PaperPlayer biorxiv pathology

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.11.246330v1?rss=1

Authors: Duran-Trio, L., Fernandes-Pires, G., Simicic, D., Grosse, J., Roux, C., Binz, P.-A., Sandi, C., Cudalbu, C., Braissant, O.

Abstract:

Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.10.244806v1?rss=1

Authors: Albrecht, T., White, S., Layton, M., Stenglein, M. D., Haley, S., Nachappa, P.

Abstract:

The wheat curl mite (WCM)-transmissible wheat streak disease complex is the most serious disease of wheat in the U.S. Great Plains. In the current study, we determined the genetic variability in WCM and mite-transmitted viruses in Colorado and identified sources of resistance in Colorado wheat germplasm to wheat streak disease complex. We identified two distinct genotypes of WCM, Type 1 and Type 2 based on the ribosomal ITS1 region. Both genotypes were found to co-exist throughout the wheat producing regions of Colorado. Analysis of the whole genome and partial coat protein sequences revealed rich diversity of wheat streak mosaic virus (WSMV) and High Plains wheat mosaic virus (HPWMoV) isolates collected from Colorado, whereas triticum mosaic virus (TriMV) showed low sequence variability. Analysis of WSMV isolates revealed two novel isolates and one that was 100% similar to a new variant of WSMV from Kansas. Interestingly, between 2-4 genotypes of all 8 RNA segments of HPWMoV were identified, which suggests new variants of emaraviruses and co-occurrence of multiple strains within host populations. Several novel viruses including mycoviruses were identified for the first time in Colorado. We found variation in WSMV resistance among wheat varieties; however a variety that harbored dual resistance to mite and WSMV had lower virus titer compared to varieties that contained single resistance gene. This suggests that pyramiding genes will ensure improved and durable resistance. Future research may be aimed at elucidating the dynamics, diversity, and distribution of the new WSMV and HPWMoV isolates and their responses to wheat genotypes.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.06.240796v1?rss=1

Authors: Yin, J., Kasper, B., Petersen, F., Yu, X.

Abstract:

SARS-CoV-2 enters into human airway epithelial cells via membrane fusion or endocytosis, and this process is dependent on ACE2, TMPRSS2, and cathepsin L. In this study, we examined the expression profiles of the three SARS-CoV-2 entry-related genes in primary human airway epithelial cells isolated from donors with different physiological and pathological backgrounds such as smoking, COPD, asthma, lung cancer, allergic rhinitis, cystic fibrosis, or viral infections. By reanalyzing 54 GEO datasets comprising transcriptomic data of 3428 samples, this study revealed that i) smoking is associated with an increased expression of ACE2 and TMPRSS2 and a decreased expression of cathepsin L; ii) infection of rhinovirus as well as poly(I:C) stimulation leads to high expression of all three SARS-CoV-2 entry-related genes; iii) expression of ACE2 and cathepsin L in nasal epithelial cells are decreased in patients with asthma and allergic rhinitis. In conclusion, this study implicates that infection of respiratory viruses, cigarette smoking and allergic respiratory diseases might affect the susceptibility to and the development of COVID-19.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.07.239806v1?rss=1

Authors: Cenaj, O., Allison, D. H. R., Imam, R., Zeck, B., Drohan, L. M., Chiriboga, L., Llewellyn, J., Liu, C. Z., Park, Y. N., Wells, R. G., Theise, N. D.

Abstract:

Bodies have "reticular networks" comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, that are continuous within and around all organs. Fibrous tissue coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently described fluid flow through such human fibrous tissues. It remains unclear whether these interstitial spaces are continuous through the body or are discontinuous, confined within individual organs. We investigated IS continuity using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. We also exploited hyaluronic acid, a macromolecular component of interstitial spaces. Both techniques demonstrate continuity of interstitial spaces within and across organ boundaries, including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest a body-wide network of fluid-filled interstitial spaces with significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.03.235630v1?rss=1

Authors: Luo, M.-H., Yang, B., Yao, Y., Wu, H., Yang, H., Ma, X.-H., Li, D., Wang, X.-Z., Huang, S.-N., Jiang, X., Cheng, S., Sun, J.-Y., Huang, Z.-L., Zhao, C., McVoy, M. A., Ahn, J.-H., Zeng, W.-B., Britt, W. J., Gong, S.

Abstract:

We previously reported that human cytomegalovirus (HCMV) utilizes the cellular protein WDR5 to facilitate capsid nuclear egress. Here, we further show that HCMV infection drives WDR5 to the perinuclear region by a mechanism that requires viral replication and intact microtubules. WDR5 accumulated in the virion assembly compartment (vAC) and co-localized with vAC markers of gamma-tubulin (g-tubulin), early endosomes, and viral vAC marker proteins pp65, pp28, and glycoprotein B (gB). WDR5 interacted with multiple virion proteins, including MCP, pp150, pp65, pIRS1, and pTRS1, which may explain the increasing WDR5 accumulation in the vAC during infection. WDR5 was then incorporated into HCMV virions and localized to the tegument layer, as demonstrated by fractionation and immune-gold electron microscopy. Thus, WDR5 is driven to the vAC and incorporated into virions, suggesting that WDR5 facilitates HCMV replication at later stage of virion assembly besides the capsid nuclear egress stage. These data highlight that WDR5 is a potential target for antiviral therapy.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.01.231639v1?rss=1

Authors: Levy, J., Haudenschild, C., Bar, C., Christensen, B., Vaickus, L.

Abstract:

Whole-slide images (WSI) are digitized representations of thin sections of stained tissue from various patient sources (biopsy, resection, exfoliation, fluid) and often exceed 100,000 pixels in any given spatial dimension. Deep learning approaches to digital pathology typically extract information from sub-images (patches) and treat the sub-images as independent entities, ignoring contributing information from vital large-scale architectural relationships. Modeling approaches that can capture higher-order dependencies between neighborhoods of tissue patches have demonstrated the potential to improve predictive accuracy while capturing the most essential slide-level information for prognosis, diagnosis and integration with other omics modalities. Here, we review two promising methods for capturing macro and micro architecture of histology images, Graph Neural Networks, which contextualize patch level information from their neighbors through message passing, and Topological Data Analysis, which distills contextual information into its essential components. We introduce a modeling framework, WSI-GTFE that integrates these two approaches in order to identify and quantify key pathogenic information pathways. To demonstrate a simple use case, we utilize these topological methods to develop a tumor invasion score to stage colon cancer.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.225532v1?rss=1

Authors: Turner, M. E., Lansing, A. P., Jeronimo, P. S., Lee, L. H., Svajger, B. A., Zelt, J. G., Petkovich, M. P., Holden, R. M., Adams, M. A.

Abstract:

Background: Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is particularly critical in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC). In the present study, the objective was to determine whether the processes involved in the development and progression of VC are also normally involved in the systemic acute response to oral phosphate. Methods: Acute circulating and physiological phosphate movement and tissue deposition was assessed in two experimental rat models of VC using radio-labelled phosphate challenge. In an adenine-induced model of CKD, VC was induced with high dietary phosphate. Animals were euthanized 2 and 6 hours after oral consumption of radiolabelled phosphate. A non-CKD model of VC was induced with 0.5ug/kg calcitriol and then withdrawn, and radiolabelled phosphate was then given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. Samples of 50 different tissues were collected to assess tissue accumulation of de novo phosphate in response the challenges. Results: Animals with CKD and VC have a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition can be traced to the calcifying vasculature. Deposition of de novo phosphate is present until at least 6 hours, which after active gut absorption. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate. The extent of new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. Conclusions: Our data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.226894v1?rss=1

Authors: Hayward, A., Skuce, P. J., McNeilly, T. N.

Abstract:

Liver fluke (Fasciola spp.) are important helminth parasites of livestock globally and cause significant reductions in health and productivity of beef cattle. Attempts to control fluke have been thwarted by the difficulty of vaccine design, the evolution of flukicide resistance, and the need to control the intermediate snail host. Mechanisms to reduce the impact of parasites on animal performance have typically focused on promoting host resistance, defined as the ability of the host to kill and remove the parasite from its system, and such strategies include improving protein nutrition or selectively breeding for resistance. Organisms, however, have another broad mechanism for mitigating the impact of parasites: they can show tolerance, defined as the ability to maintain health or performance under increasing parasite burden. Tolerance has been studied in the plant literature for over a century, but there are very few empirical studies of parasite tolerance in livestock. In this study, we used data collected from >90,000 beef cattle to estimate the impact of the severity of liver fluke infection on performance and variation in tolerance of fluke. Severity of liver fluke infection was estimated using liver fibrosis score on a scale of 0-3 and performance estimated as (1) age at slaughter and (2) daily dead weight gain. Animals with higher fibrosis scores were slaughtered around two weeks later than animals with no fluke, and gained around 10g less weight per day. There was also considerable variation in these effects of fibrosis score, such that animals from different producers and breeds varied in their tolerance of fluke infection. While breeds did not vary in the association between fibrosis and age at slaughter, there was considerable variation among producers: high fibrosis score delayed slaughter by up to 50 days in some producers, but not at all in others. Meanwhile, there was support for variation in the slope of daily dead weight gain on fibrosis score among both breeds and producers, with some unaffected by high fluke scores and some breeds and producers experiencing a 20g/day lower weight gain under high fluke scores. Our results point to the potential for both environmental and genetic variation in tolerance of liver fluke in cattle, paving the way for quantitative genetic and nutritional research into the feasibility of promoting tolerance as a disease mitigation strategy.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.224170v1?rss=1

Authors: Batarseh, A. M., Vafaee, F., Hosseini-Beheshti, E., Chen, A., Cohen, A., Juillard, A., Hunt, N. H., Mariani, M., Mitchell, T., Grau, G. E. R.

Abstract:

Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms, which include an excessive release of microvesicles (MV). Plasma MV levels have been found elevated in CM patients and in the experimental mouse model. We compared lipid profiles in circulating MV purified from CBA mice infected with P. berghei ANKA (PbA), which causes CM, to those from P. yoelii (Py), which does not. Here we show that plasma MV produced at the time of CM differed dramatically from those from non-CM mice, in spite of identical levels of parasitaemia. Using high-resolution LCMS, we identified over 300 lipid species within 12 lipid classes. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to uninfected mice, while they were unchanged in Py MV, and lysophosphatidylcholine (LPC) was more significantly reduced in PbA mice compared to the other two groups. These results suggest, for the time, that experimental CM is characterised by specific changes in lipid composition of circulating MV, pointing towards triglycerides (TG) especially docosahexaenoic acid (DHA 22:6) containing species, phosphatidylethanolamine (PE), LPC, LPE, and diacylglycerol (DG) as potential important players in CM pathogenesis.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.218115v1?rss=1

Authors: Gheberemedhin, A., Salam, A. B., Adu-Addai, B., Noonan, S., Stratton, R., Ahmed, M. S. U., khantwal, C., Martin, G., Huixian, L., Andrews, C., Balasubramanyam, K., Udo, R., Henry, L., Jaynes, J., Yates, C.

Abstract:

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro , resulting in a time-dependent decrease in CD206 expression , and a transient increase in M1 marker TNF, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-{beta}1 and -SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNF, IL-6, IL-10, INF-{gamma}, CXCL1/2, and fibrosis markers TGF-{beta}1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

Copy rights belong to original authors. Visit the link for more info