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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

At least 919 records · Page 51Linked to original sources

bioRxiv2018

Targeted memory reactivation during sleep elicits neural signals related to learning content

Reactivation of learning-related neural activity patterns is thought to drive memory stabilization. However, finding reliable, non-invasive, content-specific indicators of reactivation remains a central challenge. Here, we attempted to decode the content of reactivated memories in the electroencephalogram (EEG) during sleep. During encoding, human participants learned to associate spatial locations of visual objects with left- or right-hand movements, and each object was accompanied by an inherently related sound. During subsequent slow-wave sleep within an afternoon nap, we presented half of the sound cues that were associated (during wake) with left- and right-hand movements before bringing participants back for a final post-nap test. We trained a classifier on sleep EEG data (focusing on lateralized EEG features that discriminated left- vs. right-sided trials during wake) to predict learning content when we reactivated the memories during sleep. Discrimination performance was significantly above chance and predicted subsequent memory, supporting the idea that reactivation leads to memory stabilization. Moreover, these lateralized signals increased with post-cue spindle power, demonstrating that reactivation has a strong relationship with spindles. These results show that lateralized activity related to individual memories can be decoded from sleep EEG, providing an effective indicator of offline reactivation.

neuroscience↗

bioRxiv2018

A conserved principle of glial organization in the paleocortex and neocortex

The organizational principles of glia remain largely unknown despite their vital role in nervous system function. Previous work has shown that the number of glia per unit volume of neocortex is constant across mammalian species. We hypothesize that the conservation of glia volume density within brain regions might be a governing principle of organization across species. To test this hypothesis, we used stereology, light microscopy, and data available in the literature to examine five brain regions: the cerebral cortex and four brain regions that differ from the cerebral cortex and each other - the anterior piriform cortex, the posterior piriform cortex, the entorhinal cortex, and the cerebellum. We discovered two orderly relationships: First, glia volume density within a brain region was constant across species, including humans, although it significantly differed between regions, suggesting that glia density might constitute a region-specific marker. Second, the ratio of glia to neuron increased with brain volume according to a [1/4] power law in the primate frontal cortex and the neocortex, the mammalian paleocortex, and the cerebellum. These relationships show that the development of glia and neurons are coupled, and suggest that what a neural circuit computes depends as much on its glial components as on its neurons. Main PointsO_LIThe volume density of glia (i.e., number of glia per unit volume) within a brain region is con-served across mammalian species including humans. C_LIO_LIThe ratio of glia to neuron increases with bigger brains. C_LIO_LIThe volume density of glia is significantly different across functionally and architecturally dif-ferent brain regions and could function as a region-specific marker. C_LIO_LIGlia obey scaling constraints that are different from scaling constraints for neurons. C_LI

neuroscience↗

bioRxiv2018

Single-cell RNA-seq reveals that glioblastoma recapitulates normal brain development

SummaryCancer stem cells are critical for cancer initiation, development, and resistance to treatments. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA-sequencing on 38 296 glioblastoma cells and 22 637 normal human fetal brain cells. Using an unbiased approach, we mapped the lineage hierarchy of the developing human brain and compared the transcriptome of each cancer cell to this roadmap. We discovered a conserved neural trilineage cancer hierarchy with glial progenitor-like cells at the apex. We also found that this progenitor population contains the majority of cancers cycling cells and is the origin of heterogeneity. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, unravels the origin of glioblastoma heterogeneity, and helps to identify cancer stem cell-specific targets.

cancer biology↗

bioRxiv2018

Scaling principles of distributed circuits

Distributed circuits like the olfactory cortex, hippocampus, and cerebellum contain sub-circuits whose inputs distribute their axons over the entire circuit creating a puzzle of how information is encoded. One method for approaching the puzzle is to view them as scalable systems. In scalable systems the quantitative relationship between circuit components is conserved across brain sizes, and by mapping circuit size to functional abilities - e.g. visual acuity in the visual circuit - scientists have explained information encoding. This approach has not been applied to anti-map circuits as their scalability is unknown. To address this gap in knowledge, we obtained quantitative descriptions of the olfactory bulb and piriform cortex in six mammals using stereology techniques and light microscopy. We found that the olfactory circuit is scalable as it satisfies three requirements of scalable systems. First, quantitative relationships between circuit components are conserved: the number piriform neurons n scales with bulb glomeruli g as n ~ g3/2. Second, the olfactory circuit has an invariant property: the average number of synapses between a bulb glomerulus and piriform neuron is one. Third, the olfactory circuit is symmorphic, i.e. olfactory ability improves with circuit size. Other distributed circuits with similar properties might also be scalable.

neuroscience↗

bioRxiv2018

Complement 3 signaling is necessary for the developmental refinement of olfactory bulb circuitry

The olfactory system depends upon organizational maps that are developmentally refined and maintained, however the cellular and molecular mechanisms that underlie these processes are unknown. Studies have shown that microglia and complement molecules are important for the developmental refinement of circuitry within the visual system, thus we asked whether they played a similar role in the olfactory system through the formation of the olfactory bulb (OB) maps, the glomerular and intrabulbar maps. Our findings revealed that microglia in mature animals engulf olfactory sensory neuron (OSN) axons and the synaptic terminals of tufted cells in the glomerular and intrabulbar maps respectively, suggesting microglia could anatomically shape the mature OB circuitry. To determine the mechanisms underlying this axonal pruning activity we used complement 3 (C3) and complement receptor 3 (CR3) knockout mice to investigate if C3 signaling was necessary for precise OB map development. Our results demonstrate that glomerular and intrabulbar map disorganization as typically present in early postnatal mice persists into adulthood when C3 signaling is disrupted. These data clearly establish the C3/CR3 pathway as necessary for the proper developmental refinement of both olfactory maps. We further present the olfactory system as a unique platform to study the role of glia in the development and adult refinement of regenerating circuits.

neuroscience↗

bioRxiv2018

Predicting the future with multi-scale successor representations

The successor representation (SR) is a candidate principle for generalization in reinforcement learning, computational accounts of memory, and the structure of neural representations in the hippocampus. Given a sequence of states, the SR learns a predictive representation for every given state that encodes how often, on average, each upcoming state is expected to be visited, even if it is multiple steps ahead. A discount or scale parameter determines how many steps into the future SR's generalizations reach, enabling rapid value computation, subgoal discovery, and flexible decision-making in large trees. However, SR with a single scale could discard information for predicting both the sequential order of and the distance between states, which are common problems in navigation for animals and artificial agents. Here we propose a solution: an ensemble of SRs with multiple scales. We show that the derivative of multi-scale SR can reconstruct both the sequence of expected future states and estimate distance to goal. This derivative can be computed linearly: we show that a multi-scale SR ensemble is the Laplace transform of future states, and the inverse of this Laplace transform is a biologically plausible linear estimation of the derivative. Multi-scale SR and its derivative could lead to a common principle for how the medial temporal lobe supports both map-based and vector-based navigation.

neuroscience↗

bioRxiv2018

Hox gene expression in postmetamorphic juveniles of the brachiopod Terebratalia transversa

BackgroundHox genes encode a family of homeodomain containing transcription factors that are clustered together on chromosomes of many Bilateria. Some bilaterian lineages express these genes during embryogenesis in spatial and/or temporal order according to their arrangement in the cluster, a phenomenon referred to as collinearity. Expression of Hox genes is well studied during embryonic and larval development of numerous species; however, relatively few studies focus on the comparison of pre- and postmetamorphic expression of Hox genes in animals with biphasic life cycle. Recently, the expression of Hox genes was described for embryos and larvae of Terebratalia transversa, a rhynchonelliformean brachiopod, which possesses distinct metamorphosis from planktonic larvae to sessile juvenile. During premetamorphic development, T. transversa does not exhibit spatial collinearity and several of its Hox genes are recruited for the morphogenesis of novel structures. In our study we determined expression of Hox genes in post-metamorphic juveniles of T. transversa in order to examine metamorphosis-related changes of expression patterns and to test if Hox genes are expressed in the spatially collinear way in the postmetamorphic juveniles.\n\nResultsHox genes are expressed in a spatially non-collinear manner in juveniles, generally showing similar patterns as ones observed in competent larvae: genes labial and Post1 are expressed in chaetae-related structures, sex comb reduced in the shell forming epithelium, whereas Lox5 and Lox4 in dorso-posterior epidermis. After metamorphosis expression of genes proboscipedia, Hox3, Deformed and Antennapedia becomes restricted to, respectively, shell musculature, prospective hinge rudiments, and pedicle musculature and epidermis.\n\nConclusionsAll developmental stages of T. transversa, including postmetamorphic juveniles, exhibit a spatial non-collinear Hox genes expression with only minor changes observed between pre- and postmetamorphic stages. Our results are concordant with morphological observation that metamorphosis in rhynchonelliformean brachiopods, despite being rapid, is rather gradual. The most drastic changes in Hox genes expression patterns observed during metamorphosis could be explained by the inversion of the mantle lobe, which relocates some of the more posterior larval structures into the anterior edge of the juveniles. Cooption of Hox genes for the morphogenesis of novel structures is even more pronounced in post-metamorphic brachiopods when compared to larvae.

developmental biology↗

bioRxiv2018

Heart Rate n-Variability (HRnV): A Novel Representation of Beat-to-Beat Variation in Electrocardiography

Heart rate variability (HRV) is a widely adopted tool for evaluating changes in cardiac autonomic regulation. The majority of efforts have focused on developing methods to assess HRV by deriving sophisticated parameters with linear and nonlinear techniques and adopting advanced signal processing tools for efficient noise removal and accurate QRS detection. In this paper, we propose a novel representation of beat-to-beat variation in an electrocardiogram (ECG), called heart rate n-variability (HRnV), as an alternative to conventional HRV measures. We derived two novel HRnV measures based on non-overlapped and overlapped RR intervals. We also conducted a simulation study by using an ECG record from the MIT-BIH Normal Sinus Rhythm Database to demonstrate the feasibility of calculating HRnV parameters. Among the time domain parameters, we observed that the values were generally incremental with the increase in n. We observed the same trend of changes for the frequency domain parameters. In the nonlinear analysis, the differences between HRV and HRnV from Poincare plot measures were obvious, while those from entropy and detrended fluctuation analysis metrics were not. HRnV measures enable us to augment conventional HRV measures with additional parameters. Although issues remain to be addressed regarding HRnV, we hope to stimulate a new stream of research on this new representation of HRV. HRnV is an important addition to HRV and will contribute to extending the landscape of current studies on HRV.

bioengineering↗

bioRxiv2018

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Bile canaliculi (BC) are the smallest vessels of the biliary tree. They are formed from the apical surfaces of adjoining hepatocytes, resulting in lumenal conduits for bile flow. Bile is propelled along the BC by hepatocyte contractions that arise from cyclic waves of apico-basal Ca2+, but the source and regulation of Ca2+ has been unclear. We report that BC contraction correlates with cyclic transfer of Ca2+ from BC lumen to apico-basal Ca2+ waves in adjacent hepatocytes, and does not correlate with endoplasmic reticulum Ca2+. BC contractility was triggered by ionophore A23187 and unaffected by Thapsigargin. The cycles of Ca2+ transfer could be blocked by the mechanosensitive calcium channel inhibitor GsMTx-4, resulting in cholestatic generation of BC-derived vesicles. The mechanosensitive calcium channel Piezo-1 is preferentially localized at BC membranes, and its hyper-activation by Yoda1 causes increased Ca2+ transfer and increased BC contractility. We propose that canaliculi achieve biomechanical homeostasis through the following feedback system: the pressure of accumulated bile is sensed by mechanosensitive channel, which transmit biliary calcium into adjacent hepatocytes for contraction of the BC lumen and propulsion of the bile.

cell biology↗

bioRxiv2018

The ability of transcription factors to differentially regulate gene expression is a crucial component of the mechanism underlying inversion, a frequently observed genetic interaction pattern

Genetic interactions, a phenomenon whereby combinations of mutations lead to unexpected effects, reflect how cellular processes are wired and play an important role in complex genetic diseases. Understanding the molecular basis of genetic interactions is crucial for deciphering pathway organization as well as understanding the relationship between genetic variation and disease. Several putative molecular mechanisms have been linked to different genetic interaction types. However, differences in genetic interaction patterns and their underlying mechanisms have not yet been compared systematically between different functional gene classes. Here, differences in the occurrence and types of genetic interactions are compared for two classes, gene-specific transcription factors (GSTFs) and signaling genes (kinases and phosphatases). Genome-wide gene expression data for 63 single and double deletion mutants in bakers yeast reveals that the two most common genetic interaction patterns are buffering and inversion. Buffering is typically associated with redundancy and is well understood. In inversion, genes show opposite behavior in the double mutant compared to the corresponding single mutants. The underlying mechanism is poorly understood. Although both classes show buffering and inversion patterns, the prevalence of inversion is much stronger in GSTFs. To decipher potential mechanisms, a Petri Net modeling approach was employed, where genes are represented as nodes and relationships between genes as edges. This allowed over 9 million possible three and four node models to be exhaustively enumerated. The models show that a quantitative difference in interaction strength is a strict requirement for obtaining inversion. In addition, this difference is frequently accompanied with a second gene that shows buffering. Taken together, these results provide a mechanistic explanation for inversion. Furthermore, the ability of transcription factors to differentially regulate expression of their targets provides a likely explanation why inversion is more prevalent for GSTFs compared to kinases and phosphatases.\n\nAuthor SummaryThe relationship between genotype and phenotype is one of the major challenges in biology. While many previous studies have identified genes involved in complex genetic diseases, there is still a gap between genotype and phenotype. One of the difficulties in filling this gap has been attributed to genetic interactions. Large-scale studies have revealed that genetic interactions are widespread in model organisms such as bakers yeast. Several molecular mechanisms have been proposed for different genetic interaction types. However, differences in occurrence and underlying molecular mechanism of genetic interactions have not yet been compared between gene classes of different function. Here, we compared genetic interaction patterns identified using gene expression profiling for two classes of genes: gene specific transcription factors and signaling related genes. We modelled all possible molecular networks to unravel putative molecular differences underlying different genetic interaction patterns. Our study proposes a new mechanistic explanation for a certain genetic interaction pattern that is more strongly associated with transcription factors compared to signaling related genes. Overall, our findings and the computational methodologies implemented here can be valuable for understanding the molecular mechanisms underlying genetic interactions.

genetics↗

bioRxiv2018

Impaired chromosome segregation results in sperms with excess centrosomes in emb-27APC6 mutant C. elegans

The anaphase-promoting complex (APC) is a major regulator of chromosome segregation and is implicated in centriole engagement, whose de-regulation causes abnormal number of centrosomes. The emb-27 gene in C. elegans encodes a subunit of APC. The paternal emb-27 mutant was reported to show cell division with multiple furrows, suggesting the presence of excess centrosomes. In this study, we examined the number of centrosomes and the mechanism underlying de-regulation of centrosome number in emb-27 mutants. Our observations indicated excess centrosomes in emb-27 sperms, which resulted in zygotes with excess centrosomes. Further, the secondary spermatocyte of emb-27 produced reduced number of spermatids, which is likely the direct cause of the excess number of centrosomes per sperm. We propose that a chromosome segregation defect in emb-27 induced centrosome separation defect, resulting in reduced number of buds. Additionally, treatment with cytoskeletal inhibiting drugs indicated presence of three kinds of forces working in combination to move the centrosomes into the spermatids. The present study suggested a novel role of microtubule in the budding cytokinesis of spermatocytes.

cell biology↗

bioRxiv2018

The genome of the plague-resistant great gerbil reveals species-specific duplication of an MHCII gene

The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious diseases and is defined as a key reservoir species for plague (Yersinia pestis). Studies from the wild have shown that the great gerbil is largely resistant to plague but the genetic basis for resistance is yet to be determined. Here, we present a highly contiguous annotated genome assembly of great gerbil, covering over 96 % of the estimated 2.47 Gb genome. Comparative genomic analyses focusing on the immune gene repertoire, reveal shared gene losses within TLR gene families (i.e. TLR8, TLR10 and all members of TLR11-subfamily) for the Gerbillinae lineage, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes. The great gerbil genome provides new insights into the genomic landscape that confers immunological resistance towards plague. The high affinity for Yersinia epitopes could be key in our understanding of the high resistance in great gerbils, putatively conferring a faster initiation of the adaptive immune response leading to survival of the infection. Our study demonstrates the power of studying zoonosis in natural hosts through the generation of a genome resource for further comparative and experimental work on plague survival and evolution of host-pathogen interactions.

genomics↗

bioRxiv2018

DNA-mediated self-assembly of gold nanoparticles on protein superhelix

Recent advances in protein engineering have enabled methods to control the self-assembly of protein on various length-scales. One attractive application for designed proteins is to direct the spatial arrangement of nanomaterials of interest. Until now, however, a reliable conjugation method is missing to facilitate site-specific positioning. In particular, bare inorganic nanoparticles tend to aggregate in the presence of buffer conditions that are often required for the formation of stable proteins. Here, we demonstrated a DNA mediated conjugation method to link gold nanoparticles with protein structures. To achieve this, we constructed de novo designed protein fibers based on previously published uniform alpha-helical units. DNA modification rendered gold nanoparticles with increased stability against ionic solutions and the use of complementary strands hybridization guaranteed the site-specific binding to the protein. The combination of high resolution placement of anchor points in designed protein assemblies with the increased control of covalent attachment through DNA binding can enable investigations of multilevel physical coupling events of nanocomponents on protein templates and expand the application of protein structures to material sciences.

biophysics↗

bioRxiv2018

MicroRNA-200c suppresses epithelial-mesenchymal transition of ovarian cancer by targeting cofilin-2

This study investigated the effects of microRNA-200c (miR-200c) and cofilin-2 (CFL2) in regulating epithelial-mesenchymal transition (EMT) in ovarian cancer. The level of miR-200c was lower in invasive SKOV3 cells than that in non-invasive OVCAR3 cells, whereas CFL2 showed the opposite trend. Bioinformatics analysis and dual-luciferase reporter gene assays indicated that CFL2 was a direct target of miR-200c. Furthermore, SKOV3 and OVCAR3 cells were transfected with miR-200c mimic or inhibitor, pCDH-CFL2 (CFL2 overexpression), or CFL2 shRNA (CFL2 silencing). MiR-200c inhibition and CFL2 overexpression resulted in elevated levels of both CFL2 and vimentin while reducing E-cadherin expression. They also increased ovarian cancer cell invasion and migration in vitro and in vivo and increased the tumor volumes. Conversely, miR-200c mimic and CFL2 shRNA exerted the opposite effects as those aforementioned. In addition, the effects of pCDH-CFL2 and CFL2 shRNA were reversed by the miR-200c mimic and inhibitor, respectively. This finding suggested that miR-200c could be a potential tumor suppressor by targeting CFL2 in the EMT process.

cancer biology↗

bioRxiv2018

Acute but not inherited demyelination in mouse models leads to brain tissue stiffness changes

The alteration or decrease of axonal myelination is an important hallmark of aging and disease. Demyelinated axons are impaired in their function and degenerate over time. Oligodendrocytes, the cells responsible for myelination of axons, are sensitive to mechanical properties of their environment. Growing evidence indicates that mechanical properties of demyelinating lesions are different from the healthy state and thus have the potential to affect myelinating potential of oligodendrocytes. We performed a high-resolution spatial mapping of the mechanical heterogeneity of demyelinating lesions using Atomic Force Microscope enabled indentation. Our results indicate that the stiffness of specific regions of mouse brain tissue is influenced by age and degree of myelination. Here we specifically demonstrate that acute but not inherited demyelination leads to decreased tissue stiffness, which could lower remyelination potential of oligodendrocytes. We also demonstrate that specific brain regions have unique ranges of stiffness in white and grey matter. Our ex vivo findings may help the design of future in vitro models to mimic mechanical environment of the brain in healthy and disease state. Reported here, mechanical properties of demyelinating lesions may facilitate novel approaches in treating demyelinating diseases such as multiple sclerosis.

biophysics↗

bioRxiv2018

Macrophage migration inhibitory factor (MIF) of Syrian golden hamster (Mesocricetus auratus) has similar structure and function as human MIF and promotes pancreatic tumor growth in vivo

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize structure and function of hamster MIF, and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant hamster MIF (rha-MIF) was cloned, expressed and purified in bacterial expression system. The rha-MIF primary sequence, biochemical properties and crystal structure analysis showed a greater similarity with human MIF. The crystal structure of hamster MIF illustrates that it forms a homotrimer as known in human and mouse. However, hamster MIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that rha-MIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of rha-MIF into HapT1 pancreatic tumor bearing hamsters significantly enhanced the tumor growth and tumor associated angiogenesis. Together, the current study shows a structural and functional similarity between hamster and human MIF. Moreover, it has demonstrated that a high-level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.

biochemistry↗

bioRxiv2018

Evolution of gene regulatory networks by means of selection and random genetic drift

The evolution of a population by means of genetic drift and natural selection operating on a gene regulatory network (GRN) of an individual has not been scrutinized in depth. Thus, the relative importance of various evolutionary forces and processes on shaping genetic variability in GRNs is understudied. Furthermore, it is not known if existing tools that identify recent and strong positive selection from genomic sequences, in simple models of evolution, can detect recent positive selection when it operates on GRNs. Here, we propose a simulation framework, called EvoNET, that simulates forward-in-time the evolution of GRNs in a population. Since the population size is finite, random genetic drift is explicitly applied. The fitness of a mutation is not constant, but we evaluate the fitness of each individual by measuring its genetic distance from an optimal genotype. Mutations and recombination may take place from generation to generation, modifying the genotypic composition of the population. Each individual goes through a maturation period, where its GRN reaches equilibrium. At the next step, individuals compete to produce the next generation. As time progresses, the beneficial genotypes push the population higher in the fitness landscape. We examine properties of the GRN evolution such as robustness against the deleterious effect of mutations and the role of genetic drift. We confirm classical results from Andreas Wagners work that GRNs show robustness against mutations and we provide new results regarding the interplay between random genetic drift and natural selection.

bioinformatics↗

bioRxiv2018

Cortico-brainstem mechanisms of biased perceptual decision-making in the context of pain

Perceptual decision-making is commonly studied using stimuli with different physical properties but of comparable affective value. Here, we investigate neural processes underlying human perceptual decisions in the affectively rich domain of pain using a drift-diffusion model in combination with a probabilistic cueing paradigm. This allowed us to characterize a novel role for the dorsolateral prefrontal cortex (DLPFC), whose anticipatory responses reflecting a decision bias were dependent on the affective value of the stimulus. During intense noxious stimulation, these model-based anticipatory DLPFC responses were linked to an engagement of the periaqueductal gray (PAG), a midbrain region implicated in defensive responses including analgesia. Complementing these findings on biased decision-making, the model parameter reflecting sensory processing predicted subcortical responses (in amygdala and PAG) when expectations were violated. Our findings highlight the importance of taking a broader perspective on perceptual decisions and link decisions about pain with subcortical circuitry implicated in endogenous pain modulation.

neuroscience↗