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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 83,433 bioRxiv papers from 359,611 authors.

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in category pathology

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

61: Multi-task learning of a deep k-nearest neighbour network for histopathological image classification and retrieval
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Posted to bioRxiv 06 Jun 2019

Multi-task learning of a deep k-nearest neighbour network for histopathological image classification and retrieval
655 downloads pathology

Tingying Peng, Melanie Boxberg, Wilko Weichert, Nassir Navab, Carsten Marr

Deep neural networks have achieved tremendous success in image recognition, classification and object detection. However, deep learning is often criticised for its lack of transparency and general inability to rationalize its predictions. The issue of poor model interpretability becomes critical in medical applications, as a model that is not understood and trusted by physicians is unlikely to be used in daily clinical practice. In this work, we develop a novel multi-task deep learning framework for simultaneous histopathology image classification and retrieval, leveraging on the classic concept of k-nearest neighbours to improve model interpretability. For a test image, we retrieve the most similar images from our training databases. These retrieved nearest neighbours can be used to classify the test image with a confidence score, and provide a human-interpretable explanation of our classification. Our original framework can be built on top of any existing classification network (and therefore benefit from pretrained models), by (i) adding a triplet loss function with a novel triplet sampling strategy to compare distances between samples and (ii) a Cauchy hashing loss function to accelerate neighbour searching. We evaluate our method on colorectal cancer histology slides, and show that the confidence estimates are strongly correlated with model performance. The explanations provided by nearest neighbours are intuitive and useful for expert evaluation by giving insights into understanding possible model failures, and can support clinical decision making by comparing archived images and patient records with the actual case.

62: Rats and axolotls share a common molecular signature after spinal cord injury enriched in collagen-1
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Posted to bioRxiv 05 Sep 2017

Rats and axolotls share a common molecular signature after spinal cord injury enriched in collagen-1
653 downloads pathology

Athanasios Didangelos, Katalin Bartus, Jure Tica, Michele Puglia, Bernd Roschitzki, Elizabeth J. Bradbury

Spinal cord injury (SCI) in mammals leads to irreversible tissue damage and loss of function. In contrast, axolotls are able to regenerate scar-free the injured spinal cord. To explore new pathological mechanisms, we compared rat versus axolotl transcriptomics and isolated genes shared between species post-SCI. Unexpectedly, multiple transcripts involved in extracellular matrix remodelling, in particular collagen-1, were upregulated in both species after SCI. Proteomics validated persistent expression of the collagen-enriched matrix signature at the protein level. Collagen-1 accumulated in early and advanced rat lesions. Importantly, collagen-1 was likely associated with pathological vascular remodelling rather than classic fibrosis and the transcription factor SP1 was predicted and validated to regulate, at least in part, the expression of collagen-1 in rat lesions.

63: Disrupted remapping of place cells and grid cells in knock-in model of Alzheimer’s disease
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Posted to bioRxiv 23 Oct 2019

Disrupted remapping of place cells and grid cells in knock-in model of Alzheimer’s disease
648 downloads pathology

Heechul Jun, Shogo Soma, Takashi Saito, Takaomi C. Saido, Kei M Igarashi

Patients with Alzheimer’s disease (AD) frequently suffer from spatial memory impairment and wandering behavior, but brain circuits causing such symptoms remain largely unclear. In healthy brains, spatially-tuned hippocampal place cells and entorhinal grid cells represent distinct spike patterns in different environments, a circuit function called “remapping” that underlies pattern separation of spatial memory. We investigated whether knock-in expression of mutated amyloid precursor protein deteriorates the remapping of place cells and grid cells. We found that the remapping of CA1 place cells was disrupted although their spatial tuning was only mildly diminished. Grid cells in the medial entorhinal cortex (MEC) were impaired, sending severely disrupted remapping signals to the hippocampus. Furthermore, fast gamma oscillations were disrupted in both CA1 and MEC, resulting in impaired fast gamma coupling in the MEC→CA1 circuit. These results point to the link between grid cell impairment and remapping disruption as a circuit mechanism causing spatial memory impairment in AD.

64: Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis
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Posted to bioRxiv 15 Apr 2017

Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis
647 downloads pathology

Natalia Becares, Matthew C Gage, Lucia Martin-Gutierrez, Elina Shrestha, Rikah Louie, Benoit Pourcet, Oscar M. Pello, Tu Vinh Luong, Saioa Goñi, Ning Liang, Cesar Pichardo, Hanne Røberg-Larsen, Vanessa Diaz, Knut R. Steffensen, Michael J. Garabedian, Krista Rombouts, Eckardt Treuter, Inés Pineda-Torra

Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXRα) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXRα exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXRα phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXRα phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXRα phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.

65: Relevance of enriched expression of SARS-CoV-2 binding receptor ACE2 in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients
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Posted to bioRxiv 15 Apr 2020

Relevance of enriched expression of SARS-CoV-2 binding receptor ACE2 in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients
645 downloads pathology

Ashutosh Kumar, Muneeb A. Faiq, Vikas Pareek, Khursheed Raza, Ravi K. Narayan, Pranav Prasoon, Pavan Kumar, Maheswari Kulandhasamy, Chiman Kumari, Kamla Kant, Himanshu N. Singh, Rizwana Qadri, Sada N. Pandey, Santosh Kumar

COVID-19, is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structure on its surface called the S-spike. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variation of ACE2 expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. Materials and Methods: The data were downloaded from the Human Protein Atlas available at (https://www.proteinatlas.org/search/ACE2) and the tissue specific expression (both mRNA and protein) of ACE2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) was analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (https://biit.cs.ut.ee/gprofiler/gost) utility and the data were visualized using Cytoscape software, version 3.7.2 (https://cytoscape.org/). Results: The correlated expression (genomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, GB showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. Conclusions: Based on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and gall bladder make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. ### Competing Interest Statement The authors have declared no competing interest.

66: Transcriptional trajectories of human kidney disease progression
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Posted to bioRxiv 08 Jun 2018

Transcriptional trajectories of human kidney disease progression
636 downloads pathology

Pietro E Cippà, Bo Sun, Jing Liu, Liang Chen, Maarten Naesens, Andrew P. McMahon

Our molecular understanding of clinical conditions progressing from acute organ injury to irreversible dysfunction is limited. We used renal transplantation as a model to characterize the transcriptional response along the transition from acute kidney injury to allograft fibrosis in humans. The integrated analysis of 163 transcriptomes with machine learning techniques identified shared and divergent transcriptional trajectories determining distinct clinical outcomes in a heterogeneous population. The molecular map of renal responses to injury was validated in a mouse ischemia-reperfusion injury model and highlighted early markers of disease progression. This generally applicable approach opens the way for an unbiased analysis of progressive diseases.

67: Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)
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Posted to bioRxiv 04 May 2018

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)
633 downloads pathology

Daryl M Okamura, Chris M Brewer, Paul Wakenight, Nadia Bahrami, Kristina Bernardi, Amy Tran, Jill Olson, Xiaogang Shi, Adrian M Piliponsky, Branden R Nelson, David R. Beier, Kathleen J Millen, Mark W. Majesky

Solid organ fibrosis is a major burden on global health and medical care costs. Muroid rodents of the genus Acomys (African Spiny mice) are terrestrial mammals that evolved remarkable abilities to regenerate severe skin wounds without scar formation. However, whether scar-free wound repair in Acomys extends beyond skin to vital internal organs is not known. Here, we used two aggressive kidney injury models known to produce severe renal fibrosis and show that despite equivalent acute kidney injury, there was rapid restoration of nephron structure and function without fibrosis in Acomys compared to extensive fibrosis leading to renal failure in Mus musculus. These results suggest Acomys species have evolved genomic adaptations for wound healing that activate regenerative repair pathways not only in skin, but also in vital internal organs. Our findings have important implications for discovering a long-sought evolutionary solution to internal organ injury and regeneration.

68: Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration
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Posted to bioRxiv 23 Nov 2018

Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration
617 downloads pathology

Ivana Prokic, Belinda Cowling, Candice Kutchukian, Christine Kretz, Hichem Tasfaout, Josiane Hergueux, Olivia Wendling, Arnaud Ferry, Anne Toussaint, Christos Gavriilidis, Vasugi Nattarayan, Catherine Koch, Jeanne Lainné, Roy Combe, Laurent Tiret, Vincent Jacquemond, Fanny Pilot-Storck, Jocelyn Laporte

Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies, that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive, muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1 deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role of BIN1 on intracellular organization in addition to membrane remodeling. Whereas restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, BIN1 ubiquitous function is necessary for muscle development and function while its muscle-specific isoforms fine-tune muscle regeneration in adulthood, supporting that BIN1 centronuclear myopathy with congenital onset are due to developmental defects while later onset may be due to regeneration defects.

69: Comparative Transcriptome Profiling Conferring Of Resistance To Fusarium Oxysporum Infection Between Resistant And Susceptible Tomato
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Posted to bioRxiv 15 Mar 2017

Comparative Transcriptome Profiling Conferring Of Resistance To Fusarium Oxysporum Infection Between Resistant And Susceptible Tomato
617 downloads pathology

Min Zhao, Hui-Min Ji, Yin Gao, Xin-Xin Cao, Hui-Yin Mao, Peng Liu, Shou-Qiang Ouyang

Tomato Fusarium wilt caused by Fusarium oxysporum f. sp. lycopersici (FOL) is a destructive disease of tomato worldwide which causes severe yield loss of the crops. As exploring gene expression and function approaches constitute an initial point for investigating pathogen-host interaction, we performed a transcriptional analysis to unravel regulated genes in tomato infected by FOL. Differentially expressed genes (DEG) upon inoculation with FOL were presented at twenty-four hours post-inoculation including four treatments: Moneymaker_H2O, Moneymaker_FOL, Motelle_H2O and Motelle_FOL. A total of more than 182.6 million high quality clean reads from the four libraries were obtained. A large overlap was found in DEGs between susceptible tomato cultivar Moneymaker and resistant tomato cultivar Motelle. All Gene Ontology terms were mainly classified into catalytic activity, metabolic process and binding. However, Gene Ontology enrichment analysis evidenced specific categories in infected Motelle. Statistics of pathway enrichment of DEGs resulted that the taurine and hypotaurine metabolism, the stibenoid, diarylheptanoid and gingerol biosynthesis, the starch and sucrose metabolism were the top three pathway affected in both groups. Interestingly, plant-pathogen pathway was greatly regulated in Motelle treated with FOL. Combining with qRT-PCR facilitated the identification of regulated pathogenicity associated genes upon infected resistant or susceptible tomato. Our data showed that a coordinated machinery played a critical role in prompting the response, which could help in generating models of mediated resistance responses with assessment of genomic gene expression patterns.

70: An improved experimental model of cystic hydatid disease in liver resembling natural infection route with stable growing dynamics and immune reaction
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Posted to bioRxiv 24 Jun 2017

An improved experimental model of cystic hydatid disease in liver resembling natural infection route with stable growing dynamics and immune reaction
601 downloads pathology

Ruiqing Zhang, Xinhua Chen, Hao Wen

Cystic echinococcosis is an endemic parasitic infection in Xinjiang, China and is causing serious economic and public health concern. An experimental murine model for hepatic cystic echinococcosis was established in 31 C57B/6 mice by injection of human protoscolices via the portal vein with three different concentrations. Mice were followed up for up to 10 months by ultrasound, gross anatomy, pathological and immunological examinations. The protoscolice migration in portal vein, hydatid cyst growth, host immune reaction and hepatic histopathology were inspected periodicly. The infection rate of the mice in the high, medium, and low concentration groups were 90%, 100%, and 63.6%, respectively. The protoscolices migrate in the portal vein with blood flow, settle in the liver and develop into orthotopic hepatic hydatid cysts, resembling the natural infection route and course. This study established an improved experimental model of low biohazard risk but stable growing dynamic for hydatid disease research.

71: Pangenomic analysis reveals pathogen-specific regions and novel effector candidates in Fusarium oxysporum f.sp. cepae
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Posted to bioRxiv 30 Sep 2017

Pangenomic analysis reveals pathogen-specific regions and novel effector candidates in Fusarium oxysporum f.sp. cepae
600 downloads pathology

Andrew D. Armitage, Andrew Taylor, Maria K. Sobczyk, Laura Baxter, Bethany P.J. Greenfield, Helen J. Bates, Fiona Wilson, Alison C Jackson, Sascha Ott, R.J. Harrison, John P Clarkson

A reference-quality assembly of Fusarium oxysporum f. sp. cepae (Foc), the causative agent of onion basal rot has been generated along with genomes of additional pathogenic and non-pathogenic isolates. Phylogenetic analysis confirmed a single origin of the Foc pathogenic lineage. Genome alignments with other F. oxysporum ff. spp. and non pathogens revealed high levels of syntenic conservation of core chromosomes but little synteny between lineage specific (LS) chromosomes. Four LS contigs in Foc totaling 3.9 Mb were designated as pathogen-specific (PS). A two-fold increase in segmental duplication events was observed between LS regions of the genome compared to within core regions or from LS regions to the core. RNA-seq expression studies identified candidate effectors expressed in planta, consisting of both known effector homologs and novel candidates. FTF1 and a subset of other transcription factors implicated in regulation of effector expression were found to be expressed in planta.

72: Disrupted cholinergic modulation can underlie abnormal gamma rhythms in schizophrenia and and auditory hallucination
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Posted to bioRxiv 31 Aug 2016

Disrupted cholinergic modulation can underlie abnormal gamma rhythms in schizophrenia and and auditory hallucination
593 downloads pathology

Jung Hoon Lee

The pathophysiology of auditory hallucination, a common symptom of schizophrenia, has yet been understood, but during auditory hallucination, primary auditory cortex (A1) shows paradoxical responses. When auditory stimuli are absent, A1 becomes hyperactive, while A1 responses to auditory stimuli are reduced. Such activation pattern of A1 responses during auditory hallucination is consistent with aberrant gamma rhythms in schizophrenia observed during auditory tasks, raising the possibility that the pathology underlying abnormal gamma rhythms can account for auditory hallucination. Moreover, A1 receives top-down signals in the gamma frequency band from an adjacent association area (Par2), and cholinergic modulation regulates interactions between A1 and Par2. In this study, we utilized a computational model of A1 to ask if disrupted cholinergic modulation could underlie abnormal gamma rhythms in schizophrenia. Furthermore, based on our simulation results, we propose potential pathology by which A1 can directly contribute to auditory hallucination.

73: Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity
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Posted to bioRxiv 06 Dec 2018

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity
581 downloads pathology

Marion Régnier, Arnaud Polizzi, Sarra Smati, Céline Lukowicz, Anne Fougerat, Yannick Lippi, Edwin Fouché, Frédéric Lasserre, Claire Naylies, Colette Bétoulières, Valentin Barquissau, Etienne Mouisel, Justine Bertrand-Michel, Aurélie Batut, Talal Al Saati, Cécile Canlet, Marie Tremblay-Franco, Sandrine Ellero-Simatos, Dominique Langin, Catherine Postic, Walter Wahli, Nicolas Loiseau, Hervé Guillou, Alexandra Montagner

Objectives: Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. Methods/Results: We have investigated the role of hepatocyte PPARα in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Pparα-/-) mice and in mice lacking Pparα in hepatocyte (Pparαhep-/-). We provide evidence that Pparα deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Conclusion: Taken together, our data support hepatocyte PPARα as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.

74: A novel real-time PCR assay panel for detection of common respiratory pathogens in a convenient, strip-tube array format
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Posted to bioRxiv 29 Oct 2018

A novel real-time PCR assay panel for detection of common respiratory pathogens in a convenient, strip-tube array format
573 downloads pathology

Mohammad Rubayet Hasan, Hassan Al Mana, Virginia Young, Patrick K.C. Tang, Eva Thomas, Rusung Tan, Peter Tilley

Commercial multiplex assays, built on different chemistries and platforms are widely available for simultaneous detection of pathogens that cause respiratory infections. However, these tests are often difficult to implement in a resource limited setting because of high cost. In this study, we developed and validated a method for simultaneous testing of common respiratory pathogens (Respanel) by real-time PCR in a convenient, strip-tube array format. Primers and probes for sixteen PCR assays were selected from the literature or newly designed. Following optimization of individual PCR assays, strip-tube arrays were prepared by dispensing primer-probe mixes (PPM) into two sets of 8-tube strips. Nucleic acid extracts from specimens were mixed with PCR master mix, and dispensed column-wise into 2X8-wells of a 96-well plate. PPMs from strip-tubes were then added to the wells using a multichannel pipette for real-time PCR. Individual PCR assays were optimized using previously known specimens (n=397) with 91%-100% concordance with culture, DFA or PCR results. Respanel was then tested in a routine manner at two different sites using specimens (n=147) previously tested by Qiagen Resplex I&II or Fast-Track Diagnostics Respiratory Pathogens 21 assays. The sensitivity, specificity and accuracy of Respanel were 94%, 95% and 95%, respectively, against Resplex and 88%, 100% and 99%, respectively, against FTDRP21. Respanel detected 48% more pathogens (p<0.05) than Resplex but the rate of pathogen detection was not significantly different from FTDRP21. Respanel is a convenient and inexpensive assay that is more sensitive than Resplex and comparable to FTDRP21 for the detection of common respiratory pathogens.

75: Nimodipine prevents the development of spasticity after spinal cord injury
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Posted to bioRxiv 17 May 2019

Nimodipine prevents the development of spasticity after spinal cord injury
572 downloads pathology

Maite Marcantoni, Andrea Fuchs, Peter Löw, Ole Kiehn, Carmelo Bellardita

Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine, an FDA-approved L-type calcium channel blocker, starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of Cav 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal Cav 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

76: Use of human iPSCs and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy to treat cystinosis
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Posted to bioRxiv 01 Apr 2019

Use of human iPSCs and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy to treat cystinosis
570 downloads pathology

Jennifer A. Hollywood, Aneta Przepiorski, Patrick T Harrison, Ernst J. Wolvetang, Alan J. Davidson, Teresa M Holm

Cystinosis is a lysosomal storage disease caused by mutations in CTNS, encoding a cystine transporter, and in its severest form is characterized by cystine accumulation, renal proximal tubule dysfunction and kidney failure. Cystinosis is treated with the cystine-depleting drug cysteamine, however this only slows progression of the disease and there is an urgent need for better treatments. Here, we have generated and characterized the first human induced pluripotent stem cell (iPSC) and kidney organoid models of cystinosis. These models exhibit elevated cystine and cysteine levels, enlarged lysosomes and a block in basal autophagy flux. Cysteamine treatment ameliorates this phenotype except for the basal autophagy flux defect. We found that treatment with Everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes and activates autophagy but does not rescue the cystine/cysteine loading defect. However, dual treatment of cystinotic iPSCs or kidney organoids with cysteamine and Everolimus corrects all of the observed phenotypes indicating that a combination therapy has therapeutic potential to improve the treatment of cystinosis.

77: Drosophila melanogaster infected with Wolbachia strain wMelCS prefer cooler temperatures
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Posted to bioRxiv 21 Jun 2018

Drosophila melanogaster infected with Wolbachia strain wMelCS prefer cooler temperatures
569 downloads pathology

Pieter A. Arnold, Samantha C Levin, Aleksej L Stevanovic, Karyn N. Johnson

Temperature plays a fundamental role in host-pathogen interactions. Wolbachia is an endosymbiont that infects about 40% of arthropod species, which can affect host behaviour and reproduction. The effect of Wolbachia on host thermoregulatory behaviour is largely unknown. Here, we used a thermal gradient to test whether Drosophila melanogaster infected with Wolbachia exhibit different temperature preferences (Tp) to uninfected flies. We found that Wolbachia-infected flies preferred a cooler mean temperature (Tp = 25.06±0.25°C) than uninfected flies (Tp = 25.78±0.24°C). Our finding suggests that Wolbachia-infected hosts might seek out cooler microclimates to reduce exposure to and lessen the consequences of high temperatures.

78: Sacral agenesis: A pilot whole exome sequencing and copy number study
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Posted to bioRxiv 13 Jun 2016

Sacral agenesis: A pilot whole exome sequencing and copy number study
569 downloads pathology

Robert Milan Porsch, Elisa Merello, Patrizia De Marco, Guo Cheng, Laura Rodriguez, Manting So, Pak C Sham, Paul K. Tam, Valeria Carpa, Stacey S. Cherny, Maria-Mercè Garcia-Barcelo, Desmond D. Campbell

Background Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Results In this pilot study, exome sequencing and copy number variation (CNV) analyses of 4 CRS trios implicate a number of candidate genes, including MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous) as well as in CRS-related genes PTEN (heterozygous) and VANGL1 (heterozygous). In addition, a compound heterozygous mutation in GLTSCR2, a direct regulator of PTEN was identified. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.

79: 3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression
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Posted to bioRxiv 09 Mar 2019

3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression
568 downloads pathology

Fabián Segovia-Miranda, Hernán Morales-Navarrete, Michael Kücken, Vincent Moser, Sarah Seifert, Urska Repnik, Fabian Rost, Alexander Hendriks, Sebastian Hinz, Christoph Röcken, Dieter Lüthjohann, Yannis Kalaidzidis, Clemens Schafmayer, Lutz Brusch, Jochen Hampe, Marino Zerial

Early disease diagnosis is key for the effective treatment of diseases. It relies on the identification of biomarkers and morphological inspection of organs and tissues. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D structural changes that are consequence of functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially-resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of new morphometric cellular parameters correlated with disease progression. Moreover, we found profound topological defects in the 3D bile canaliculi (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and zonated cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially-resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multi-parametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

80: Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy – Results from a multicentric UK based study
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Posted to bioRxiv 04 Feb 2019

Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy – Results from a multicentric UK based study
568 downloads pathology

Emad Rakha, Francisco Beca, Mariangela D'Andrea, Areeg Abbas, William Petrou-Nunn, Abeer M Shaaban, Aneeshya Kandiyil, Samantha Smith, Sindhu Menon, Somaia Elsheikh, Maysa E ElSayed, Andrew H S Lee, Nisha Sharma

AIMS: The clinical significance of radial scar/complex sclerosing lesion (RS/CSL) with high risk lesions (epithelial atypia) diagnosed on needle core biopsy (NCB) is not well defined. We aimed at assessing the upgrade rate to carcinoma in-situ (DCIS) and invasive on the surgical excision specimen in a large cohort of RS/CSL associated with atypia. METHODS: 161 women with NCB diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings including different forms of the atypical lesions and final histological outcome in the excision specimens were retrieved and analysed and the upgrade rate for malignancy and invasive carcinoma calculated. RESULTS: 76% of the cases were associated with an atypical ductal hyperplasia (ADH) whereas lobular neoplasia was seen in 24%. On final histology 38 cases were malignant (overall upgrade rate of 25%); 12 invasive and 27 DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia the upgrade rate was 12%. The upgrade rates variability was also considerably lower and showing less variability when considering the upgrade to invasive carcinoma alone. CONCLUSION: The upgrade rate for ADH diagnosed on NCB with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with LN is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.

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