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bioRxiv2018

Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

Granolocyte-macrophage colony stimulating factor (GM-CSF) induces production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. Nociceptor-specific voltage gated Na+ channels Nav1.7, Nav1.8 and Nav1.9 were found to be selectively up-regulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Jak2 and Stat3 signaling pathway which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly targeted knocking down either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons alleviated the hyperalgesia in rats. Our findings describe a new bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.

neuroscience↗

bioRxiv2018

eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data

The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3,435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (s.e.= 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimers disease in which brain shrinkage is a key biomarker.

genetics↗

bioRxiv2018

FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for Gria2 mRNA processing

Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function and pathology have not been explored. Here, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity include TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS translocation occurs through a calcium-dependent mechanism and coincides with striking alterations in nucleocytoplasmic transport. Further, glutamate-induced upregulation of Gria2 in neurons was dependent on FUS expression, consistent with a functional role for FUS under excitotoxic stress. These findings reveal a link between prominent factors in neurodegenerative disease, namely excitotoxicity, disease-associated RBPs and nucleocytoplasmic transport.

neuroscience↗

bioRxiv2018

Evolutionarily developed connections compromised in schizophrenia

The genetic basis and uniquely human character of schizophrenia has led to the notion of human brain evolution to have resulted in vulnerability to the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in-vivo neuroimaging data from humans, chimpanzees and macaque monkeys. We find that evolutionary changes in human connectome organization overlap with the pattern of schizophrenia-related changes in brain connectivity, with connections evolutionary enhanced in the human brain showing significantly more involvement in schizophrenia pathology than connections shared between humans and non-human primates (effects shown in three independent patient-control datasets). Our findings suggest that the evolution of brain wiring in support of complex brain function in humans may have come at the cost of an increased vulnerability to brain dysfunction in disease.

neuroscience↗

bioRxiv2018

Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries.

BackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD.\n\nMethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups.\n\nResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Need to include RNA and IHC.\n\nConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the

physiology↗

bioRxiv2018

Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection

The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs).\n\nThe IL-10 family of receptors, comprising combinations of subunits IL-10R, IL-10R{beta}, IL-22R and IL-28R, modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22R and IL-28R are dispensable in the host response to whipworms, IL-10 signalling through IL-10R and IL-10R{beta} is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10R and IL-10R{beta} results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10R and IL-10R{beta}-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10R and IL-10R{beta} in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10R on IECs. Our findings emphasize the pivotal role of systemic IL-10R signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworms infections.\n\nAuthor summaryThe human gut is home to millions of bacteria, collectively called the microbiota, and also to parasites that include whipworms. The interactions between gut cells, the microbiota and whipworms define conditions for balanced parasitism. Cells lining the gut host whipworms but also interact with gut immune cells to deploy measures that control or expel whipworms whilst maintaining a barrier to prevent microbial translocation. Whipworms affect the composition of the microbiota, which in turn impacts the condition of the gut lining and the way in which immune cells are activated. In order to avoid tissue damage and disease, these interactions are tightly regulated. Here we show that signalling through a member of the IL-10 receptor family, IL-10R, in gut immune cells is critical for regulating of these interactions. Lack of this receptor on gut immune cells results in persistence of whipworms in the gut accompanied by an uncontrolled inflammation that destroys the gut lining. This tissue damage is accompanied by the overgrowth of members of the microbiota that act as opportunistic pathogens. Furthermore, the destruction of the gut barrier allows these bacteria to reach the liver where they cause organ failure and fatal disease.

immunology↗

bioRxiv2018

Identification of dysregulation of atrial proteins in rats with chronic obstructive apnea using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry

Obstructive sleep apnea (OSA) affects an estimated 20% of adults worldwide with up to 80% of patients remaining undiagnosed. OSA has been associated with electrical and structural abnormalities of the atria, although the molecular mechanisms are not well understood. We have implemented a rat model of OSA involving the surgical implantation of a tracheal obstructive device. Rats were divided into severe and moderate apnea groups, receiving 23 seconds (severe) or 13 seconds (moderate) apneas per minute, 60 apneas per minute for 8 hours a day over 2 weeks. We recently performed a pilot study using onedimensional polyacrylamide gel electrophoresis (1D PAGE) and nanoliquid chromatography-tandem mass spectrometry (NanoLC-MS/MS) to investigate the protein dysregulations in rat atria which was induced with OSA using the rat model we developed. We found, among others, that some aerobic and anaerobic glycolytic enzymes and Krebs cycle enzymes were downregulated, suggesting that apnea may be a result of paucity of oxygen and production of ATP and reducing equivalents. Here, we used twodimensional polyacrylamide gel electrophoresis (2D PAGE) coupled with nanoLC-MS/MS as a complementary approach to investigate the proteins that are dysregulated in the atria from severe and moderate apnea when compared to control. We not only found that the entire glycolytic pathway and Krebs cycle are downregulated, but also found evidence that additional enzymes involved in the beta-oxidation, electron transport chain and Krebs cycle anaplerotic reactions were also downregulated. Other protein dysregulations identified are involved in metabolic, structural, or inflammatory pathways, suggesting that these proteins may play a role in atrial pathology developing via chronic obstructive apnea and hypoxia.

biochemistry↗

bioRxiv2018

Multiscale dynamic mean field (MDMF) model to relate resting state brain dynamics with local cortical excitatory-inhibitory neurotransmitter homeostasis in health and disease.

Previous neuro-computational studies have established the connection of spontaneous resting-state brain activity with "large-scale" neuronal ensembles using dynamic mean field approach and showed the impact of local excitatory-inhibitory (E-I) balance in sculpting dynamical patterns. Here, we argue that whole brain models that link multiple scales of physiological organization namely brain metabolism that governs synaptic concentrations of gamma-aminobutyric acid (GABA) and glutamate on one hand and neural field dynamics that operate on the macroscopic scale. The multiscale dynamic mean field (MDMF) model captures the synaptic gating dynamics over a cortical macrocolumn as a function of neurotransmitter kinetics. Multiple MDMF units were placed in brain locations guided by an anatomical parcellation and connected by tractography data from diffusion tensor imaging. The resulting whole-brain model generates the resting-state functional connectivity and also reveal that optimal configurations of glutamate and GABA captures the dynamic working point of the brain, that is the state of maximum metsatability as observed in BOLD signals. To demonstrate test-retest reliability we validate the observation that healthy resting brain dynamics is governed by optimal glutamate-GABA configurations using two different brain parcellations for model set-up. Furthermore, graph theoretical measures of segregation (modularity and clustering coefficient) and integration (global efficiency and characteristic path length) on the functional connectivity generated from healthy and pathological brain network studies could be explained by the MDMF model. In conclusion, the MDMF model could relate the various scales of observations from neurotransmitter concentrations to dynamics of synaptic gating to whole-brain resting-state network topology in health and disease.

neuroscience↗

bioRxiv2018

Nonsteroidal anti-inflammatory drugs alter the microbiota and exacerbate Clostridium difficile colitis while dysregulating the inflammatory response

Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of nosocomial CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and intestinal pathology associated with CDI in mice. We demonstrate that in C. difficile-infected animals, indomethacin lead to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by an increased recruitment of intestinal neutrophils and CD4+ cells. Together, these data implicate NSAIDs in perturbation of the gut microbiota and disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses.

microbiology↗

bioRxiv2018

AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

The human 1q21.1 deletion of ten genes is associated with increased risk schizophrenia. The deletion involves the {beta}-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand its impact on behavior and potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, as its main role is proposed to be to reestablish neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required to maintain proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPK{beta} loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPK{beta} loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion. Sleep is regulated by circadian and homeostatic processes. While the circadian clock is well studied, the molecular mechanism underlying homeostasis remains largely unknown. Our data suggest that AMPK is required for sleep maintenance and may be involved in the homeostatic process of sleep regulation.\n\nAuthor SummaryThe human 1q21.1 chromosomal deletion is associated with increased risk of schizophrenia. Because this deletion affects only a small number of genes, it provides a unique opportunity to identify the specific disease-causing gene(s) using animal models. Here, we report the use of a Drosophila model to identify the potential contribution of one gene affected by the 1q21.1 deletion - PRKAB2 - to the pathology of the 1q21.1 deletion syndrome. PRKAB2 encodes a subunit of the AMP-activated protein kinase (AMPK) complex, the main cellular energy sensor. We show that AMPK deficiency reduces lifespan and causes structural abnormalities in neuronal dendritic structures, a phenotype which has been linked to schizophrenia. Furthermore, cognitive impairment and altered sleep patterning are some of the most common symptoms of schizophrenia. Therefore, to understand the potential contribution of PRKAB2 to the 1q21.1 syndrome, we tested whether AMPK alterations would cause defects in learning and sleep. Our study shows that lack of PRKAB2 and AMPK-complex activity, in the nervous system leads to reduced learning and to dramatic sleep disturbances. Thus, our data links a single 1q21.1-related gene with phenotypes that resemble common symptoms of schizophrenia, suggesting that this gene, PRKAB2, may contribute to the risk of developing schizophrenia.

neuroscience↗

bioRxiv2018

Tendon Structure Quantified using Ultrasound Imaging Differs Based on Location and Training Type

Achilles tendinopathy is ten-times more common amongst running athletes compared to age-matched peers. Load induced tendon remodeling and its progression in an at-risk population of developing symptomatic tendinopathy is not well understood. The purpose of this study was to prospectively characterize Achilles and patellar tendon structure in competitive collegiate distance runners over different competitive seasons using quantitative ultrasound imaging. Twenty-two collegiate cross country runners and eleven controls were examined for this study. Longitudinal and cross-sectional ultrasound images of bilateral Achilles and patellar tendons were obtained at the one week prior to start of formal collegiate cross country practices, one week after the conclusion of cross country season, and one week prior to outdoor track and field championships. Collagen organization, mean echogenicity, tendon thickness, and neovascularity were determined using well established image processing techniques. We found that Achilles and patellar tendons respond differently to high-volume running and transitions from one sport season to another, suggesting that tendon structure is sensitive to differences in tendon loading biomechanics. Our findings indicate that Achilles tendon structure in trained runners differ structurally to control tendons but is stable throughout training while patellar tendon structure changes in response to the transition in training volume between cross country and track seasons. These findings expand upon prior reports that some degree of tendon remodeling may act as a protective adaptation for sport specific loading.\n\nNews and NoteworthyIn this study we prospectively examined the Achilles and patellar tendon structure of distance runners to determine if continued training through multiple seasons elicits tendon remodeling or pathology. We found that Achilles and patellar tendons respond uniquely to the changing loads required during each season. Achilles tendon collagen alignment is mostly stable throughout the competitive cycle, but the patellar tendon undergoes structural changes following the transition from cross-country to track season.

bioengineering↗

bioRxiv2018

Association of Prevotella enterotype with polysomnographic data in obstructive sleep apnea/hypopnea syndrome patients

Intermittent hypoxia and sleep fragmentation are critical pathophysiological processes involved in obstructive sleep apnea/hypopnea syndrome (OSAHS). These manifestation independently affect similar brain regions and contribute to OSAHS-related comorbidities that are known to be related to the host gut alteration microbiota. We hypothesized that microbiota disruption influences the pathophysiological processes of OSAHS through a microbiota-gut-brain axis. Thus, we aim to survey enterotypes and polysomnographic data of OSAHS patients. Subjects were diagnosed by polysomnography, from whom fecal samples were obtained and analyzed for the microbiome composition by variable regions 3-4 of 16S rRNA pyrosequencing and bioinformatic analyses. We examined blood cytokines level of all subjects. Three enterotypes Bacteroides (n=73), Ruminococcus (n=14), and Prevotella (n=26) were identified. Central apnea indices, mixed apnea indices, N1 sleep stage, mean apnea-hypopnea duration, and arousal indices were increased in apnea-hypopnea indices (AHI) [≥]15 patients with the Prevotella enterotype. However, for AHI<15 subjects, obstructive apnea indices and systolic blood pressure were significantly observed in Ruminococcus and Prevotella enterotypes, respectively. The present study indicates the possibility of pathophysiological interplay between enterotypes and sleep structure disruption in sleep apnea through a microbiota-gut-brain axis and offers some new insight toward the pathogenesis of OSAHS.\n\nImportanceIntermittent hypoxia (IH) and sleep fragmentation (SF) are hallmarks of are the predominant mechanism underlying obstructive sleep apnea/hypopnea syndrome (OSAHS). Moreover, IH and SF of pathophysiological roles in the gut microbiota dysbiosis in OSAHS have been demonstrated. We hypothesized that gut microbiota disruption may cross-talk the brain function via microbiota-gut-brain axis. Indeed, we observed central apnea indices and other parameters of disturbances during sleep were significantly elevated in AHI[≥]15 patients with the Prevotella enterotype. This enterotype prone to endotoxin production, driving systemic inflammation, ultimately contributes to OSAHS-linked comorbidities. Vice versa, increasing the arousal index leads to systemic inflammatory changes and accompanies metabolic dysfunction. We highlight that the possibility that the microbiota-gut-brain axis operates a bidirectional effect on the development of OSAHS pathology.

microbiology↗

bioRxiv2018

Nuclear Tau modulates VGluT1 expression: a new function for Tau

Summary\n\nTau displacement from microtubules is the first step in the onset of tauopathies, and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and DNA-bound fractions. We show that nuclear Tau regulates the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Impeding Tau/tubulin interaction in the cytosol favours its nuclear translocation and increases VGluT1 expression. Remarkably, the P301L mutation impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration.

molecular biology↗

bioRxiv2018

Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease

A variety of Alzheimers disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid {beta} (A{beta}) and forming plaques However, the degree to which these models mimic spatiotemporal patterns of A{beta} deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of A{beta} plaques across ages in three APP-overexpression mouse lines (APP/PS1, Tg2576, hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial 2-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; e.g., the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional A{beta} deposition patterns described in AD.

neuroscience↗

bioRxiv2018

22kHz and 55kHz ultrasonic vocalizations differentially influence neural and behavioral outcomes: Implications for modeling anxiety via auditory stimuli in the rat

The communicative role of ultrasonic vocalizations (USVs) in rodents is well established, with distinct USVs indicative of different affective states. USVs in the 22kHz range are typically emitted by adult rats when in anxiety-or fear-provoking situations (e.g. predator odor, social defeat), while 55kHz range USVs are emitted in appetitive situations (e.g., play, anticipation of reward). Previous work indicates that USVs (real-time and playback) can effectively communicate these affective states and influence changes in behavior and neural activity of the receiver. Changes in cFos activation following 22kHz USVs have been seen in cortical and limbic regions involved in anxiety, including the basolateral amygdala (BLA). However, it is unknown how USV playback influences cFos activity within the basal nucleus of the stria terminalis (BNST), a region also thought to be critical in processing anxiety-related information. The present work sought to characterize distinct behavioral, physiological, and neural responses in rats presented with aversive (22kHz) compared to appetitive (55kHz) USVs or silence. Our findings show that rats exposed to 22kHz USVs: 1) engage in anxiety-like behaviors in the open field and elevated zero maze, and 2) show distinct patterns of cFos activation within the BLA and BNST that contrast those seen in 55kHz playback. Specifically, 22kHz USVs increased cFos density in the anterodorsal nuclei, while 55kHz playback increased cFos in the oval nucleus of the BNST. These results provide important groundwork for leveraging ethologically-relevant stimuli in the rat to improve our understanding of anxiety-related responses in both typical and pathological populations.

neuroscience↗

bioRxiv2018

Network analysis of lymphocyte nucleus staining image

Background: A complex network has been studied and applied in various disciplines. As network analysis and image processing are based on matrices, this research analysed the changes in the chromatin image of lymphocyte nuclei in peripheral blood of humans using a network motif and static features (static parameters), so as to complete image classification with network method.\n\nMethods: Image processing technology was used to establish a chromatin image network of a cell nucleus; Network analysis tool Pajek was used to display the special motif of an isolated structural hole with different symmetric line values; afterwards, the frequency of occurrence of this structural hole in patients with nasopharyngeal carcinoma and AIDS, and healthy people was computed. Then by applying the network static features as variables, the chromatin images of stained lymphocytes from the three groups of people were classified and recognised by using an extreme learning machine (ELM).\n\nResults: The frequency of occurrence of the isolated structural hole with different symmetric line values was adopted to distinguish the structures of the chromatins of peripheral blood lymphocytes in patients with nasopharyngeal carcinoma and AIDS, and healthy people. Similarly, The static features of the chromatin image network of a cell nucleus were applied to classify and recognise the morphological and structural changes in chromatins for peripheral blood lymphocytes in the three groups of people.\n\nConclusion: The surface chemical and physical characteristics, as well as the polymerisation link status of biomacromolecules such as DNA, RNA, and protein in the lymphocyte nucleus change under certain pathological conditions. The change influences the combination of small molecular staining materials and any associated biomacromolecules. Therefore, various macroscopic and microscopic changes were found in the chromatin images of the cell nucleus. The microscopic changes include the variations of the extent of staining of chromatin in the nuclei, coarseness and direction of the texture therein, the size of stained conglomerations, etc. These changes contribute to the differences in chromatin image networks among the same type of cells across the three groups. Based on this, the model can be used to classify and reorganise certain diseases. The results prove that using complex network to analyse the chromatin structure of a cell nucleus is of significance.

bioinformatics↗

bioRxiv2018

Comparative Multi-scale Hierarchical Structure of the Tail, Plantaris, and Achilles Tendons in the Rat

Rodent tendons are widely used to study human pathology, such as tendinopathy and repair, and to address fundamental physiological questions about development, growth, and remodeling. However, how the gross morphology and the multi-scale hierarchical structure of rat tendons, such as the tail, plantaris, and Achillles tendons, compare to that of human tendons are unknown. In addition, there remains disagreement about terminology and definitions. Specifically, the definition of fascicle and fiber are often dependent on the diameter size and not their characteristic features, which impairs the ability to compare across species where the size of the fiber and fascicle might change with animal size and tendon function. Thus, the objective of the study was to select a single species that is widely used for tendon research (rat) and tendons with varying mechanical functions (tail, plantaris, Achilles) to evaluate the hierarchical structure at multiple length scales. This study was designed including, histology, SEM, and confocal imaging. We confirmed that rat tendons do not contain fascicles, and thus the fiber is the largest tendon subunit in the rat. In addition, we provided a structurally-based definition of a fiber as a bundle of collagen fibrils that is surrounded by elongated cells, and this definition was supported by both histologically processed and unprocessed tendons. In all rat tendons studied, the fiber diameters were consistently 10-50 {micro}m, and this diameter appears to be conserved across larger species. Specific recommendations were made for the strengths and limitations of each rat tendon as tendon research models. Understanding the hierarchical structure of tendon can advance the design and interpretation of experiments and development of tissue engineered constructs.

bioengineering↗

bioRxiv2018

PARylation modulates stress granule assembly, phase separation, and neurotoxicity of ALS-related RNA-binding proteins

Mutations in RNA-binding proteins localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregations, which are pathological hallmarks in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of PARylation, an important PTM involved in DNA damage repair and cell death, in RNP-related neurodegeneration. We reveal that PARylation levels are a major regulator of the dynamic assembly-disassembly of RNP granules, and the disease-related RNPs such as hnRNP A1 and TDP-43 can both be PARylated and bind to PARylated proteins. We further identify the PARylation site of hnRNP A1 at K298, which controls the cytoplasmic translocation of hnRNP A1 in response to stress, as well as the PAR-binding motif (PBM) of hnRNP A1, which is required for the delivery and association of hnRNP A1 to stress granules. Moreover, we show that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, we establish that both genetic and pharmacological inhibition of PARP mitigates hnRNP A1 and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings indicate a novel and crucial role of PARylation in regulating the assembly and the dynamics of RNP granules, and dysregulation of PARylation may contribute to ALS disease pathogenesis.

neuroscience↗