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Results for “Pathology”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Restoring wild type-like network dynamics and behaviour during adulthood in a mouse model of schizophrenia

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioural traits relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. Here we studied an animal model of the 22q11 deletion syndrome, which is the highest genetic risk to develop the pathology. We report a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches is sufficient to restore wild type-like network dynamics and behaviour during adulthood. In conclusion, our data provide mechanistic insights underlying network dysfunction relevant to schizophrenia and demonstrate the potential of reverse engineering in fostering new therapeutic strategies to alleviate the burden of neurodevelopmental disorders.

neuroscience↗

bioRxiv2017

TECPR2 a positive regulator of autophagy is implicated in healthy brain ageing

Understanding the healthy brain aging process is key to uncovering the mechanisms leading to pathological age-related neurodegeneration, including progression to Alzheimers disease (AD). Here, we report the first deep whole genome sequencing study aiming to identify variants that are associated specifically to healthy brain aging defined on both clinical and neuropathological level, thus tacking the issue of pathological heterogeneity that often underlies a clinical AD diagnosis. We studied samples from the VITA brain bank and followed an extreme phenotypic ends study design comparing neuropathologically \"healthy\" aging individuals above 80 years of age with pure AD patients of the same age. Focusing on the extreme ends of the phenotypic distribution, and potentially functional variants, we discover a single variant (rs10149146) carried by 53.6% of the \"healthy\" brain elderly individuals in our study (15/28 individuals) and none of the 12 AD cases. This variant lies on the autophagy and cell cycle associated TECPR2 gene. Autophagy dysfunction has been previously implicated in multiple progressive neurodegenerative diseases. An additional non-synonymous variant on the CINP gene (encoding a cell-cycle checkpoint protein) is also found in 46% of healthy controls and absent from all the AD cases. TECPR2 and CINP appear to be \"partner\" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Our study is the first to support the hypothesis that a TECPR2 non-synonymous variant carries a significant neuroprotective effect pointing to key molecules for the involvement of autophagy and cell cycle control in protection from neurodegeneration.

genomics↗

bioRxiv2017

Inert and seed-competent tau monomers elucidate the structural origins of aggregation

Tauopathies feature progressive accumulation of tau amyloids. Pathology may begin when these amplify from a protein template, or seed, whose structure is unknown. We have purified and characterized distinct forms of tau monomer--inert (Mi) and seed-competent (Ms). Recombinant Ms triggered intracellular tau aggregation, induced tau fibrillization in vitro, and self-assembled. Ms from Alzheimers disease also seeded aggregation and self-assembled in vitro to form seed-competent multimers. We used crosslinking with mass spectrometry to probe structural differences in Mi vs. Ms. Crosslinks informed models of local peptide structure within the repeat domain which suggest relative inaccessibility of residues that drive aggregation (VQIINK/VQIVYK) in Mi, and exposure in Ms. Limited proteolysis supported this idea. Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form.

neuroscience↗

bioRxiv2017

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

BackgroundThere is an urgent need for the early identification of nondemented individuals at the highest risk of progressing to Alzheimers disease (AD) dementia for early therapeutic interventions. Our goal was to evaluate whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo CSF or PET biomarkers of amyloid or tau pathology to prospectively predict cognitive decline and clinical progression to AD dementia in nondemented older individuals.\n\nMethodsWe evaluated 347 cognitive normal (CN) and 599 mild cognitively impaired (MCI) individuals. We first investigated whether PHS can predict CSF or PET amyloid and tau deposition. We evaluated differences in positive and negative predictive values of biomarker status, as a function of PHS risk. Next, we used linear mixed-effects (LME) to examine if PHS and biomarker status in conjunction, best predict longitudinal cognitive and clinical progression. Lastly, we used survival analysis to investigate whether a combination of PHS and biomarker positivity predicts progression to AD dementia better than using PHS or biomarker positivity alone.\n\nFindingsIn CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%. Similarly, for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. Beyond APOE, high PHS individuals with amyloid and tau pathology showed the fastest rate of longitudinal cognitive decline and time to AD dementia progression. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression.\n\nInterpretationAmong asymptomatic and mildly symptomatic older individuals, PHS considerably improves the predictive value of CSF or PET amyloid and tau biomarkers. Beyond APOE, PHS may be useful for risk stratification and cohort enrichment for MCI and preclinical AD therapeutic trials.

genetics↗

bioRxiv2017

SOD1A4V aggregation alters ubiquitin homeostasis in ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving the selective death of upper and lower motor neurons in the primary motor cortex and spinal cord. A hallmark of ALS pathology is the accumulation of ubiquitinated protein inclusions within motor neurons. Previous studies suggest the sequestration of ubiquitin (Ub) into inclusions reduces the availability of free Ub, which is essential for cellular function and survival. However, the dynamics of the Ub landscape in ALS have not yet been described. Here we show that Ub homeostasis is altered in a SOD1 cell model of ALS. Utilising fluorescently tagged Ub, we followed the distribution of Ub in living cells expressing SOD1 and show that Ub is present at the earliest stages of SOD1 aggregation. We also report that cells containing aggregates of mutant SOD1 have greater ubiquitin-proteasome system (UPS) dysfunction as measured by the accumulation of the fluorescent proteasome reporter tdTomatoCL1. Furthermore, SOD1 aggregation is associated with the redistribution of Ub and depletion of the free Ub pool. Ubiquitomics analysis indicates that mutant SOD1 is associated with a shift of Ub to a pool of supersaturated proteins including those associated with oxidative phosphorylation and metabolism, corresponding with altered mitochondrial morphology and function. Taken together, these results suggest misfolded SOD1 contributes to UPS dysfunction and that Ub homeostasis is an important target for monitoring pathological changes in ALS.

molecular biology↗

bioRxiv2017

OptoGap: an optogenetics-enabled assay for quantification of cell-cell coupling in multicellular cardiac tissue

Intercellular electrical coupling is an essential means of communication between cells. It is important to obtain quantitative knowledge of such coupling between cardiomyocytes and nonexcitable cells when, for example, pathological electrical coupling between myofibroblasts and cardiomyocytes yields increased arrhythmia risk or during the integration of donor (e.g. cardiac progenitor) cells with native cardiomyocytes in cell-therapy approaches. Currently, there is no direct method for assessing heterocellular coupling within multicellular tissue. Here we demonstrate experimentally and computationally a new contactless assay for electrical coupling, OptoGap, based on selective illumination of inexcitable cells that express optogenetic actuators and optical sensing of the response of coupled excitable cells, e.g. cardiomyocytes, that are light-insensitive. Cell-cell coupling is quantified by the energy required to elicit an action potential via junctional current from the light-stimulated cell(s). The proposed technique is experimentally validated against the standard indirect approach, GapFRAP, using light-sensitive cardiac fibroblasts and non-transformed cardiomyocytes in a two-dimensional setting. Its potential applicability to the complex three-dimensional setting of the native heart is corroborated by computational modeling and proper calibration.\n\nIntercellular coupling is a fundamental form of communication between cells, essential for the synchronization of physiological processes in different organs. Pathologically altered coupling or the emergence of de novo coupling between native and donor cells are problems of interest in many cardiac applications, e.g. during cell delivery and cell integration for cardiac repair therapy1,2. In particular, interactions between cardiomyocytes and fibroblasts are of interest, especially the pro-arrhythmic increase in coupling as the latter transition to myofibroblasts3-6.\n\nElectrical coupling in cardiac tissue is mediated primarily by low-resistance paths formed by gap-junctional proteins (connexins), that can link cardiomyocytes (CMs) to each other and to non-cardiomyocytes (nCMs), such as fibroblasts. Qualitative and quantitative methods, e.g. immunofluorescence, messenger RNA and Western blots, are often used to assay connexin expression levels as a surrogate measure of coupling, but they do not provide functional information. A method for direct quantification of cell-cell coupling within the multicellular tissue context is highly desirable.

bioengineering↗

bioRxiv2017

Expanding primary cells from mucoepidermoid and other salivary gland neoplasms for genetic and chemosensitivity testing

Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes in addition to screening for cancer-risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated Amphiregulin-Mechanistic Target of Rapamycin-AKT/Protein kinase B (AKT) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. In contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies and can be used to build sustainable bio-banks for future inquiries.

cancer biology↗

bioRxiv2017

A gut pathobiont synergizes with the microbiota to instigate inflammatory disease marked by immunoreactivity against other symbionts but not itself

Inflammatory bowel diseases (IBD) are likely driven by aberrant immune responses directed against the resident microbiota. Although IBD is commonly associated with a dysbiotic microbiota enriched in putative pathobionts, the etiological agents of IBD remain unknown. Using a pathobiont-induced intestinal inflammation model and a defined bacterial community, we provide new insights into the immune-microbiota interactions during disease. In our model system, the pathobiont Helicobacter bilis instigates disease following sub-pathological dextran sulfate sodium treatment. We show that H. bilis causes mild inflammation in mono-associated mice, but severe disease in the presence of a microbiota, demonstrating synergy between the pathobiont and microbiota in exacerbating pathology. Remarkably, inflammation depends on the presence of H. bilis, but is marked by a predominant Th17 response against specific members of the microbiota and not the pathobiont, even upon the removal of the most immune-dominant taxa. Neither increases in pathobiont burden nor unique changes in immune-targeted microbiota member abundances are observed during disease. Collectively, our findings demonstrate that a pathobiont instigates inflammation without being the primary target of a Th17 response or by altering the microbiota community structure. Moreover, our findings point toward monitoring pathobiont-induced changes in microbiota immune targeting as a new concept in IBD diagnotics.

immunology↗

bioRxiv2017

Intrinsic functional connectivity of the central extended amygdala

The central extended amygdala (EAc)--including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)--plays a key role in orchestrating states of fear and anxiety and is implicated in the development and maintenance of anxiety disorders, depression, and substance abuse. Although it is widely thought that these disorders reflect the coordinated actions of large-scale functional circuits in the brain, the architecture of the EAc functional network, and the degree to which the BST and the Ce show distinct patterns of intrinsic functional connectivity, remains incompletely understood. Here, we leveraged a combination of approaches to trace the connectivity of the BST and the Ce in 130 psychiatrically healthy, racially diverse, community-dwelling adults with enhanced power and precision. Multiband imaging, high-precision data registration techniques, and spatially unsmoothed data were used to maximize anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala ( substantia innominata), the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed significant coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed significantly stronger connectivity with prefrontal territories--including the vmPFC, anterior MCC and pregenual anterior cingulate cortex--as well as the thalamus, striatum, and the periaqueductal gray. The only regions showing stronger functional connectivity with the Ce were located in the anterior hippocampus and dorsal amygdala. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and highlight the value of several new approaches to image registration which may be particularly useful for researchers working with de-identified neuroimaging data.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC=\"FIGDIR/small/178533_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@10ce93corg.highwire.dtl.DTLVardef@a467ceorg.highwire.dtl.DTLVardef@19b4550org.highwire.dtl.DTLVardef@e38e2a_HPS_FORMAT_FIGEXP M_FIG Intrinsic functional connectivity of bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) in 130 psychiatrically healthy adults.\n\nC_FIG HIGHLIGHTSO_LIBST and Ce implicated in normal and pathological fear and anxiety\nC_LIO_LITraced the intrinsic functional connectivity of the BST and the Ce in 130 adults\nC_LIO_LIMultiband imaging, high-precision registration, unsmoothed data, newly developed seeds\nC_LIO_LIBST and Ce show robust coupling with one another, hippocampus, insula, MCC, and vmPFC\nC_LIO_LIBST shows stronger coupling with prefrontal/cingulate territories and brainstem/PAG\nC_LI

neuroscience↗

bioRxiv2017

Sepsis: Partial least squares structural equation modelling (PLS-SEM) suggests a critical role for anti-inflammatory responses in clinical severity

BackgorundDespite major advances in medicine, Sepsis remains one of the major killers in critical care wards around the world. For several years it was widely believed that an early pro-inflammatory host response is followed by an overwhelming anti-inflammatory phase. The hypo-inflammatory status, termed as Compensatory anti-inflammatory response syndrome (CARS), was proposed to be the primary cause of sepsis-associated mortality. However, this paradiam changed in recent years since there was little evidence to support the linear model of host response and pathogenesis in sepsis. Currently held view is that both inflammatory and anti-inflammatory host responses are stimulated in an overlapping manner. In this study a robust statistical model to study the complex interplay of host cytokines in human sepsis has been developed to evaluate host responses in sepsis that contribute significantly to clinical pathology.\n\nMethodsTwentyseven cytokines/ chemokines were quantified in 139 sepsis patients and multivariate analysis of variance (MANOVA) was performed to assess differences in host responses in different categories of clinical severity. Partial least squares regression based structural equation modelling (PLS-SEM) was used to assess interactions between different groups of cytokines and their contribution to clinical pathology. An array of 23 cytokines was analysed in a mouse model of endotoxemia and a similar mathematical model was constructed.\n\nResultsThe results of MANOVA demonstrated the ability of combined cytokine response to discriminate sepsis patients according to clinical severity or outcome. Structural equation modelling revealed strong positive association between inflammatory and anti-inflammatory cytokines. In human sepsis, anti-inflammatory cytokines emerged as a significant entity associated with clinical severity as assessed by APACHE II scores.\n\nConclusionPLS-SEM modeling of cytokine responses and APACHE II score in human sepsis revealed that anti-inflammatory molecules contribute significantly towards clinical severity. More critically, the model offers emperical evidence for failures of clinical trials conducted during the last two decades in which antagonists of inflammatory host responses for human Sepsis were used for sepsis. The model also provides credence to the notion that inflammatory and anti-inflammatory host responses occur concurrently in both experimental endotoxemia and in human sepsis.

immunology↗

bioRxiv2017

Mapping nonapoptotic caspase activity with a transgenic reporter in mice

The protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. As a proof of concept, we first obtained evidence that nonapoptotic caspase activity influences neurophysiology in an amygdalar circuit. Then focusing on the amygdala, we were able to quantify a sex-specific persistent elevation in caspase activity in females after restraint stress. This simple in vivo caspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathological models. Significance StatementCaspase-3 is an enzyme that can cause cell death when highly active but can also perform important cellular functions, such as maturation and structural changes, when only weakly or transiently active. Despite the importance of this nonlethal type of caspase activity, there is no straightforward method to measure it in live rodents. We therefore developed mice that have a fluorescent reporter that is sensitive enough to detect nonlethal caspase activity. Surprisingly, we found that weak caspase activity influences the synchrony of neuronal firing across different brain regions. We also observed increased caspase activity in female mice after severe stress. This simple caspase activity reporter can subserve multiple applications in behavior and pathology research.

neuroscience↗

bioRxiv2017

Classification and Mutation Prediction from Non-Small Cell Lung Cancer Histopathology Images using Deep Learning

Visual analysis of histopathology slides of lung cell tissues is one of the main methods used by pathologists to assess the stage, types and sub-types of lung cancers. Adenocarcinoma and squamous cell carcinoma are two most prevalent sub-types of lung cancer, but their distinction can be challenging and time-consuming even for the expert eye. In this study, we trained a deep learning convolutional neural network (CNN) model (inception v3) on histopathology images obtained from The Cancer Genome Atlas (TCGA) to accurately classify whole-slide pathology images into adenocarcinoma, squamous cell carcinoma or normal lung tissue. Our method slightly outperforms a human pathologist, achieving better sensitivity and specificity, with [~]0.97 average Area Under the Curve (AUC) on a held-out population of whole-slide scans. Furthermore, we trained the neural network to predict the ten most commonly mutated genes in lung adenocarcinoma. We found that six of these genes - STK11, EGFR, FAT1, SETBP1, KRAS and TP53 - can be predicted from pathology images with an accuracy ranging from 0.733 to 0.856, as measured by the AUC on the held-out population. These findings suggest that deep learning models can offer both specialists and patients a fast, accurate and inexpensive detection of cancer types or gene mutations, and thus have a significant impact on cancer treatment.

cancer biology↗

bioRxiv2017

Temporal differentiation of bovine airway epithelial cells grown at an air-liquid interface

The respiratory epithelium is exposed to assault by toxins and pathogens through the process of inhalation, which has numerous implications on both human and animal health. As such, there is a need to develop and characterise an in vitro model of the airway epithelium to study respiratory pathologies during infection or toxicology experiments. This has been achieved by growing airway epithelial cells at an air-liquid interface (ALI). Characterisation of ALI models are not well-defined for airway epithelial cells derived from non-human species. In this study we have fully characterised a bovine airway epithelial cell models (AECM) grown at an ALI in relation to ex vivo tissue. The morphology of the model was monitored at three day intervals, to identify the time-period at which the culture was optimally differentiated. The model was shown to be fully-differentiated by day 21 post-ALI. The culture formed a stereotypical pseudostratified, columnar epithelium containing the major cell types of the bronchial epithelium (ciliated-, goblet- and basal cells). Once fully differentiated the bovine AECM displayed both barrier function, through the formation of tight-junctions, and active mucociliary clearance, important properties of the mucosal barrier. The bovine bronchial epithelial cells remained stable for three weeks, with no evidence of deterioration or dedifferentiation. The window in which the model displayed full differentiation was determined to be between day 21-42 post-ALI. Through comparison with ex vivo tissue derived from donor animals, our bovine AECM was shown to be highly representative of the in vivo bovine bronchial epithelium and can be utilised in the study of respiratory pathologies.

microbiology↗

bioRxiv2017

The circadian hippocampus and its reprogramming in epilepsy: impact for chronotherapeutics

Gene and protein expression displays circadian oscillations in numerous body organs. These oscillations can be disrupted in diseases, thus contributing to the disease pathology. Whether the molecular architecture of cortical brain regions oscillates daily and whether these oscillations are modified in brain disorders is less understood. We identified 1200 daily oscillating transcripts in the hippocampus of control mice. More transcripts (1600) were oscillating in experimental epilepsy, with only one fourth oscillating in both conditions. Proteomics confirmed these results. Metabolic activity and targets of antiepileptic drugs displayed different circadian regulation in control and epilepsy. Hence, the hippocampus, and perhaps other cortical regions, shows a daily remapping of its molecular landscape, which would enable different functioning modes during the night/day cycle. The impact of this remapping in brain pathologies needs to be taken into account not only to study their mechanisms, but also to design drug treatments and time their delivery.

neuroscience↗

bioRxiv2017

RECONSTITUTION OF HELICAL SOLUBLE α-SYNUCLEIN THROUGH TRANSIENT INTERACTION WITH LIPID INTERFACES

-synuclein (Syn) is one of the key players in the pathogenesis of Parkinsons disease (PD) and other synucleinopathies. Its misfolding and subsequent aggregation into intracellular inclusions are the pathological hallmark of these diseases and may also play a central role in the molecular cascade leading to neurodegeneration. In this work, we report the existence of a novel soluble -helical conformer of Syn, an archetypal \"intrinsically disordered protein\" (IDP), obtained through transient interaction with lipid interfaces. We describe how the stability of this conformer is highly dependent on the continuous, dynamic oligomerization of the folded species. The conformational space of Syn appears to be highly context-dependent, and lipid bilayers might play crucial roles as molecular chaperones for cytosolic species in a cellular environment, as they do in the case of this previously unreported structure.\n\nSignificance StatementBoth genetic and histopathologic evidence tie -synuclein (Syn) to the pathogenesis of Parkinsons disease (PD), a widespread neurodegenerative disorder. Lipids play a central role in the dynamics of Syn in physiology and disease. Syn undergoes a coil-to-helix transition when binding to lipid vesicles and it is involved in the regulation of synaptic vesicle trafficking. Furthermore, recently discovered -helical, aggregation-resistant \"multimers\" of Syn could constitute a protective conformational pathway. We report the existence of a folded, lipid-unbound Syn conformer that forms upon transient interaction with lipids and is stabilized by dynamic homooligomerization, suggesting that synaptic activity could modulate resistance towards aggregation. Our results are therefore important both for the molecular pathology of PD and the structural biology of intrinsically disordered proteins.

biophysics↗

bioRxiv2017

Bipolar oscillations between positive and negative mood states in a computational model of Basal Ganglia

Bipolar disorder is characterized by mood swings - oscillations between manic and depressive states. The swings (oscillations) mark the length of an episode in a patients mood cycle (period), and can vary from hours to years. The proposed modeling study uses decision making framework to investigate the role of basal ganglia network in generating bipolar oscillations. In this model, the basal ganglia system performs a two-arm bandit task in which one of the arms leads to a positive outcome, while the other leads to a negative outcome. In healthy conditions, the model chooses positive action and avoids negative one, whereas under bipolar conditions, the model exhibits slow oscillations in its choice of positive or negative outcomes, reminiscent of bipolar oscillations. The model is cast at three levels of abstraction: 1) a two-dimensional dynamical system model, 2) a phenomenological basal ganglia model, 3) a detailed network model of basal ganglia. Phase-plane analyses on the simple reduced dynamical system with two variables reveal the essential parameters that generate pathological bipolar-like oscillations. Phenomenological and network models of the basal ganglia extend that logic, and interpret bipolar oscillations in terms of the activity of dopaminergic and serotonergic projections on the cortico-basal ganglia network dynamics. The networks dysfunction, specifically in terms of reward and risk sensitivity, is shown to be responsible for the pathological bipolar oscillations. The study proposes a computational model that explores the effects of impaired serotonergic neuromodulation on the dynamics of the cortico basal ganglia network, and relates this impairment to abstract mood states (manic and depressive episodes) and oscillations of bipolar disorder.

neuroscience↗

bioRxiv2017

Computational discovery of tissue morphology biomarkers in very long-term survivors with pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, with an average 5-year survival rate of only 8%. Within PDAC patients, however, there is a small subset of patients who survive >10 years. Deciphering underlying reasons behind prolonged survival could potentially provide new opportunities to treat PDAC; however, no genomic, transcriptomic, proteomic, or clinical signatures have been found to robustly separate this subset of patients. Digital pathology, in combination with machine learning, provides an opportunity to computationally search for tissue morphology patterns associated with disease outcomes. Here, we developed a computational framework to analyze whole-slide images (WSI) of PDAC patient tissue and identify tissue-morphology signatures for very long term surviving patients. Our results indicate that less tissue morphology heterogeneity is significantly linked to better patient survival and that the extra-tumoral space encodes prognostic information for survival. Based on information from morphological heterogeneity in the tumor and its adjacent area, we established a machine learning model with an AUC of 0.94. Our analysis workflow highlighted a quantitative visual-based tissue phenotype analysis that also allows direct interaction with pathology. This study demonstrates a pathway to accelerate the discovery of undetermined tissue morphology associated with pathogenesis states and prognosis and diagnosis of patients by utilizing new computational approaches.

bioinformatics↗

bioRxiv2017

Skeletal muscle fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH-dependent regulation of adipogenesis

Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fat infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. Nonetheless, factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, revealed that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. These results offer a basis for rationalizing the pathological outcomes of fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fatty depositions in muscles of dystrophic patients.\n\nHighlightsO_LISingle-cell mass cytometry reveals that wt and mdx FAPs are in different cell states.\nC_LIO_LIActivation of the NOTCH signaling pathway negatively regulates adipogenesis of wt but not mdx FAPs.\nC_LIO_LIDeep proteomics suggests a mechanism explaining the different sensitivity of mdx- FAPs to NOTCH.\nC_LIO_LITNF-a stimulation restores the anti-adipogenic effect of NOTCH in mdx FAPs.\nC_LI

cell biology↗