Biology subjects

Baker, C.

Publications and source records attributed to Baker, C..

44 records · Page 3Linked to original sources

bioRxiv2020

Septins disruption controls tumor growth and enhances efficacy of Herceptin

Septin expressions are altered in cancer cells and exhibit poor prognoses in malignancies. As the first approach to develop a septin filament targeting agent, we optimized the structure of Forchlorfenuron (FCF), a known plant cytokinin to generate UR214-9, which contrary to FCF, causes septin-2/9 filamental structural catastrophe in cancer cells without altering cellular septin protein levels. In-silico docking using septin-2/septin-2 dimer complex showed that UR214-9 displaced the guanine carbonyl oxygen from the GDP binding domain and showed increased binding energy than FCF(-8.59vs-7.21). UR214-9 reduced cancer cell growth, downregulated HER2/STAT-3 axis and controlled growth of HER2+ pancreatic, breast and ovarian cancer xenografts in NSG mice and enhanced response of Herceptin against HER2+breast cancer xenograft. Transcriptome analysis of UR214-9 exposed cells demonstrated significant perturbation of <20 genes compared to afatinib which impacted >1200 genes in JIMT-1 breast cancer cells indicating target specificity and non-transcriptional functions of UR214-9. In summary, disrupting septins via UR214-9 is a new approach to control the growth of HER2+ malignancies.

cancer biology↗

bioRxiv2019

Nonlinear stimulus representations in neural circuits with approximate excitatory-inhibitory balance

Balanced excitation and inhibition is widely observed in cortical recordings. How does this balance shape neural computations and stimulus representations? This problem is often studied using computational models of neuronal networks in a dynamically balanced state. However, these balanced network models predict a linear relationship between stimuli and population responses, in contrast to the nonlinearity of cortical computations. We show that every balanced network architecture admits some stimuli that break the balanced state and these breaks in balance push the network into a "semi-balanced state" characterized by excess inhibition to some neurons, but an absence of excess excitation. The semi-balanced state is unavoidable in networks driven by multiple stimuli, consistent with experimental data, has a direct mathematical relationship to artificial neural networks, and permits nonlinear stimulus representations and nonlinear computations.

neuroscience↗

bioRxiv2019

Inference of Synaptic Connectivity and External Variability in Neural Microcircuits

A major goal in neuroscience is to estimate neural connectivity from large scale extracellular recordings of neural activity in vivo. This is challenging in part because any such activity is modulated by the unmeasured external synaptic input to the network, known as the common input problem. Many different measures of functional connectivity have been proposed in the literature, but their direct relationship to synaptic connectivity is often assumed or ignored. For in vivo data, measurements of this relationship would require a knowledge of ground truth connectivity, which is nearly always unavailable. Instead, many studies use in silico simulations as benchmarks for investigation, but such approaches necessarily rely upon a variety of simplifying assumptions about the simulated network and can depend on numerous simulation parameters. We combine neuronal network simulations, mathematical analysis, and calcium imaging data to address the question of when and how functional connectivity, synaptic connectivity, and latent external input variability can be untangled. We show numerically and analytically that, even though the precision matrix of recorded spiking activity does not uniquely determine synaptic connectivity, it is often closely related to synaptic connectivity in practice under various network models. This relation becomes more pronounced when the spatial structure of neuronal variability is considered jointly with precision.

neuroscience↗

bioRxiv2019

Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads

The sequence and assembly of human genomes using long-read sequencing technologies has revolutionized our understanding of structural variation and genome organization. We compared the accuracy, continuity, and gene annotation of genome assemblies generated from either high-fidelity (HiFi) or continuous long-read (CLR) datasets from the same complete hydatidiform mole human genome. We find that the HiFi sequence data assemble an additional 10% of duplicated regions and more accurately represent the structure of tandem repeats, as validated with orthogonal analyses. As a result, an additional 5 Mbp of pericentromeric sequences are recovered in the HiFi assembly, resulting in a 2.5-fold increase in the NG50 within 1 Mbp of the centromere (HiFi 480.6 kbp, CLR 191.5 kbp). Additionally, the HiFi genome assembly was generated in significantly less time with fewer computational resources than the CLR assembly. Although the HiFi assembly has significantly improved continuity and accuracy in many complex regions of the genome, it still falls short of the assembly of centromeric DNA and the largest regions of segmental duplication using existing assemblers. Despite these shortcomings, our results suggest that HiFi may be the most effective stand-alone technology for de novo assembly of human genomes.

genomics↗

bioRxiv2018

The crossover function of MutSγ is activated via Cdc7-dependent stabilization of Msh4

The MutS{gamma} complex, Msh4-Msh5, binds DNA joint-molecule (JM) intermediates during homologous recombination to promote crossing over and accurate chromosome segregation at the first division of meiosis. MutS{gamma} facilitates the formation and biased resolution of crossover-specific JM intermediates called double Holliday junctions. Here we show that these activities are governed by regulated proteasomal degradation. MutS{gamma} is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable. Activation of MutS{gamma} requires the Dbf4-dependent kinase, Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Phosphorylated Msh4 is chromatin bound and requires DNA strand exchange and chromosome synapsis, implying that DDK specifically targets MutS{gamma} that has already bound nascent JMs. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossover control.

genetics↗

bioRxiv2018

The correlated state in balanced neuronal networks

Understanding the magnitude and structure of inter-neuronal correlations and their relationship to synaptic connectivity structure is an important and difficult problem in computational neuroscience. Early studies show that neuronal network models with excitatory-inhibitory balance naturally create very weak spike train correlations. Later work showed that, under some connectivity structures, balanced networks can produce larger correlations between some neuron pairs, even when the average correlation is very small. All of these previous studies assume that the local neuronal network receives feedforward synaptic input from a population of uncorrelated spike trains. We show that when spike trains providing feedforward input are correlated, the downstream recurrent neuronal network produces much larger correlations. We provide an in-depth analysis of the resulting \"correlated state\" in balanced networks and show that, unlike the asynchronous state of previous work, it produces a tight excitatory-inhibitory balance consistent with in vivo cortical recordings.

neuroscience↗

bioRxiv2018

Similarity judgments and cortical visual responses reflect different properties of object and scene categories in naturalistic images

Numerous factors have been reported to underlie the representation of complex images in high-level human visual cortex, including categories (e.g. faces, objects, scenes), animacy, and real-world size, but the extent to which this organization is reflected in behavioral judgments of real-world stimuli is unclear. Here, we compared representations derived from explicit similarity judgments and ultra-high field (7T) fMRI of human visual cortex for multiple exemplars of a diverse set of naturalistic images from 48 object and scene categories. Behavioral judgements revealed a coarse division between man-made (including humans) and natural (including animals) images, with clear groupings of conceptually-related categories (e.g. transportation, animals), while these conceptual groupings were largely absent in the fMRI representations. Instead, fMRI responses tended to reflect a separation of both human and non-human faces/bodies from all other categories. This pattern yielded a statistically significant, but surprisingly limited correlation between the two representational spaces. Further, comparison of the behavioral and fMRI representational spaces with those derived from the layers of a deep neural network (DNN) showed a strong correspondence with behavior in the top-most layer and with fMRI in the mid-level layers. These results suggest that there is no simple mapping between responses in high-level visual cortex and behavior - each domain reflects different visual properties of the images and responses in high-level visual cortex may correspond to intermediate stages of processing between basic visual features and the conceptual categories that dominate the behavioral response.\n\nSignificance StatementIt is commonly assumed there is a correspondence between behavioral judgments of complex visual stimuli and the response of high-level visual cortex. We directly compared these representations across a diverse set of naturalistic object and scene categories and found a surprisingly and strikingly different representational structure. Further, both types of representation showed good correspondence with a deep neural network, but each correlated most strongly with different layers. These results show that behavioral judgments reflect more conceptual properties and visual cortical fMRI responses capture more general visual features. Collectively, our findings highlight that great care must be taken in mapping the response of visual cortex onto behavior, which clearly reflect different information.

neuroscience↗

bioRxiv2017

Functional Characterization of the Morpheus Gene Family

DATA ACCESSThe cDNA sequences reported in this paper have been deposited in the GenBank database (accession numbers): KF175165-KF175225 and BACs accession numbers that are used in this study: AC148621, AC190226, AC097327, AC097332, AC190226, AC097333, AC145401, AC187943, AC166855, AC166597, AC167295, AC235773, AC202644, and AC234805.\n\nABSTRACTThe burst of segmental duplications during human and great ape evolution focuses on a set of \"core\" duplicons encoding great-ape-specific gene families. Characterization of these gene families is complicated by their high copy number, incomplete sequence, and polymorphic nature. We investigate the structure, transcriptional diversity, and protein localization of the nuclear pore complex-interacting protein (NPIP) or Morpheus gene family. The corresponding core, LCRA, encodes one of the most rapidly evolving genes in the human genome; LCRA has expanded to ~20 copies from a single ancestral locus in Old World monkey and is associated with most of the recurrent chromosome 16 microdeletions implicated in autism and mental retardation. Phylogenetic analysis and cDNA sequencing suggest two distinct subfamilies or subtypes, NPIPA and NPIPB. The latter expanded recently within the great apes due to a series of structural changes within the canonical gene structure. Among Old World monkey, we observe a testis-specific pattern of expression that contrasts with the ubiquitous pattern observed among human tissues. This change in the expression profile coincides with the structural events that reshaped the structure and organization of the gene family. Most of the expressed human copies are capable of producing an open reading frame. Immunofluorescence analyses of the morpheus genes showed a primary localization to both the nucleus and its periphery. We show that morpheus genes may be upregulated upon pI:C treatment and find evidence of human autoantibodies produced against the NPIPB protein, raising the possibility that morpheus genes may be related to immune- or autoimmune-related function.

evolutionary biology↗