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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 631 records · Page 35Linked to original sources

bioRxiv2018

Inhibition of thrombocyte activation restores protective immunity to mycobacterial infection

Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced mycobacterial burden demonstrating a detrimental role for infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to mycobacterial infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.\n\nKey PointsO_LIInhibition of thrombocyte activation improves control of mycobacterial infection.\nC_LIO_LIInhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.\nC_LI

immunology↗

bioRxiv2018

Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Proteins with low-complexity domains continue to emerge as key players in both normal and pathological cellular processes. Although low-complexity domains are often grouped into a single class, individual low-complexity domains can differ substantially with respect to amino acid composition. These differences may strongly influence the physical properties, cellular regulation, and molecular functions of low-complexity domains. Therefore, we developed a bioinformatic approach to explore relationships between amino acid composition, protein metabolism, and protein function. We find that local compositional enrichment within protein sequences affects the translation efficiency, abundance, half-life, subcellular localization, and molecular functions of proteins on a proteome-wide scale. However, these effects depend upon the type of amino acid enriched in a given sequence, highlighting the importance of distinguishing between different types of low-complexity domains. Furthermore, many of these effects are discernible at amino acid compositions below those required for classification as low-complexity or statistically-biased by traditional methods and in the absence of homopolymeric amino acid repeats, indicating that thresholds employed by classical methods may not reflect biologically relevant criteria. Application of our analyses to composition-driven processes, such as the formation of membraneless organelles, reveals distinct composition profiles even for closely related organelles. Collectively, these results provide a unique perspective and detailed insights into relationships between amino acid composition, protein metabolism, and protein functions.\n\nAuthor SummaryLow-complexity domains in protein sequences are regions that are composed of only a few amino acids in the protein \"alphabet\". These domains often have unique chemical properties and play important biological roles in both normal and disease-related processes.While a number of approaches have been developed to define low-complexity domains, these methods each possess conceptual limitations. Therefore, we developed a complementary approach that focuses on local amino acid composition (i.e. the amino acid composition within small regions of proteins). We find that high local composition of individual amino acids is associated with pervasive effects on protein metabolism, subcellular localization, and molecular function on a proteome-wide scale. Importantly, the nature of the effects depend on the type of amino acid enriched within the examined domains, and are observable in the absence of classically-defined low-complexity (and related) domains. Furthermore, we define the compositions of proteins involved in the formation of membraneless, protein-rich organelles such as stress granules and P-bodies. Our results provide a coherent view and unprecedented resolution of the effects of local amino acid enrichment on protein biology.

bioinformatics↗

bioRxiv2018

AQ-seq: Accurate quantification of microRNAs and their variants

MicroRNAs (miRNAs) modulate diverse biological and pathological processes via post-transcriptional gene silencing. High-throughput small RNA sequencing (sRNA-seq) has been widely adopted to investigate the functions and regulatory mechanisms of miRNAs. However, accurate quantification has been limited owing to the severe ligation bias in conventional sRNA-seq methods. Here we present a high-throughput protocol, termed AQ-seq (accurate quantification by sequencing), that utilizes adapters with terminal degenerate sequences and a high concentration of polyethylene glycol (PEG), which removes the ligation bias during library preparation. By accurately measuring miRNAs and their variants (known as isomiRs), we identify alternatively processed miRNAs and correct the 5' end usage and strand preference that have been misannotated. We also uncover highly modified miRNAs that are uridylated and adenylated. Taken together, AQ-seq reveals the complexity of the miRNA isoform landscape, allowing us to refine miRNA annotation and to advance our understanding of miRNA regulation. Furthermore, AQ-seq can be adopted to improve other ligation-based sequencing methods including crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome profiling (Ribo-seq).

molecular biology↗

bioRxiv2018

ER-to-Golgi trafficking of procollagen in the absence of large carriers.

Secretion and assembly of collagen is fundamental to the function of the extracellular matrix. Defects in the assembly of a collagen matrix lead to pathologies including fibrosis and osteogenesis imperfecta. Owing to the size of fibril-forming procollagen molecules it is assumed that they are transported from the endoplasmic reticulum to the Golgi in specialised large COPII-dependent carriers. Here, analysing endogenous procollagen and a new engineered GFP-tagged form, we show that transport to the Golgi occurs in the absence of large carriers. Large GFP-positive structures are observed occasionally but these are non-dynamic, are not COPII-positive, and label with markers of the ER. We propose a \"short-loop\" model of COPII-dependent ER-to-Golgi traffic that, while consistent with models of ERGIC-dependent expansion of COPII carriers, does not invoke long-range trafficking of large vesicular structures. Our findings provide an important insight into the process of procollagen trafficking and reveal a short-loop pathway from the ER to the Golgi, without the use of large carriers.\n\nSummaryTrafficking of procollagen is essential for normal cell function. Here, imaging of GFP-tagged type I procollagen reveals that it is transported from the endoplasmic reticulum to the Golgi, without the use of large carriers.

cell biology↗

bioRxiv2018

Proteomic Analysis of Rat Serum Revealed the Effects of Chronic Sleep Deprivation on Metabolic, Cardiovascular and Nervous System

Sleep is an essential and fundamental physiological process that plays crucial roles in the balance of psychological and physical health. Sleep disorder may lead to adverse health outcomes. The effects of sleep deprivation were extensively studied, but its mechanism is still not fully understood. The present study aimed to identify the alterations of serum proteins associated with chronic sleep deprivation, and to seek for potential biomarkers of sleep disorder mediated diseases. A label-free quantitative proteomics technology was used to survey the global changes of serum proteins between normal rats and chronic sleep deprivation rats. A total of 309 proteins were detected in the serum samples and among them, 117 proteins showed more than 1.8-folds abundance alterations between the two groups. Functional enrichment and network analyses of the differential proteins revealed a close relationship between chronic sleep deprivation and several biological processes including energy metabolism, cardiovascular function and nervous function. And four proteins including pyruvate kinase M1, clusterin, kininogen1 and profilin-1were identified as potential biomarkers for chronic sleep deprivation. The four candidates were validated via parallel reaction monitoring (PRM) based targeted proteomics. In addition, protein expression alteration of the four proteins was confirmed in myocardium and brain of rat model. In summary, the comprehensive proteomic study revealed the biological impacts of chronic sleep deprivation and discovered several potential biomarkers. This study provides further insight into the pathological and molecular mechanisms underlying sleep disorders at protein level.

bioinformatics↗

bioRxiv2018

Corilagin controls post-parasiticide schistosome egg-induced liver fibrosis by inhibiting Stat6 signalling pathway

This study aims to explore the effect of Corilagin (Cor) on post-parasiticide schistosome egg-induced hepatic fibrosis through the Stat6 signalling pathway in vitro and in vivo. Cellular and animal models were established and treated by Corilagin. The inhibitory effect of Corilagin was also confirmed in RAW264.7 cells in which Stat6 was overexpressed based on the GV367-Stat6-EGFP lentiviral vector system and in which Stat6 was knock-downed by gene specific siRNAs. As a result, Corilagin prevented increases in the protein level of Phospho-Stat6 (P-Stat6). Both the mRNA and protein levels of the downstream mediators SOCS1, KLF4, and PPAR{gamma}/{delta} were markedly suppressed after Corilagin treatment. Expression of ARG1 and FIZZ1/Retnla, Ym1, TGF-{beta} and PDGF in serum were also inhibited by Corilagin. The pathological changes, area of granulomas of liver sections, and degree of hepatic fibrosis were significantly alleviated in the Corilagin group. The areas of CD68- and CD206-positive cells stained by immunofluorescence were significantly decreased by Corilagin. In conclusion, Corilagin can suppress post-parasiticide schistosome egg-induced hepatic fibrosis by inhibiting the Stat6 signalling pathway and provide a new therapeutic strategy for schistosomiasis liver fibrosis.

pharmacology and toxicology↗

bioRxiv2018

Software-aided workflow for predicting protease-specific cleavage sites using physicochemical properties of the natural and unnatural amino acids in peptide-based drug discovery.

Peptide drugs have been used in the treatment of multiple pathologies. During peptide discovery, it is crucially important to be able to map the potential sites of cleavages of the proteases. This knowledge is used to later chemically modify the peptide drug to adapt it for the therapeutic use, making peptide stable against individual proteases or in complex medias. In some other cases it needed to make it specifically unstable for some proteases, as peptides could be used as a system to target delivery drugs on specific tissues or cells. The information about proteases, their sites of cleavages and substrates are widely spread across publications and collected in databases such as MEROPS. Therefore, it is possible to develop models to improve the understanding of the potential peptide drug proteolysis. We propose a new workflow to derive protease specificity rules and predict the potential scissile bonds in peptides for individual proteases. WebMetabase stores the information from experimental or external sources in a chemically aware database where each peptide and site of cleavage is represented as a sequence of structural blocks connected by amide bonds and characterized by its physicochemical properties described by Volsurf descriptors. Thus, this methodology could be applied in the case of non-standard amino acid. A frequency analysis can be performed in WebMetabase to discover the most frequent cleavage sites. These results were used to train several models using logistic regression, support vector machine and ensemble tree classifiers to map cleavage sites for several human proteases from four different families (serine, cysteine, aspartic and matrix metalloproteases). Finally, we compared the predictive performance of the developed models with other available public tools PROSPERous and SitePrediction.

bioinformatics↗

bioRxiv2018

Thermodynamic constraints on the regulation of metabolic fluxes

Nutrition and metabolism are fundamental to cellular function in physiological and pathological contexts. Metabolic activity (i.e. rates, flow, or most commonly referred to as flux) is constrained by thermodynamics and regulated by the activity of enzymes. The general principles that relate biological and physical variables to metabolic control are incompletely understood. Using metabolic control analysis in several representative topological structures of metabolic pathways as models, we derive exact results and conduct computer simulations that define relationships between thermodynamics, enzyme activity, and flux control. We confirm that metabolic pathways that are very far from equilibrium are controlled by the activity of upstream enzymes. However, in general, metabolic pathways have a more adaptable pattern of regulation, controlled minimally by thermodynamics and not necessarily by the specific enzyme that generates the given reaction. These findings show how the control of metabolic pathways, which are rarely very far from equilibrium, is largely set by the overall flux through a pathway rather than by the enzyme which generates the flux or by thermodynamics.

biophysics↗

bioRxiv2018

Rapid, specific detection and quantification of Yersinia pestis using a species-specific SNP in the ferric uptake regulator gene (furMAMA)

Yersinia pestis, the causative agent of plague, is responsible for about 700 human cases of bubonic and pneumonic plague each year. Yet the disease is far more prevalent within rodent reservoirs than in humans. One of the main means of outbreak prevention is extensive wildlife surveillance, where accurate and rapid detection is essential to prevent spillover into the human population from which, it may otherwise spread more rapidly and over larger distances. Moreover, detection and quantification of the agent aids in investigative studies to understand aspects of the pathogen such as transmission mechanics, pathology, contamination risk and more. Partially based on a previously developed assay by Gabitzsch et al. 2008 we designed a TaqMan(R) mismatch amplification mutation assay (TaqMAMA) where a primer leverages a species-specific SNP in the chromosomal single copy ferric uptake regulator gene of Yersinia pestis. The assay allows for specific, rapid detection and quantification of Yersinia pestis using only a single species-specific marker in a highly conserved virulence gene. This low-cost and simple modification of an existing assay eliminates the need for running multiple molecular markers for pathogen detection or performing time-consuming culturing and counting of colonies for quantification.

molecular biology↗

bioRxiv2018

A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimers disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

neuroscience↗

bioRxiv2018

Quantifying platelet margination in diabetic blood flow

Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on the RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a non-monotonic variation with the highest near-wall concentration corresponding to platelets with moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tend to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions, and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.

biophysics↗

bioRxiv2018

Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation

The mechanism of activation and ubiquitin conjugation by the E3 ligase parkin is pivotal to understand the molecular pathology of early-onset Parkinsons disease. Parkin is normally autoinhibited but is activated by the kinase PINK1 that phosphorylates parkins N-terminal ubiquitin-like (pUbl) domain and ubiquitin. How these alter the structure of parkin to allow recruitment of an E2~Ub conjugate to enhance ubiquitination is an unresolved question. We present the structure of an incoming E2~Ub conjugate with the phospho-ubiquitin bound C-terminus of parkin (R0RBR). We show the UbcH7~Ub conjugate is recruited by R0RBR parkin in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR experiments indicate there is re-modelling near the RING0/RING2 interface remote from the E2-binding site. This, and parkin phosphorylation lead to rapid reactivity of the RING2(Rcat) catalytic cysteine in parkin, needed for ubiquitin transfer. Parkin phosphorylation also leads to relocation and weak interaction of the pUbl domain with the RING0 domain that is enhanced upon E2~Ub recruitment indicating these events act synergistically to drive parkin activity.

biochemistry↗

bioRxiv2018

The Evolution of White Matter Microstructural Changes After Mild Traumatic Brain Injury: A Longitudinal DTI and NODDI Study

Neuroimaging biomarkers show promise for improving precision diagnosis and prognosis after mild traumatic brain injury (mTBI), but none has yet been adopted in routine clinical practice. Biophysical modeling of multishell diffusion MRI, using the neurite orientation dispersion and density imaging (NODDI) framework, may improve upon conventional diffusion tensor imaging (DTI) in revealing subtle patterns of underlying white matter microstructural pathology, such as diffuse axonal injury (DAI) and neuroinflammation, that are important for detecting mTBI and determining patient outcome. With a cross-sectional and longitudinal design, we assessed structural MRI, DTI and NODDI in 40 mTBI patients at 2 weeks and 6 months after injury and 14 matched control participants with orthopedic trauma but not suffering from mTBI at 2 weeks. Self-reported and performance-based cognitive measures assessing postconcussive symptoms, memory, executive functions and processing speed were investigated in post-acute and chronic phase after injury for the mTBI subjects. Machine learning analysis was used to identify mTBI patients with the best neuropsychological improvement over time and relate this outcome to DTI and NODDI biomarkers. In the cross-sectional comparison with the trauma control group at 2 weeks post-injury, mTBI patients showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) on DTI mainly in anterior tracts that corresponded to white matter regions of elevated free water fraction (FISO) on NODDI, signifying vasogenic edema. Patients showed decreases from 2 weeks to 6 months in white matter neurite density on NODDI, predominantly in posterior tracts. No significant longitudinal changes in DTI metrics were observed. The machine learning analysis divided the mTBI patients into two groups based on their recovery. Voxel-wise group comparison revealed associations between white matter orientation dispersion index (ODI) and FISO with degree and trajectory of improvement within the mTBI group. In conclusion, white matter FA and MD alterations early after mTBI might reflect vasogenic edema, as shown by elevated free water on NODDI. Longer-term declines in neurite density on NODDI suggest progressive axonal degeneration due to DAI, especially in tracts known to be integral to the structural connectome. Overall, these results show that the NODDI parameters appear to be more sensitive to longitudinal changes than DTI metrics. Thus, NODDI merits further study in larger cohorts for mTBI diagnosis, prognosis and treatment monitoring.

neuroscience↗

bioRxiv2018

Cerebrovascular damages induce lymphatic invasion into brain parenchyma to guide vascular regeneration

Damage to regional cerebrovascular network and neuronal tissues occurs during acute cerebrovascular diseases, such as ischemic stroke. The promotion of vascular regeneration is the most promising therapeutic approach. To understand cellular and molecular mechanisms underlying brain vascular regeneration, we developed two zebrafish cerebrovascular injury models using genetic ablation and photochemical thrombosis. Although brain parenchyma is physiologically devoid of lymphatic vasculature, we found that cerebrovascular injuries induce rapid ingrowth of meningeal lymphatics into the injured parenchyma. The ingrown lymphatics on one hand become lumenized drain interstitial fluid to resolve brain edema, on the other hand act as \"growing tracks\" for nascent blood vessels. The ingrown lymphatic vessels undergo apoptosis and clearance after cerebrovascular regeneration. This study reveals a pathological function of meningeal lymphatics, through previously unexpected ingrowth into brain parenchyma and a newly identified lymphatic function as vascular \"growing tracks\".\n\nHIGHLIGHTSCerebrovascular injuries induce lymphatic ingrowth into the injured brain parenchyma The ingrown lymphatics drain interstitial fluid to resolve brain edema Nascent blood vessels use the ingrown lymphatic vessels as \"growing tracks\" The ingrown lymphatic vessels undergo apoptosis after vascular regeneration completes

developmental biology↗

bioRxiv2018

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

BACKGROUNDCadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Many individuals exposed to dietary Cd are also infected by seasonal influenza virus. The H1N1 strain causes mild to severe pneumonia which can be fatal.\n\nOBJECTIVESTo determine the influence of low-dose Cd exposure on inflammatory responses to H1N1 influenza A virus.\n\nMETHODSWe exposed mice to low-dose (1 mg CdCl2/l) Cd or vehicle (water) for 16 weeks prior to infection with a sub-lethal dose of H1N1. Lung inflammation was assessed by histopathology and flow cytometry. We used a combination of transcriptomics, metabolomics and bioinformatics to determine the molecular associations of inflammatory cells important in Cd-exacerbated responses.\n\nRESULTSCd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-a, interferon and complement, and decreasing myogenesis) were also exacerbated. Global correlations with immune cell counts, leading edge gene transcripts and metabolites revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-{gamma}, and metabolites in amino acid, nucleobase, glycerophospholipid and vitamin B3 pathways.\n\nDISCUSSIONCd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.

pharmacology and toxicology↗

bioRxiv2018

Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) in DEGS1, encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-based DEGS1 knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable.\n\nAbbreviations

genetics↗

bioRxiv2018

Default mode and primary visual network coupling is associated with increased mind-wandering frequency in Parkinson’s disease with visual hallucinations

A mismatch between top-down expectations and incoming sensory information is thought to be associated with hallucinations across a range of neuropsychiatric disorders. In Parkinsons disease with visual hallucinations, abnormal activity within the default network, and its pattern of connectivity with early visual regions, has been identified as a potential pathological source of the internally generated expectations that override incoming sensory input. In the context of attention deficits and visual dysfunction, mental imagery and perceptual expectancies generated across the default network are suggested to exert excessive influence over earlier visual regions, leading to aberrant perceptual experiences. Whilst converging neuroimaging evidence has identified unconstrained default network activity in Parkinsons disease with hallucinations, to date there has been a lack of behavioural evidence to confirm the consequences of an over-engaged default mode network - therefore the contributions it might make to hallucination phenomenology remain speculative. To address this, we administered a validated thought-sampling task to 38 Parkinsons disease patients (18 with hallucinations; 20 without) and 40 controls, to test the hypothesis that individuals with hallucinations experience an increased frequency of mind-wandering - a form of spontaneous cognition strongly associated with mental imagery and default network activity. The neural correlates of mind-wandering frequency were examined in relation to resting-state functional connectivity. Our results showed that patients with hallucinations exhibited significantly higher mind-wandering frequencies compared to non-hallucinators, who in turn had reduced levels of mind-wandering relative to controls. Inter-network connectivity and seed-to-voxel analyses confirmed that increased mind-wandering in the hallucinating vs. non-hallucinating group was associated with greater coupling between the primary visual cortex and dorsal default network. Taken together, both elevated mind-wandering and increased default-visual network coupling emerged as a distinguishing feature of the hallucinatory phenotype. We propose that the finding of increased mind-wandering reflects unconstrained spontaneous thought and mental imagery, which in turn furnish the content of visual hallucinations. Our findings suggest that primary visual cortex to dorsal default network coupling may provide a neural substrate by which regions of the default network exert disproportionate influence over ongoing visual perception. These findings refine current models of visual hallucinations by identifying a specific cognitive phenomenon and neural substrate consistent with the top-down influences over perception that have been implicated in visual hallucinations.

neuroscience↗

bioRxiv2018

Chronic estrus disrupts uterine gland development and homeostasis

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By 20 weeks of age, uterine gland development was comparable to controls, but pathologies, including squamous neoplasia, tubal neoplasia, and cribriform glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue post-pubertal uterine gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in post-pubertal uterine gland development. However, progesterone treatment did not rescue post-pubertal uterine gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts post-pubertal uterine gland development and homeostasis.

developmental biology↗