance. These taxa may serve as key modulators in the gut-brain axis, connecting cardiovascular and brain health. Conversely, higher Clostridium abundance was associated with poorer cognitive performance. This study highlights the significance of comprehensive cardiovascular health metrics in shaping gut microbiota and enhancing cognitive resilience. Our findings underscore the therapeutic potential of targeting gut microbiota to mitigate cognitive decline, warranting further exploration through longitudinal and metagenomic studies.

neuroscience↗

bioRxiv2024

Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment

Alzheimers disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 {+/-} 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such as Dialister, Fretibacterium, and Mycoplasma in CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, including Shuttleworthia, Holdemania, and Subdoligranulum, which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.

neuroscience↗

bioRxiv2024

A New Halogenated Solvent For Ex Vivo Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) is a prominent non-invasive imaging technique. Structural MRI, the most common MRI modality, interacts with the hydrogen nuclei in samples, also called protons. When using structural MRI to scan ex vivo tissues, the biological samples are often placed in proton-free liquids containing no hydrogen atoms to obtain clean images that do not require background removal. Several proton-free liquids have been used during the last two decades, but they are all per- and polyfluoroalkyl substances (PFAS), and PFAS have recently been recognized as a significant environmental concern. To find replacement solutions, new families of proton-free liquids without fluorine atoms will need to be investigated for stability and safety and to check potential effects on subsequent tissue staining. The present work is a preliminary step in that direction. We validate the MRI properties of a broadly used, affordable, non-PFAS, proton-free solvent that has, as far as we know, never been considered for ex vivo MRI scanning.

neuroscience↗

bioRxiv2024

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations

INTRODUCTIONMulti-omics studies in Alzheimers disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODSTo bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTSWe generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSIONInclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

neuroscience↗

bioRxiv2023

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments

Introductory paragraphOverexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klothos knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimers Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

neuroscience↗

bioRxiv2023

DECODING COMPLEXITY IN BIOMOLECULAR RECOGNITION OF DNA I-MOTIFS

DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10,976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone, and the iMab antibody. iMab microarray screens demonstrated that pH 6.5, 5% BSA buffer was optimal, and fluorescence was correlated with iM C-tract length. hnRNP K broadly recognizes diverse iM sequences, favoring 3-5 cytosine repeats flanked by thymine-rich loops of 1-3 nucleotides. Array binding mirrored public ChIP-Seq datasets, in which 35% of well-bound array iMs are enriched in hnRNP K peaks. In contrast, other reported iM-binding proteins had weaker binding or preferred G-quadruplex (G4) sequences instead. Mitoxantrone broadly binds both shorter iMs and G4s, consistent with an intercalation mechanism. These results suggest that hnRNP K may play a role in iM-mediated regulation of gene expression in vivo, whereas hnRNP A1 and ASF/SF2 are possibly more selective in their binding preferences. This powerful approach represents the most comprehensive investigation of how biomolecules selectively recognize genomic iMs to date.

biochemistry↗

bioRxiv2023

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease

IntroductionFemales with Alzheimers disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). MethodsWe analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. ResultsNAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DiscussionOur findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

bioinformatics↗

bioRxiv2022

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses to prioritize genes that are likely functionally relevant, and shared with closely related traits and risk factors. For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Our study identified genetic risks underlying all-cause dementia, demonstrating overlap with neurodegenerative processes, vascular risk factors (Type-II diabetes, blood pressure, lipid) and cerebral small vessel disease. These novel insights could lead to new prevention and treatment strategies for all dementias.

genetics↗

bioRxiv2022

Data Descriptor: Human whole exome genotype data for Alzheimer's Disease

Bigger sample size can help to identify new genetic variants contributing to an increased risk of developing Alzheimers disease. However, the heterogeneity of the whole-exome sequencing (WES) data generation methods presents a challenge to a joint analysis. Here we present a bioinformatics strategy for joint calling 20,504 WES samples collected across nine studies and sequenced using ten different capture kits in fourteen sequencing centers in the Alzheimers Disease Sequencing Project. gVCFs of samples were joint-called by the Genome Center for Alzheimers Disease into a single VCF, containing only positions within the union of capture kits. The VCF was then processed using specific strategies to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 15% are missense variants. 1.8% of the variants are with CADD>30. Our new strategy for processing these diversely generated WES samples has shown to generate high-quality data. The improved ability to combine data sequenced in different batches benefits the whole genomics research community. The WES data are accessible to the scientific community via https://dss.niagads.org/.

genetics↗

bioRxiv2022

Cerebral Small Vessel Disease Burden is Associated with Decreased Abundance of Gut Barnesiella intestinihominis Bacterium in the Framingham Heart Study

A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimers disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p-values < 0.001), as well as better executive function (p-values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and {beta}-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.

neuroscience↗

bioRxiv2022

RNA-sequencing of human post-mortem hypothalamus and nucleus accumbens identifies expression profiles associated with obesity.

Obesity, the accumulation of body fat to excess, may cause serious negative health effects, including increased risk of heart disease, type 2 diabetes, stroke and certain cancers. The biology of obesity is complex and not well understood, involving both environmental and genetic factors and affecting metabolic and endocrine mechanisms in tissues of the gut, adipose, and brain. Previous RNA sequencing studies have identified transcripts associated with obesity and body mass index in blood and fat, often using animal models, but RNA sequencing studies in human brain tissue related to obesity have not been previously undertaken. We conducted both large and small RNA sequencing of hypothalamus (207 samples) and nucleus accumbens (276 samples) from individuals defined as consistently obese (124 samples), consistently normal weight as controls (148 samples) or selected without respect to BMI and falling within neither case nor control definition (211 samples), based on longitudinal BMI measures. The samples were provided by three cohort studies with brain donation programs; the Framingham Heart Study (FHS), the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). For each brain region and large/small RNA sequencing set, differential expression of obesity, BMI, brain region and sex was performed. Analyses were done transcriptome-wide as well as with a priori defined sets of obesity or BMI-associated mRNAs and microRNAs (miRNAs). There are sixteen mRNAs and five microRNAs that are differentially expressed (adjusted p < 0.05) by obesity or BMI in these tissues, several of which were validated with qPCR data. The results include many that are BMI-associated, such as APOBR and CES1, as well as many associated with the immune system and some with addiction, such as the gene sets "cytokine signaling in immune system" and "opioid signaling". In spite of the relatively large number of samples, our study was likely under-powered to detect other transcripts or miRNA with relevant but smaller effects.

genomics↗

bioRxiv2019

Neuronal avalanches in input and associative layers of auditory cortex

The primary auditory cortex processes acoustic sequences for the perception of behaviorally meaningful sounds such as speech. Sound information arrives at its input layer 4 from where activity propagates to associative layer 2/3. It is currently not known whether there is a particular organization of neuronal population activity that is stable across layers and sound levels during sound processing. We used in vivo 2-photon imaging of pyramidal neurons in cortical layers L4 and L2/3 of mouse A1 to characterize the populations of neurons that were active spontaneously, i.e. in the absence of a sound stimulus, and those recruited by single-frequency tonal stimuli at different sound levels. Single-frequency sounds recruited neurons of widely ranging frequency selectivity in both layers. We defined neural ensembles as neurons being active within or during successive temporal windows at the temporal resolution of our imaging. For both layers, neuronal ensembles were highly variable in size during spontaneous activity as well as during sound presentation. Ensemble sizes distributed according to power laws, the hallmark of neuronal avalanches, and were similar across sound levels. Avalanches activated by sound were composed of neurons with diverse tuning preference, yet with selectivity independent of avalanche size. Thus, spontaneous and evoked activity in both L4 and L2/3 of A1 are composed of neuronal avalanches with similar power law relationships. Our results demonstrate network principles linked to maximal dynamic range, optimal information transfer and matching complexity between L4 and L2/3 to shape population activity in auditory cortex.

neuroscience↗

bioRxiv2018

What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk?\n\nFindingWe find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education.\n\nMeaningIntervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors.\n\nImportanceLower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown.\n\nObjectiveTo investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes.\n\nDesignMultivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data.\n\nSettingUK Biobank and international genome-wide association study consortia.\n\nParticipantsPredominantly individuals of European ancestry.\n\nMain outcomes and measuresThe effects of education (per 1-standard deviation increase, equivalent to 3.6 years) on coronary heart disease, cardiovascular disease (all subtypes), myocardial infarction and stroke risk (all measured in odds ratio, OR), and the degree to which this is mediated through body mass index, systolic blood pressure and smoking.\n\nResultsEach additional standard deviation of education associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in Mendelian randomization analysis. As a proportion of the total risk reduction, body mass index mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and Mendelian randomization estimates, respectively. Corresponding estimates for systolic blood pressure were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 33% (95% CI 17% to 49%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95 % CI 16% to 63%) of the effect of education on coronary heart disease in observational and Mendelian randomization respectively. Similar results were obtained when investigating risk of stroke, myocardial infarction and all-cause cardiovascular disease.\n\nConclusions and relevanceBMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of CVD attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

epidemiology↗