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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 65,094 bioRxiv papers from 288,491 authors.

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in category pathology

323 results found. For more information, click each entry to expand.

301: Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment
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Posted to bioRxiv 24 Sep 2019

Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment
100 downloads pathology

Sean K Ryan, Michael V Gonzalez, James P Garifallou, Frederick C Bennett, Kimberly S Williams, Hakon K Hakonarson, Stewart A Anderson, Kelly L Jordan-Sciutto

HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals worldwide, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive. We developed a human-induced pluripotent stem cell (HiPSC) based model; whereby, we independently differentiate HiPSCs into neurons, astrocytes, and microglia and systematically combine to generate a tri-culture with or without HIV-infection and ART. scRNAseq analysis on tri-cultures including HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Remarkably, EFZ alone induced a similar response to infection. Treatment with the antiretroviral compound Efavirenz (EFZ) mostly resolved these signatures; However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in TNFa expression. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of HIV infection and its treatment with antiretrovirals.

302: Modelling Inoculum Availability of Plurivorosphaerella nawae in Persimmon Leaf Litter with Bayesian Beta Regression
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Posted to bioRxiv 18 Sep 2019

Modelling Inoculum Availability of Plurivorosphaerella nawae in Persimmon Leaf Litter with Bayesian Beta Regression
99 downloads pathology

Joaquin Martinez-Minaya, David Conesa, Antonio Lopez-Quilez, Jose Luis Mira, Antonio Vicent

Circular leaf spot (CLS), caused by Plurivorosphaerella nawae, is a serious disease of persimmon (Diospyros kaki) inducing necrotic lesions on leaves, defoliation and fruit drop. Under Mediterranean conditions, P. nawae forms pseudothecia in the leaf litter during winter and ascospores are released in spring infecting susceptible leaves. Persimmon growers are advised to apply fungicides for CLS control during the period of inoculum availability, which was defined based on ascospore counts under the microscope. A model of inoculum availability of P. nawae was developed and evaluated as an alternative to ascospore counts. Leaf litter samples were collected weekly in L'Alcudia from 2010 to 2015. Leaves were soaked, placed in a wind tunnel, and released ascospores of P. nawae were counted. Hierarchical Bayesian beta regression methods were used to fit the dynamics of ascospore production in the leaf litter. The selected model, having the lowest values of DIC, WAIC and LCPO, included accumulated degree days (ADD) and ADD taking into account the vapor pressure deficit (ADDvpd) as fixed effects, and year as a random effect. This model had a MAE of 0.042 and RMSE of 0.062. The beta regression model was evaluated in four orchards for different years from 2010 to 2015. Higher accuracy was obtained at the beginning and the end of the ascospore production period, which are the events of interest to schedule fungicide sprays for CLS control in Spain. This same modelling framework can be extended to other fungal plant pathogens whose inoculum dynamics are expressed as proportion data.

303: The Effects of Leukocyte- and Platelet-Rich Plasma (L-Prp) and Pure Platelet-Rich Plasma (P-Prp) an a Rat Endometriosis Model
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Posted to bioRxiv 11 Oct 2019

The Effects of Leukocyte- and Platelet-Rich Plasma (L-Prp) and Pure Platelet-Rich Plasma (P-Prp) an a Rat Endometriosis Model
99 downloads pathology

Ali Doğukan Anğın, ismet gün, önder sakin, muzaffer seyhan çıkman, Zehra Meltem Pirimoğlu, ahmet kale, kayhan başak, Pınar Kaygın, serpil oğuztüzün

Our aim was to investigate the effect of platelet-rich plasma (PRP) derivatives, which can be produced from the patient’s own blood and have minimal side effects, on endometriosis. To the best of our knowledge, this is the first study in the literature that studies the relationship between PRP and endometriosis. Endometriosis foci were created in the first operation. In the second operation (30 th day) groups were formed. Group 1 (n= 8) was administered saline, group 2 (n= 7) leukocyte- and platelet-rich plasma (L-PRP), and group 3 (n= 8) pure platelet-rich plasma (P-PRP). Group 4 (n= 10) was used to obtain PRP. In the last operation (60 th day), the endometriotic foci were measured, and then excised. There was no statistically significant difference between the pre and post volumes of the endometriotic foci, between their volume differences and volume difference rates (p > .05). However, it was observed that existing implant volumes in all groups decreased statistically significantly within their own groups by the end of the experiment compared to the previous volumes (p < .05). When the implants were assessed through histopathological scoring in terms of edema, vascular congestion, inflammatory cell infiltration, hemorrhage, epithelial line, and hemosiderin accumulation and immunohistochemical staining in terms of VEGF, there was no significant difference in the comparison between the groups. Although L-PRP and P-PRP generated more reduction in the endometriosis foci, they did not create any statistical differences.

304: Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson's disease
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Posted to bioRxiv 31 Jul 2019

Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson's disease
97 downloads pathology

Nelson Leung-sang Tang, Joannie Hui, Dan Huang, Man Fung Tang, Xingyan Wang, Junyi Wu, Iris Chan, Ting-fan Leung

Background: With spot urine collected from a large control sample of preschool children (aged 3-7 years), reference range of spot urine copper excretion indexes and their biological variation were defined. Methods: In order to investigate their test performance in screening of Wilson disease in this age group, multiple spot urine samples from 6 WD patients diagnosed at presymptomatic stage were analysed. Cut-off values for spot urine copper concentration, copper to creatinine ratio and copper to osmolality ratio at 0.5 umol/L, 0.1 umol/mmol and 0.00085 umol/mOsmol (32 ug/L, 56 ug/g creatinine and 0.054 ug/mOsmol, respectively, in conventional units) have potential application in differentiation of WD patients. Results: The data provides a new insight that the inter-individual variation of spot urine copper indexes (CVg) were moderate with figures around 60% which was similar to other clinically useful urine tests, such as urine albumin excretion ratio. Spot urine copper excretion strongly correlated with both urine creatinine and osmolality. And more than 95% of data points in health preschool children fell within prediction regions by linear regression suggesting a good utility of normalisation by these 2 analytes. Receiver operator curve (ROC) showed that copper to osmolality ratio was the best index with an area under curve (AUC) greater than 0.98. Conclusions: Based on the data, a new WD screening time window targeting preschool children is proposed. Application of a bivariate screening strategy using spot urine copper concentration and urine osmolality may be useful in a population screening program for preschool children.

305: Accuracy of serological tests for diagnosis of chronic pulmonary aspergillosis: a systematic review and meta-analysis
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Posted to bioRxiv 09 Sep 2019

Accuracy of serological tests for diagnosis of chronic pulmonary aspergillosis: a systematic review and meta-analysis
95 downloads pathology

CLÁUDIA ELIZABETH VOLPE CHAVES, SANDRA MARIA DO VALLE LEONE DE OLIVEIRA, JAMES VENTURINI, ANTONIO JOSE GRANDE, TATIANE FERNANDA SYLVESTRE, RINALDO PONCIO MENDES, ANAMARIA MELLO MIRANDA PANIAGO

Chronic pulmonary aspergillosis (CPA) is a disease that benefits from cavities as after-effects of tuberculosis, presenting a high mortality rate. Serological tests like double agar gel immunodiffusion test (DID) or the counterimmunoelectrophoresis (CIE) test have been routinely used for CPA diagnosis in the absence of positive cultures; however, they have been replaced by enzyme-linked immunoassay (ELISA), with a variety of methods. This systematic review aims to compare the accuracy of the ELISA test with the reference test (DID and/or CIE) in CPA diagnosis. It was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). The study was registered in PROSPERO under the registration number CRD42016046057. We searched the electronic databases MEDLINE (PubMed), EMBASE (Elsevier), LILACS (VHL), Cochrane library, and ISI Web of Science. Gray literature was researched in Google Scholars and conference abstracts. We included articles with patients or serum samples from CPA patients who underwent two serological tests: ELISA (index test) and IDD and/or CIE (reference test), using the accuracy of the tests as a result. Original articles were considered without a restriction of date or language. The pooled sensitivity, specificity, and summary receiver operating characteristic curves were estimated. We included 13 studies in the review, but only four studies were included in the meta-analysis. The pooled sensitivities and specificities were 0.93 and 0.97 for the ELISA test. For the reference test (DID and/or CIE), these values were 0.64 and 0.99. Analyses of summary receiver operating characteristic curves yielded 0.99 for ELISA and 0.99 for the reference test (DID and/or CIE). Our meta-analysis suggests that the diagnostic accuracy of ELISA is greater than that of the reference tests (DID and/or CIE) in early detection of CPA .

306: Monodelphis domestica as a fetal intra-cerebral inoculation model for Zika virus pathogenesis
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Posted to bioRxiv 27 Sep 2019

Monodelphis domestica as a fetal intra-cerebral inoculation model for Zika virus pathogenesis
95 downloads pathology

John M. Thomas, Juan Garcia, Matthew Terry, Ileana Lozano, Susan Mahaney, Oscar Quintanilla, Dionn Carlo-Silva, Marisol Morales, John VandeBerg

Monodelphis domestica , also known as the laboratory opossum, is a marsupial native to South America.  At birth, these animals are developmentally equivalent to human embryos at approximately 5 weeks of gestation which, when coupled with other characteristics including the size of the animals, the development of a robust immune system during juvenile development, and the relative ease of experimental manipulation, have made M. domestica a valuable model in many areas of biomedical research.  However, their suitability as models for infectious diseases, especially diseases caused by viruses such as Zika virus (ZIKV), is currently unknown.  Here, we describe the replicative effects of ZIKV using a fetal intra-cerebral model of inoculation.  Using immunohistochemistry and in situ hybridization, we found that opossum embryos and fetuses are susceptible to infection by ZIKV administered intra-cerebrally, that the infection persists long term, and that the infection and viral replication consistently results in neural pathology and may occasionally result in global growth restriction.  These results demonstrate the utility of M. domestica as a new animal model for investigating ZIKV infection in vivo. This new model will facilitate further inquiry into viral pathogenesis, particularly for those viruses that are neurotropic, that may require a host with the ability to support sustained viral infection, and/or that may require intra-cerebral inoculations of large numbers of embryos or fetuses.

307: Effects of Shift-Work on the Carotid Artery and Cerebral Blood Flow of SHR Rats and WKY Rats
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Posted to bioRxiv 20 Aug 2019

Effects of Shift-Work on the Carotid Artery and Cerebral Blood Flow of SHR Rats and WKY Rats
90 downloads pathology

Yunlei Wang, Tong Zhang, YuGe Zhang, Yan Yu, Fan Bai, HaoJie Zhang, YaFei Chi, Shan Gao

Objective: The objective was to investigate the effects of shift-work (SW) on the carotid arteries. Methods: This study used two inverted photoperiods (inverted light:dark [ILD]16:8 and ILD12:12) to create the SW model. We recorded the rhythm and performed serological tests, carotid ultrasound, magnetic resonance imaging, and carotid biopsy. Results: SW induced elevated blood pressure and increased angiotensin-II, apolipoprotein E, blood glucose, and triglycerides. SW increased the carotid intima-media thickness. SW led to the development of carotid arterial thrombosis, reduced cerebral blood flow, and increased the number of collagen fibers, expression of angiotensin receptor and low-density lipoprotein receptor in the carotid arteries. SW decreased 3-hydroxy-3-methylglutaryl-CoA reductase and nitric oxide. SW induced the atherosclerotic plaque in the aorta. Multiple results of SHR were worse than WKY rats. Conclusion: SW can induce metabolic disorders and elevated blood pressure. SW can cause intima-media thickening of the carotid artery and aorta atherosclerosis. SW may result in carotid arterial thrombosis and affect cerebral blood flow. Hypertension can aggravate the adverse effects of SW. Keywords: shift-work, hypertension, metabolic disorders, thrombosis, atherosclerosis

308: MicroRNA and Gene Expression Analysis on Placenta Tissue: An Approach to Understanding Obstetric Antiphospholipid Syndrome at the Molecular Level
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Posted to bioRxiv 23 Sep 2019

MicroRNA and Gene Expression Analysis on Placenta Tissue: An Approach to Understanding Obstetric Antiphospholipid Syndrome at the Molecular Level
90 downloads pathology

ahmad asnawi Binti asral wirda, Muhammad Aliff Mohamad, Nur Fariha Binti Mohd Manzor, Muhammad Shazwan Suhiman, Jameela Sathar, Hayati Binti Abdul Rahman, Maiza Binti Masri, Nur Syahrina Binti Abdul Rahim, Nazefah Binti Abdul Hamid, Nor Nadeeya Binti Mohamad

Obstetric antiphospholipid syndrome is initiated by the action of antiphospholipid antibodies on placenta. The characteristics of APS in pregnancy include vascular thrombosis, inflammation and impairment of trophoblast implantation. MicroRNA (miRNA) expression has been suggested as one of the genetic factors that contribute to the development of this syndrome. miRNAs regulate gene expressions in a vast assortment of cellular biological mechanisms include the development of placental tissue. Hence, further investigation on the regulation of placental miRNA in APS is required. In this study, we aimed to profile miRNA expressions from placenta tissue of patients with APS. Differentially expressed miRNAs were determined for its targeted genes and pathways. Agilent microarray platform was used to measure placental microRNA expressions between normal placental tissue and those obtained from patients with APS. Differentially expressed miRNAs were detected using GeneSpring GX software 14.2 and sequences were mapped using TargetScan software to generate the predicted target genes. Pathway analysis for the genes was then performed on PANTHER and REACTOME software. Selected miRNAs and their associated genes of interest were validated using qPCR. Microarray findings revealed, 9 downregulated and 21 upregulated miRNAs expressed in placenta of patients with APS. Quantitative expressions of 3 selected miRNAs were in agreement with the microarray findings, however only miR-525-5p expression was statistically significant. Pathway analysis revealed that the targeted genes of differentially expressed miRNAs were involved in several hypothesized signalling pathways such as the vascular endothelial (VE) growth factor (VEGF) and inflammatory pathways. VE-cadherin, ras homolog member A (RHOA) and tyrosine kinase receptor (KIT) showed significant downregulation from the qPCR data while retinoblastoma gene (RET), dual specificity protein phosphatase 10 (DUSP10) and B-lymphocyte kinase (BLK) were significantly upregulated. These preliminary findings suggest the involvement of miRNAs and identified novel associated genes involvement in the mechanism of obstetric APS, particularly through the alteration of vascular-associated regulators and the inflammatory signalling cascade.

309: Cathepsin G Degrades Synovial Fluid Lubricin: Relevance For Osteoarthritis Pathogenesis
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Posted to bioRxiv 15 Oct 2019

Cathepsin G Degrades Synovial Fluid Lubricin: Relevance For Osteoarthritis Pathogenesis
89 downloads pathology

Shan Huang, Kristina A. Thomsson, Chunsheng Jin, Sally Alweddi, Andre Struglics, Ola Rolfson, Lena I Bjorkman, Sebastian Kalamajsk, Tannin A. Schmidt, Gregory D. Jay, Roman Krawetz, Niclas G. Karlsson, Thomas Eisler

Lubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff in gels, and with proteomics. Full length lubricin (~300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (~250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in different domains of lubricin. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the lubrication of OA joints.

310: Does skin surface temperature variation account for Buruli ulcer lesion distribution?
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Posted to bioRxiv 06 Sep 2019

Does skin surface temperature variation account for Buruli ulcer lesion distribution?
89 downloads pathology

Nicola Kate Sexton-Oates, Andrew Stewardson, Arvind Yerramilli, Paul Johnson

Background Buruli ulcer is a necrotising infection of skin and soft tissue caused by Mycobacterium ulcerans (M. ulcerans). Buruli ulcer most often occurs on limbs, and it is hypothesized this is explained by direct exposure to the environment. However, even on exposed areas Buruli ulcer is not randomly distributed. M. ulcerans prefers an in vitro temperature of 30-33°C and growth is inhibited at higher temperatures. This study investigated whether variations in skin surface temperature distribution in healthy volunteers could partly account for Buruli ulcer lesion distribution. Methodology/Principal Findings In this observational study, a thermal camera (FLIR E8) was used to measure skin surface temperature at the sternal notch and at 44 predetermined locations on the limbs of 18 human participants. Body locations of high, middle and low Buruli ulcer incidence were identified from existing density maps of lesion distribution. Skin temperature of the three incidence location groups were compared, and differences in age and sex groups were also analysed. We found an inverse relationship between skin temperature and lesion distribution, where high incidence locations were significantly cooler and low incidence locations significantly warmer (Kruskal-Wallis test p<0.0001). Linear mixed effects regression analysis estimated that skin surface temperature accounts for 9.5% of the variance in Buruli ulcer lesion distribution (marginal R-squared = 0.095). Men had warmer upper and lower limbs than females (Mann-Whitney U test p=0.0003 and p<0.0001 respectively). Conclusions/Significance We have found an inverse relationship between skin temperature and Buruli ulcer lesion distribution, however this association is weak. Additional unknown factors are likely to be involved that explain the majority of the variation in Buruli lesion distribution.

311: First description of the sexual stage of Venturia effusa, causal agent of pecan scab
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Posted to bioRxiv 30 Sep 2019

First description of the sexual stage of Venturia effusa, causal agent of pecan scab
86 downloads pathology

Nikki D Charlton, Mihwa Yi, Clive H Bock, Minling Zhang, Carolyn Young

Venturia effusa , cause of pecan scab, is the most prevalent disease of pecan in the southeastern USA; epidemics of the disease regularly result in economic losses to the pecan industry. Recent characterization of the mating type distribution revealed the frequency of the MAT idiomorphs are in equilibrium at various spatial scales, indicative of regular sexual recombination. However, the occurrence of the sexual stage of V. effusa has never been observed, and the pathogen was previously believed to rely entirely on asexual reproduction. To explore the existence of a sexual cycle, we paired opposite mating types on oatmeal culture media. In initial experiments, cultures were incubated at 24 C for 2 mo for hyphal interactions to occur between mating types and then maintained at 4 C for 4 mo. Immature pseudothecia were initially observed but following exposure to a 12 h photoperiod for 2 weeks at 24 C, asci and ascospores developed. Further experiments explored the effect of time on pseudothecial development with 4 mo at 4 C as the optimal requirement. The results of this study demonstrate the heterothallic nature of V. effusa . Following experiments investigated progeny from a sexual cross of an albino and a wild-type isolate. Evaluation of isolate pigmentation, mating type, and multilocus genotyping of single ascospore progeny provided evidence that recombination occurred within the sexual crosses. The impact of determining the source of the overwintering ascostroma will aid in management decisions to reduce the primary inoculum in the disease cycle.

312: New North American isolates of Venturia inaequalis can overcome apple scab resistance of Malus floribunda 821
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Posted to bioRxiv 07 Oct 2019

New North American isolates of Venturia inaequalis can overcome apple scab resistance of Malus floribunda 821
83 downloads pathology

David Papp, Jugpreet Singh, David Gadoury, Awais Khan

Apple scab, caused by Venturia inaequalis (Cke.) Wint., is a destructive fungal disease of major apple cultivars worldwide, most of which are moderately to highly susceptible. Thus, development of scab resistant cultivars is one of the highest priorities of apple breeding programs. The principal source of resistance for breeding programs has been the scab resistance gene Rvi6 that originated from the Japanese crabapple Malus floribunda (Sieb.) sel. 821. Isolates of V. inaequalis able to overcome Rvi6 have been identified in Europe, but have not yet been reported on the American continents. We recently discovered scab infection on M. floribunda 821 trees in a research orchard at Geneva, New York, USA, where approximately 10% of the leaves bore profusely sporulating apple scab lesions, many of which had coalesced to cover entire leaves. Chlorosis and pinpoint pitting symptoms typical of failed infections by V. inaequalis on hosts bearing the Rvi6 and Rvi7 genes were also observed. We assessed genetic diversity and population genetic structure of six V. inaequalis isolates collected from M. floribunda 821, one isolate from 'Nova Easygro', one isolate from 'Golden Delicious' and two isolates from Europe (11 isolates in total) using 16,321 genome-wide SNPs. Population genetic structure and PCA separated the isolates into distinct European and USA groups. The forgoing suggests that the new Rvi6 virulent isolates emerged within USA populations, rather than being transported from Europe. The overcoming of resistance in M. floribunda 821 but not in descendant cultivars suggests that durable resistance to apple scab will require a more comprehensive understanding of Rvi6 mediated resistance in diverse genetic backgrounds.

313: Unmasking the tissue microecology of ductal carcinoma in situ with deep learning
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Posted to bioRxiv 28 Oct 2019

Unmasking the tissue microecology of ductal carcinoma in situ with deep learning
83 downloads pathology

Priya Lakshmi Narayanan, Shan E Ahmed Raza, Allison Hall, Jeffrey R. Marks, Lorraine King, Robert B West, Lucia Hernandez, Mitchell Dowsett, Barry Gusterson, Carlo Maley, Shelley E Hwang, Yinyin Yuan

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial distribution pattern surrounding ductal carcinoma in situ (DCIS) and its association with progression is not well understood. To characterize the tissue microecology of DCIS, we designed and tested a new deep learning pipeline, UNMaSk (UNet-IM-Net-SCCNN), for the automated detection and simultaneous segmentation of DCIS ducts. This new method achieved the highest sensitivity and recall over cutting-edge deep learning networks in three patient cohorts, as well as the highest concordance with DCIS identification based on CK5 staining. Following automated DCIS detection, spatial tessellation centred at each DCIS duct created the boundary in which local ecology can be studied. Single cell identification and classification was performed with an existing deep learning method to map the distribution of TILs. In a dataset comprising grade 2-3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, TILs co-localise significantly less with DCIS ducts in pure DCIS compared with adjacent DCIS, suggesting a more inflamed tissue ecology local to adjacent DCIS cases. Our experiments demonstrate that technological developments in deep convolutional neural networks and digital pathology can enable us to automate the identification of DCIS as well as to quantify the spatial relationship with TILs, providing a new way to study immune response and identify new markers of progression, thereby improving clinical management.

314: Protein Quality Control is a Risk Factor and Therapeutic Target in Toxin-Induced Biliary Atresia
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Posted to bioRxiv 29 Oct 2019

Protein Quality Control is a Risk Factor and Therapeutic Target in Toxin-Induced Biliary Atresia
66 downloads pathology

Xiao Zhao, Kristin Lorent, Diana Escobar-Zarate, Ramakrishnan Rajagopalan, Kathleen Loomes, Kevin Gillespie, Clementina Mesaros, Michelle Estrada, Ian Blair, Jeffrey Winkler, Nancy Spinner, Marcella Devoto, Michael Pack

Extra-hepatic biliary atresia (BA) is an important pediatric liver disease of unknown etiology. The identification of biliatresone, a plant electrophile with selective toxicity for extra-hepatic cholangiocytes (EHC) and linked to outbreaks of epidemic BA in livestock, demonstrated the feasibility of an environmental trigger for this enigmatic condition. Here, we show that susceptibility of zebrafish EHC to biliatresone arises from their inability to restore stress-induced depletion of glutathione, and that heterozygous mutations in glutathione metabolism genes differentially sensitize EHC and the normally resistant intra-hepatic cholangiocytes (IHC) to biliatresone-mediated injury. Collectively these findings argue that genetic variants in stress-response genes could be risk factors for human BA. Supporting this idea, we identified de novo loss-of-function mutations in the STIP1 and REV1 gene, both part of the HSP90 pathway, in two children with BA, respectively, and showed that modulation of their expression sensitized zebrafish larvae and human cholangiocytes to biliatresone. Using an in vivo drug screening assay, we identified activators of cGMP signaling as potent enhancers of the anti-oxidant N-acetylcysteine (NAC) in biliatresone-treated larvae and human cholangiocytes that act independently of glutathione and upstream of chaperone-mediated protein quality control (PQC) pathways. Collectively, these data highlighted novel aspects of cholangiocyte injury responses, identified new genetic risk factors for BA, and suggest combined treatment with NAC and cGMP signaling modulators as a rational therapeutic strategy for BA.

315: TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species
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Posted to bioRxiv 17 Oct 2019

TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species
65 downloads pathology

Bin Li, Zhixin Wan, Zhenglei Wang, Jiakun Zuo, Yuanyuan Xu, Xiangan Han, Vanhnaseng Phouthapane, Jinfeng Miao

Mastitis caused by Streptococcus uberis is a hazardous clinical disease in dairy animals. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2-/- and TLR4-/- mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage and bacterial count in mammary glands. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen species (mROS) to assist host control of secretion of inflammatory factors and elimination of intracellular S. uberis. Our results demonstrate that TLR2-mediated mROS have a significant effect on S. uberis-induced host defense responses in mammary glands as well as MECs.

316: Meniscal and ligament modifications in spontaneous and post-traumatic mouse models of osteoarthritis
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Posted to bioRxiv 24 Oct 2019

Meniscal and ligament modifications in spontaneous and post-traumatic mouse models of osteoarthritis
65 downloads pathology

Lorenzo Ramos-Mucci, Behzad Javaheri, Rob van 't Hof, George Bou-Gharios, Andrew A Pitsillides, Eithne Comerford, Blandine Poulet

Osteoarthritis (OA) is a whole joint disease that affects all joint tissues, with changes in the articular cartilage (AC), subchondral bone and synovium. Pathologies in menisci and ligaments, however, are rarely analysed, although both are known to play vital roles in the mechanical stability of the joint. The aim of our study was to describe the pathological changes in menisci and ligament during disease development in murine spontaneous and post-traumatic surgically-induced OA and to quantify tissue mineralisation in the joint space using microCT imaging during OA progression. Knees of Str/ort mice (spontaneous OA model; 26-40wks) and C57CBA F1 mice following destabilisation of medial meniscus (DMM) surgery (post-traumatic OA model; 8wks after DMM), were used to assess histological meniscal and ligament pathologies. Joint space mineralised tissue volume was quantified by microCT. Meniscal pathological changes in Str/ort mouse knees were associated with articular cartilage lesion severity. These meniscal changes included ossification, hyperplasia, cell hypertrophy, collagen type II deposition and SOX9 expression in the fibrous region near the attachment to the knee joint capsule. Anterior cruciate ligaments exhibited extracellular matrix changes and chondrogenesis particularly at the tibial attachment site, and ossification was seen in collateral ligaments. Similar changes were confirmed in the post-traumatic DMM model. microCT analysis showed increased joint space mineralised tissue volume with OA progression in both the post-traumatic and spontaneous OA models. Modifications in meniscal and ligament mineralisation and chondrogenesis are seen with overt AC degeneration in murine OA. Although the aetiology and the consequences of such changes remain unknown, they will influence stability and load transmission of the joint and may therefore contribute to OA progression. In addition, these changes may have important roles in movement restriction and pain, which represent major human clinical symptoms of OA. Description of such soft tissue changes, in addition to AC degradation, should be an important aspect of future studies in mouse models in order to furnish a more complete understanding of OA pathogenesis.

317: Heart rate variability as an indicator of autonomic nervous system disturbance in tetanus
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Posted to bioRxiv 04 Oct 2019

Heart rate variability as an indicator of autonomic nervous system disturbance in tetanus
64 downloads pathology

Ha Thi Hai Duong, Girmaw Abebe Tadesse, Phung Tran Huy Nhat, Nguyen Van Hao, John Prince, Tran Duc Duong, Trinh Trung Kien, Le Van Tan, Chris Pugh, Huynh Thi Loan, Chau Nguyen, Lam Minh Yen, Tingting Zhu, David Clifton, C Louise Thwaites

Autonomic nervous system dysfunction (ANSD) is a significant cause of mortality in tetanus. Currently diagnosis relies on non-specific clinical signs. Heart rate variability (HRV) may indicate underlying autonomic nervous system activity and represents a potentially valuable non-invasive tool for ANSD diagnosis in tetanus. HRV was measured from 3 5-minute ECG recordings during a 24-hour period in a cohort patients with severe tetanus, all receiving mechanical ventilation. HRV measurements from all subjects - 5 with ANSD (Ablett Grade 4) and 4 patients without ANSD (Ablett Grade 3) - showed HRV was lower than reported ranges for healthy individuals. Comparing different severities of tetanus, raw data for both time and frequency measurements of HRV were reduced in those with ANSD compared to those without. Differences were statistically significant in all except root mean square standard deviation RMSSD (p=0.07) indicating HRV may be a valuable tool in ANSD diagnosis.

318: Inter-reader agreement of 18F-FDG PET/CT for the quantification of carotid artery plaque inflammation
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Posted to bioRxiv 16 Oct 2019

Inter-reader agreement of 18F-FDG PET/CT for the quantification of carotid artery plaque inflammation
63 downloads pathology

Kjersti Johnsrud, Therese Seierstad, David Russell, Mona-Elisabeth Revheim

Background : A significant proportion of ischemic strokes are caused by emboli from unstable atherosclerotic carotid artery plaques with inflammation being a key feature of plaque instability and stroke risk. Positron emission tomography (PET) depicting the uptake of 2-deoxy-2-( 18 F)-fluoro-D-glucose ( 18 F-FDG) in carotid artery plaques is a promising technique to quantify plaque inflammation. A consensus on the methodology for plaque localization and quantification of inflammation by 18 F-FDG PET/computed tomography (CT) in atherosclerosis has not been established. High inter-reader agreement is essential if 18 F-FDG PET/CT is to be used as a clinical tool for the assessment of unstable plaques and stroke risk. The aim of our study was to assess the inter-reader variability of different methods for quantification of 18 F-FDG uptake in carotid atherosclerotic plaques with a separate CT angiography (CTA) providing anatomical guidance. Methods and results: Forty-three patients with carotid artery stenosis ≥70% underwent 18 F-FDG PET/CT. Two independent readers separately delineated the plaque in all axial PET slices containing the atherosclerotic plaque and the maximum standardized uptake value (SUV max ) from each slice was measured. Uptake values with and without background correction were calculated. Intraclass correlation coefficients were highest for uncorrected uptake values (0.97-0.98) followed by those background corrected by subtraction (0.89-0.94) and lowest for those background corrected by division (0.74-0.79). There was a significant difference between the two readers definition of plaque extension, but this did not affect the inter-reader agreement of the uptake parameters. Conclusions : Quantification methods without background correction have the highest inter-reader agreement for 18 F-FDG PET of carotid artery plaque inflammation. The use of the single highest uptake value (max SUV max ) from the plaque will facilitate the method’s clinical utility in stroke prevention.

319: Micro-electrode in vivo signatures of human periventricular heterotopia
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Posted to bioRxiv 24 Oct 2019

Micro-electrode in vivo signatures of human periventricular heterotopia
62 downloads pathology

Valerio Frazzini, Stephen Whitmarsh, Virginie Lambrecq, Katia Lehongre, Pierre Yger, Bertrand Mathon, Claude Adam, Dominique Hasboun, Vincent Navarro

Periventricular nodular heterotopia (PNH) is a common cause of drug-resistant epilepsy, characterized by nodules of ectopic neurons adjacent to the lateral ventricles. While ectopic neurons are suspected to be involved in epileptogenesis, their long-term in vivo recording in epileptic patients has so far been lacking. We report the first multi-level analysis of long-term microelectrode recordings from three nodules in two epileptic patients during presurgical evaluation. In both patients, seizures originated from the ectopic nodules. Highly consistent interictal activities were identified from microelectrodes: 1) trains of periodic slow waves , 2) isolated slow deflections, both with superimposed fast activity , and 3) epileptic spikes. Patterns were highly local and largely invisible on the adjacent macro-electrode contacts. Extracellular action potential analyses showed that the majority of units were strongly modulated during all interictal patterns. We further identified, for each individual neuron, different types of firing rate modulation, corresponding to the different interictal patterns. These results are consistent with an altered regulation of cellular excitability and suggest that periodic patterns may result from fluctuation in inhibition and rebound excitation in the same neuronal network.

320: Towards Staining Independent Segmentation of Glomerulus from Histopathological Images of Kidney
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Posted to bioRxiv

Towards Staining Independent Segmentation of Glomerulus from Histopathological Images of Kidney
56 downloads pathology

Robin Liu, Lu Wang, Jim He, Wenfang Chen

This paper introduces a detection-based framework to segment glomeruli from digital scanning image of light microscopic slide of renal biopsy specimens. The proposed method aims to better use the precise localization ability of Faster R-CNN and powerful segmentation ability of U-Net. We use a detector to localize the glomeruli from whole slide image to make the segmentation only focus on the most relevant area of the image. We explored the ef-fectiveness of the network depth on its localization and segmentation ability in glomerular classification, and then propose to use the classification net-work with enhanced ability of localization and segmentation to construct and initialize a segmentation network. We also propose a weakly supervised training strategy to train the segmentation network by taking advantage of the unique morphology of the glomerulus. Both strong initialization and weakly supervised training are used to resolve the problem of insufficient and inaccurate data annotations and enhance the adaptability of the segmentation network. Experimental results demonstrate that the proposed framework is effective and robust

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