Biology subjects

Pines, A.

Publications and source records attributed to Pines, A..

10 recordsLinked to original sources

bioRxiv2024

Reproducible Sex Differences in Personalized Functional Network Topography in Youth

BackgroundA key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex. AimsWe aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks. MethodWe leveraged person-specific atlases of functional brain networks defined using non-negative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression. ResultsSex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons. ConclusionsSex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.

neuroscience↗

bioRxiv2024

STK19 drives Transcription-Coupled Repair by stimulating repair complex stability, Pol II ubiquitylation and TFIIH recruitment

DNA damage forms a major obstacle for gene transcription by RNA polymerase II (Pol II). Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates transcription-blocking lesions (TBLs), thereby safeguarding accurate transcription, preserving correct cellular function and counteracting aging. TC-NER initiation involves the recognition of lesion-stalled Pol II by CSB, which recruits the CRL4CSA E3 ubiquitin ligase complex and UVSSA. TBL-induced ubiquitylation of Pol II at lysine 1268 of the RPB1 subunit by CRL4CSA serves as a critical TC-NER checkpoint, governing Pol II stability and initiating TBL excision by TFIIH recruitment. However, the precise regulatory mechanisms of the CRL4CSA E3 ligase activity and TFIIH recruitment remain elusive. Here, we reveal Inactive Serine/Threonine Kinase 19 (STK19) as a novel TC-NER factor, that is essential for correct TBL removal repair and subsequent transcription restart. Cryo-EM studies demonstrate that STK19 is an integral part of the Pol II-TC-NER complex, bridging CSA with UVSSA, RPB1 and downstream DNA. Live-cell imaging and interaction studies show that STK19 stimulates TC-NER complex stability and CRL4CSA activity, resulting in efficient Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core component of the TC-NER machinery and its key involvement in the cellular responses to DNA damage that interfere with transcription.

molecular biology↗

bioRxiv2023

A general exposome factor explains individual differences in functional brain network topography and cognition in youth

Our minds and brains are highly unique. Despite the long-recognized importance of the environment in shaping individual differences in cognitive neurodevelopment, only with the combination of deep phenotyping approaches and the availability of large-scale datasets have we been able to more comprehensively characterize the many inter-connected features of an individuals environment and experience ("exposome"). Moreover, despite clear evidence that brain organization is highly individualized, most neuroimaging studies still rely on group atlases to define functional networks, smearing away inter-individual variation in the spatial layout of functional networks across the cortex ("functional topography"). Here, we leverage the largest longitudinal study of brain and behavior development in the United States to investigate how an individuals exposome may contribute to functional brain network organization leading to differences in cognitive functioning. To do so, we apply three previously-validated data driven computational models to characterize an individuals multidimensional exposome, define individual-specific maps of functional brain networks, and measure cognitive functioning across broad domains. In pre-registered analyses replicated across matched discovery (n=5,139, 48.5% female) and replication (n=5,137, 47.1% female) samples, we find that a childs exposome is associated with multiple domains of cognitive functioning both at baseline assessment and two years later - over and above associations with baseline cognition. Cross-validated ridge regression models reveal that the exposome is reflected in childrens unique patterns of functional topography. Finally, we uncover both shared and unique contributions of the exposome and functional topography to cognitive abilities, finding that models trained on a single variable capturing a childs exposome can more accurately and parsimoniously predict future cognitive performance than models trained on a wealth of personalized neuroimaging data. This study advances our understanding of how childhood environments contribute to unique patterns of functional brain organization and variability in cognitive abilities.

neuroscience↗

bioRxiv2023

Functional Connectivity Development along the Sensorimotor-Association Axis Enhances the Cortical Hierarchy

Human cortical maturation has been posited to be organized along the sensorimotor-association (S-A) axis, a hierarchical axis of brain organization that spans from unimodal sensorimotor cortices to transmodal association cortices. Here, we investigate the hypothesis that the development of functional connectivity during childhood through adolescence conforms to the cortical hierarchy defined by the S-A axis. We tested this pre-registered hypothesis in four large-scale, independent datasets (total n = 3,355; ages 5-23 years): the Philadelphia Neurodevelopmental Cohort (n = 1,207), Nathan Kline Institute-Rockland Sample (n = 397), Human Connectome Project: Development (n = 625), and Healthy Brain Network (n = 1,126). In each dataset, the development of functional connectivity systematically varied along the S-A axis. Connectivity in sensorimotor regions increased, whereas connectivity in association cortices declined, refining and reinforcing the cortical hierarchy. These robust and generalizable results establish that the sensorimotor-association axis of cortical organization encodes the dominant pattern of functional connectivity development.

neuroscience↗

bioRxiv2023

Connectional Hierarchy in Human Brain Revealed by Individual Variability of Functional Network Edges

The human cerebral cortex exhibits intricate interareal functional synchronization at the macroscale, with substantial individual variability in these functional connections. However, the spatial organization of functional connectivity (FC) variability across the human connectome edges and its significance in cognitive development remain unclear. Here, we identified a connectional axis in the edge-level FC variability. The variability declined continuously along this axis from within-network to between-network connections, and from the edges linking association networks to those linking the sensorimotor and association networks. This connectional axis of functional variability is associated with spatial pattern of structural connectivity variability. Moreover, the connectional variability axis evolves in youth with an increasing flatter axis slope. We also observed that the slope of connectional variability axis was positively related to the performance in the higher-order cognition. Together, our results reveal a connectional axis in functional variability that is linked with structural connectome variability, refines during development, and is relevant to cognition. Significance StatementUnderstanding the spatial organization of inter-individual variability in functional connectivity across the human connectome can offer insights into which connections are most susceptible to insults and interventions. We identify a stable axis on functional connectome along which connectivity variability continuously varies, aligning with structural connectivity variability. We find that the pattern of this axis evolves during development, marked by a decrease in functional connectivity variability among association connections. Moreover, the variability axis is associated with individual differences in higher-order cognitions, driven by increased variability in higher-order association connections linked to enhanced cognitive performance. These findings highlight the importance of connectivity-specific plasticity in understanding both typical and atypical cognitive development across diverse populations.

neuroscience↗

bioRxiv2023

Individual Differences in Delay Discounting are Associated with Dorsal Prefrontal Cortex Connectivity in Youth

Delay discounting is a measure of impulsive choice relevant in adolescence as it predicts many real-life outcomes, including substance use disorders, obesity, and academic achievement. However, the functional networks underlying individual differences in delay discounting during youth remain incompletely described. Here we investigate the association between multivariate patterns of functional connectivity and individual differences in impulsive choice in a large sample of youth. A total of 293 youth (9-23 years) completed a delay discounting task and underwent resting-state fMRI at 3T. A connectome-wide analysis using multivariate distance-based matrix regression was used to examine whole-brain relationships between delay discounting and functional connectivity was then performed. These analyses revealed that individual differences in delay discounting were associated with patterns of connectivity emanating from the left dorsal prefrontal cortex, a hub of the default mode network. Delay discounting was associated with greater functional connectivity between the dorsal prefrontal cortex and other parts of the default mode network, and reduced connectivity with regions in the dorsal and ventral attention networks. These results suggest that delay discounting in youth is associated with individual differences in relationships both within the default mode network and between the default mode and networks involved in attentional and cognitive control.

neuroscience↗

bioRxiv2022

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, how these gradients relate to adult brain function, and whether they are maintained in the adult brain, remains unknown. Here we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately predicts the location of unseen brain tissue samples, ii) delineates known functional territories, and iii) explains the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical functional hierarchies differentiating primary sensory cortex from association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two non-human primate datasets, and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well known morphogens (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

neuroscience↗

bioRxiv2018

A pairwise maximum entropy model uncovers the white matter scaffold underlying emergent dynamics in intracranial EEG

A major challenge in systems neuroscience is to understand how the brains structural architecture gives rise to its complex functional dynamics. Here, we address this challenge by examining the inter-ictal activity of five patients with medically refractory epilepsy during [~] 15 hours of multi-channel intracranial recording. By constructing a pairwise maximum entropy model (MEM) of the observed neural dynamics, we seek to uncover the fundamental relationship between functional activity and its underlying structural substrate. Despite only incorporating the pairwise correlations in the observed neural activity, we find that the pairwise MEM robustly fits large-scale patterns of inter-ictal power dynamics across a wide range of frequency bands, notably displaying time-invariance and cross-frequency similarity. Furthermore, across all frequency bands, we demonstrate that the pairwise MEM accurately identifies the structural white matter connections between brain regions, outperforming other common model-free measures of functional connectivity. Together, our findings show that a simple pairwise MEM, which is explicitly ignorant of higher-order correlations between three or more brain regions, not only captures complex spatiotemporal patterns of neural activity across the frequency spectrum, but also suggests that the network of structural connections in the human brain is a plausible scaffold capable of supporting observed wide-band neural dynamics.

neuroscience↗

bioRxiv2018

Local structural connectivity directs seizure spread in focal epilepsy

How does the human brains structural scaffold give rise to its intricate functional dynamics? This is a central challenge in translational neuroscience, particularly in epilepsy, a disorder that affects over 50 million people worldwide. Treatment for medication-resistant focal epilepsy is often structural - through surgery, devices or focal laser ablation - but structural targets, particularly in patients without clear lesions, are largely based on functional mapping via intracranial EEG (iEEG). Unfortunately, the relationship between structural and functional connectivity in the seizing brain is poorly understood. In this study, we quantify structure-function coupling, specifically between white matter connections and iEEG, across preictal and ictal periods in 45 seizures from 9 patients with unilateral drug-resistant focal epilepsy. We use High Angular Resolution Diffusion Imaging (HARDI) tractography to construct structural connectivity networks and correlate these networks with time-varying broadband and frequency-specific functional networks derived from coregistered iEEG. Across all frequency bands, we find significant increases in structure-function coupling from preictal to ictal periods. We demonstrate that short-range structural connections are primarily responsible for this increase in coupling. Finally, we find that spatiotemporal patterns of structure-function coupling are stereotyped, and a function of each patients individual anatomy. These results suggest that seizures harness the underlying structural connectome as they propagate. Our findings suggest that the relationship between structural and functional connectivity in epilepsy may inform current and new therapies to map and alter seizure spread, and pave the way for better-targeted, patient-specific interventions.

neuroscience↗

bioRxiv2017

Refactoring the Genetic Code for Increased Evolvability

The standard genetic code is robust to mutations and base-pairing errors during transcription and translation. Point mutations are most likely to be synonymous or preserve the chemical properties of the original amino acid. Saturation mutagenesis experiments suggest that in some cases the best performing mutant requires a replacement of more than a single nucleotide within a codon. These replacements are essentially inaccessible to common error-based laboratory engineering techniques that alter single nucleotide per mutation event, due to the extreme rarity of adjacent mutations. In this theoretical study, we suggest a radical reordering of the genetic code that maximizes the mutagenic potential of single nucleotide replacements. We explore several possible genetic codes that allow a greater degree of accessibility to the mutational landscape and may result in a hyper-evolvable organism serving as an ideal platform for directed evolution experiments. We then conclude by evaluating potential applications for recoded organisms within the synthetic biology field.\n\nSignificance StatementThe conservative nature of the genetic code prevents bioengineers from efficiently accessing the full mutational landscape of a gene using common error-prone methods. Here we present two computational approaches to generate alternative genetic codes with increased accessibility. These new codes allow mutational transition to a larger pool of amino acids and with a greater degree of chemical differences, using a single nucleotide replacement within the codon, thus increasing evolvability both at the single gene and at the genome levels. Given the widespread use of these techniques for strain and protein improvement along with more fundamental evolutionary biology questions, the use of recoded organisms that maximize evolvability should significantly improve the efficiency of directed evolution, library generation and fitness maximization.

bioengineering↗