Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 77,108 bioRxiv papers from 334,389 authors.
Most downloaded bioRxiv papers, all time
in category pathology
406 results found. For more information, click each entry to expand.
7,828 downloads pathology
Fan Wu, Su Zhao, Bin Yu, Yan-Mei Chen, Wen Wang, Yi Hu, Zhi-Gang Song, Zhao-Wu Tao, Jun-Hua Tian, Yuan-Yuan Pei, Ming-Li Yuan, Yu-Ling Zhang, Fa-Hui Dai, Yi Liu, Qi-Min Wang, Jiao-Jiao Zheng, Lin Xu, Edward C. Holmes, Yong-Zhen Zhang
Emerging and re-emerging infectious diseases, such as SARS, MERS, Zika and highly pathogenic influenza present a major threat to public health–. Despite intense research effort, how, when and where novel diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city of Wuhan, Hubei province, China. At the time of writing, at least 62 suspected cases have been reported since the first patient was hospitalized on December 12nd 2019. Epidemiological investigation by the local Center for Disease Control and Prevention (CDC) suggested that the outbreak was associated with a sea food market in Wuhan. We studied seven patients who were workers at the market, and collected bronchoalveolar lavage fluid (BALF) from one patient who exhibited a severe respiratory syndrome including fever, dizziness and cough, and who was admitted to Wuhan Central Hospital on December 26th 2019. Next generation metagenomic RNA sequencing identified a novel RNA virus from the family Coronaviridae designed WH-Human-1 coronavirus (WHCV). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that WHCV was most closely related (89.1% nucleotide similarity similarity) to a group of Severe Acute Respiratory Syndrome (SARS)-like coronaviruses (genus Betacoronavirus , subgenus Sarbecovirus ) previously sampled from bats in China and that have a history of genomic recombination. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans. : #ref-1 : #ref-3 : #ref-4
6,390 downloads pathology
A quantitative model to genetically interpret the histology in whole microscopy slide images is desirable to guide downstream immunohistochemistry, genomics, and precision medicine. We constructed a statistical model that predicts whether or not SPOP is mutated in prostate cancer, given only the digital whole slide after standard hematoxylin and eosin [H&E] staining. Using a TCGA cohort of 177 prostate cancer patients where 20 had mutant SPOP, we trained multiple ensembles of residual networks, accurately distinguishing SPOP mutant from SPOP non-mutant patients (test AUROC=0.74, p=0.0007 Fisher's Exact Test). We further validated our full metaensemble classifier on an independent test cohort from MSK-IMPACT of 152 patients where 19 had mutant SPOP. Mutants and non-mutants were accurately distinguished despite TCGA slides being frozen sections and MSK-IMPACT slides being formalin-fixed paraffin-embedded sections (AUROC=0.86, p=0.0038). Moreover, we scanned an additional 36 MSK-IMPACT patient having mutant SPOP, trained on this expanded MSK-IMPACT cohort (test AUROC=0.75, p=0.0002), tested on the TCGA cohort (AUROC=0.64, p=0.0306), and again accurately distinguished mutants from non-mutants using the same pipeline. Importantly, our method demonstrates tractable deep learning in this "small data" setting of 20-55 positive examples and quantifies each prediction's uncertainty with confidence intervals. To our knowledge, this is the first statistical model to predict a genetic mutation in cancer directly from the patient's digitized H&E-stained whole microscopy slide. Moreover, this is the first time quantitative features learned from patient genetics and histology have been used for content-based image retrieval, finding similar patients for a given patient where the histology appears to share the same genetic driver of disease i.e. SPOP mutation (p=0.0241 Kost's Method), and finding similar patients for a given patient that does not have have that driver mutation (p=0.0170 Kost's Method).
4,437 downloads pathology
This document represents a brief account of ongoing project for Diabetic Retinopathy Detection (DRD) through integration of state-of the art Deep Learning methods. We make use of deep Convolutional Neural Networks (CNNs), which have proven revolutionary in multiple fields of computer vision including medical imaging, and we bring their power to the diagnosis of eye fundus images. For training our models we used publicly available Kaggle data set. For testing we used portion of Kaggle data withheld from training and Messidor-2 reference standard. Neither withheld Kaggle images, nor Messidor-2 were used for training. For Messidor-2 we achieved sensitivity 99%, specificity 71%, and AUC 0.97. These results close to recent state-of-the-art models trained on much larger data sets and surpass average results of diabetic retinopathy screening when performed by trained optometrists. With continuous development of our Deep Learning models we expect to further increase the accuracy of the method and expand it to cataract and glaucoma diagnostics.
4,268 downloads pathology
Christopher R. Merritt, Giang T Ong, Sarah Church, Kristi Barker, Gary Geiss, Margaret Hoang, Jaemyeong Jung, Yan Liang, Jill McKay-Fleisch, Karen Nguyen, Kristina Sorg, Isaac Sprague, Charles Warren, Sarah Warren, Zoey Zhou, Daniel R. Zollinger, Dwayne L. Dunaway, Gordon B. Mills, Joseph M. Beechem
We have developed Digital Spatial Profiling (DSP), a non-destructive method for high-plex spatial profiling of proteins and RNA, using oligonucleotide detection technologies with unlimited multiplexing capability. The key breakthroughs underlying DSP are threefold: (1) multiplexed readout of proteins/RNA using oligo-tags; (2) oligo-tags attached to affinity reagents (antibodies/RNA probes) through a photocleavable (PC) linker; (3) photocleaving light projected onto the tissue sample to release PC-oligos in any spatial pattern. Here we show precise analyte reproducibility, validation, and cellular resolution using DSP. We also demonstrate biological proof-of-concept using lymphoid, colorectal tumor, and autoimmune tissue as models to profile immune cell populations, stroma, and cancer cells to identify factors specific for the diseased microenvironment. DSP utilizes the unlimited multiplexing capability of modern genomic approaches, while simultaneously providing spatial context of protein and RNA to examine biological questions based on analyte location and distribution.
3,750 downloads pathology
Breast cancer is one of the main causes of cancer death worldwide. Early diagnostics significantly increases the chances of correct treatment and survival, but this process is tedious and often leads to a disagreement between pathologists. Computer-aided diagnosis systems showed potential for improving the diagnostic accuracy. In this work, we develop the computational approach based on deep convolution neural networks for breast cancer histology image classification. Hematoxylin and eosin stained breast histology microscopy image dataset is provided as a part of the ICIAR 2018 Grand Challenge on Breast Cancer Histology Images. Our approach utilizes several deep neural network architectures and gradient boosted trees classifier. For 4-class classification task, we report 87.2% accuracy. For 2-class classification task to detect carcinomas we report 93.8% accuracy, AUC 97.3%, and sensitivity/specificity 96.5/88.0% at the high-sensitivity operating point. To our knowledge, this approach outperforms other common methods in automated histopathological image classification. The source code for our approach is made publicly available at https://github.com/alexander-rakhlin/ICIAR2018.
3,252 downloads pathology
Sudden Infant Death Syndrome (SIDS) is the most common cause of postneonatal infant death. The allostatic load hypothesis posits that SIDS is the result of perinatal cumulative painful, stressful, or traumatic exposures that tax neonatal regulatory systems. To test it, we explored the relationships between SIDS and two common stressors, male neonatal circumcision (MNC) and prematurity, using latitudinal data from 15 countries and over 40 US states during the years 1999-2016. We used linear regression analyses and likelihood ratio tests to calculate the association between SIDS and the stressors. SIDS prevalence was significantly and positively correlated with MNC and prematurity rates. MNC explained 14.2% of the variability of SIDS's male bias in the US, reminiscent of the Jewish myth of Lilith, the killer of infant males. Combined, the stressors increased the likelihood of SIDS. Ecological analyses are useful to generate hypotheses but cannot provide strong evidence of causality. Biological plausibility is provided by a growing body of experimental and clinical evidence linking adversary preterm and early-life events with SIDS. Together with historical evidence, our findings emphasize the necessity of cohort studies that consider these environmental stressors with the aim of improving the identification of at-risk infants and reducing infant mortality.
3,149 downloads pathology
Over the years, several tumor biomarkers have been suggested to foresee the prognosis of oral squamous cell carcinoma (OSCC) patients. Here, we present a systematic review to identify, evaluate and summarize the evidence for OSCC reported markers. Eligible studies were identified through a literature search of MEDLINE/PubMed until January 2016. We included primary articles reporting overall survival, disease-free survival and cause-specific survival as outcomes. Our findings were analysed using REporting recommendations for tumor MARKer prognostic studies (REMARK), QuickGo tool and SciCurve trends. We found 41 biomarkers, mostly proteins evaluated by immunohistochemistry. The selected studies are of good quality, although, any study referred to a sample size determination. Considering the lack of follow-up studies, the molecules are still potential biomarkers. Further research is required to validate these biomarkers in well designed clinical cohort-based studies.
2,764 downloads pathology
The outbreak of 2019-nCoV pneumonia (COVID-19) in the city of Wuhan, China has resulted in more than 60,000 laboratory confirmed cases, and recent studies showed that 2019-nCoV (SARS-CoV-2) could be of bat origin but involve other potential intermediate hosts. In this study, we assembled the genomes of coronaviruses identified in sick pangolins. The molecular and phylogenetic analyses showed that pangolin Coronaviruses (pangolin-CoV) are genetically related to both the 2019-nCoV and bat Coronaviruses but do not support the 2019-nCoV arose directly from the pangolin-CoV. Our study also suggested that pangolin be natural host of Betacoronavirus, with a potential to infect humans. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. Conservation of wildlife and limits of the exposures of humans to wildlife will be important to minimize the spillover risks of coronaviruses from wild animals to humans.
2,602 downloads pathology
Multiplexing (mplx), labeling for multiple immunostains the very same cell or tissue section in situ, has raised considerable interest. The methods proposed include the use of labelled primary antibodies, spectral separation of fluorochromes, bleaching of the fluorophores or chromogens, blocking of previous antibody layers, all in various combinations. The major obstacles to the diffusion of this technique are high costs in custom antibodies and instruments, low throughput, scarcity of specialized skills or facilities. We have validated a method based on common primary and secondary antibodies and diffusely available fluorescent image scanners. It entails rounds of four-color indirect immunofluorescence, image acquisition and removal (stripping) of the antibodies, before another stain is applied. The images are digitally registered and the autofluorescence is subtracted. Removal of antibodies is accomplished by disulphide cleavage and a detergent or by a chaotropic salt treatment, this latter followed by antigen refolding. More than thirty different antibody stains can be applied to one single section from routinely fixed and embedded tissue. This method requires a modest investment in hardware and materials and uses freeware image analysis software. Mplx on routine tissue sections is a high throughput tool for in situ characterization of neoplastic, reactive, inflammatory and normal cells.
2,211 downloads pathology
Skeletal bone age assessment is a common clinical practice to diagnose endocrine and metabolic disorders in child development. In this paper, we describe a fully automated deep learning approach to the problem of bone age assessment using data from the 2017 Pediatric Bone Age Challenge organized by the Radiological Society of North America. The dataset for this competition is consisted of 12.6k radiological images. Each radiograph in this dataset is an image of a left hand labeled by the bone age and the sex of a patient. Our approach utilizes several deep neural network architectures trained end-to-end. We use images of whole hands as well as specific parts of a hand for both training and inference. This approach allows us to measure the importance of specific hand bones for the automated bone age analysis. We further evaluate performance of the method in the context of skeletal development stages. Our approach outperforms other common methods for bone age assessment.
2,178 downloads pathology
Yifu Ding, Daniel J. Vanselow, Maksim A. Yakovlev, Spencer R. Katz, Alex Y Lin, Darin P Clark, Phillip Vargas, Xuying Xin, Jean E Copper, Victor A Canfield, Khai C Ang, Yuxin Wang, Xianghui Xiao, Francesco De Carlo, Damian B. van Rossum, Patrick La Rivière, Keith C. Cheng
Histological studies providing cellular insights into tissue architecture have been central to biological discovery and remain clinically invaluable today. Extending histology to three dimensions would be transformational for research and diagnostics. However, three-dimensional histology is impractical using current techniques. We have customized sample preparation, synchrotron X-ray tomographic parameters, and three-dimensional image analysis to allow for complete histological phenotyping using whole larval and juvenile zebrafish. The resulting digital zebrafish can be virtually sectioned and visualized in any plane. Whole-animal reconstructions at subcellular resolution also enable computational characterization of the zebrafish nervous system by region-specific detection of cell nuclei and quantitative assessment of individual phenotypic variation. Three-dimensional histological phenotyping has potential use in genetic and chemical screens, and in clinical and toxicological tissue diagnostics.
2,076 downloads pathology
Adam Yala, Regina Barzilay, Laura Salama, Molly Griffin, Grace Sollender, Aditya Bardia, Constance Lehman, Julliette M Buckley, Suzanne B Coopey, Fernanda Polubriaginof, Judy E Garber, Barbara L Smith, Michele A Gadd, Michelle C Specht, Thomas M Gudewicz, Anthony Guidi, Alphonse Taghian, Kevin S Hughes
Purpose: Extracting information from Electronic Medical Record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest. Methods: We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital (MGH), Brigham and Womens Hospital (BWH), and Newton Wellesley Hospital (NWH), covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6,295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably. Results: The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports. Conclusions: Our learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from this data.
2,073 downloads pathology
The revolution in low-cost consumer photography and computation provides fertile opportunity for a disruptive reduction in the cost of biomedical imaging. Conventional approaches to low-cost microscopy are fundamentally restricted, however, to modest field of view (FOV) and/or resolution. We report a low-cost microscopy technique, implemented with a Raspberry Pi single-board computer and color camera combined with Fourier ptychography (FP), to computationally construct 25-megapixel images with sub-micron resolution. New image-construction techniques were developed to enable the use of the low-cost Bayer color sensor, to compensate for the highly aberrated re-used camera lens and to compensate for misalignments associated with the 3D-printed microscope structure. This high ratio of performance to cost is of particular interest to high-throughput microscopy applications, ranging from drug discovery and digital pathology to health screening in low-income countries. 3D models and assembly instructions of our microscope are made available for open source use.
1,926 downloads pathology
Andrew J. Schaumberg, Wendy C. Juarez-Nicanor, Sarah J. Choudhury, Laura G. Pastrián, Bobbi S. Pritt, Mario Prieto Pozuelo, Ricardo Sotillo Sánchez, Khanh Ho, Nusrat Zahra, Betul Duygu Sener, Stephen Yip, Bin Xu, Srinivas Rao Annavarapu, Aurélien Morini, Karra A. Jones, Kathia Rosado-Orozco, Sanjay Mukhopadhyay, Carlos Miguel, Hongyu Yang, Yale Rosen, Rola H. Ali, Olaleke O. Folaranmi, Jerad M. Gardner, Corina Rusu, Celina Stayerman, John Gross, Dauda E. Suleiman, S. Joseph Sirintrapun, Mariam Aly, Thomas J. Fuchs
Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k=1 = 0.7618+-0.0018 (chance 0.397+-0.004, mean+-stdev). The classifiers find texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g. cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, pre-neoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e. from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org. We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.
1,857 downloads pathology
Non-small cell lung cancer is a leading cause of cancer death worldwide, and histopathological evaluation plays the primary role in its diagnosis. However, the morphological patterns associated with the molecular subtypes have not been systematically studied. To bridge this gap, we developed a quantitative histopathology analytic framework to identify the gene expression subtypes of non-small cell lung cancer objectively. We processed whole-slide histopathology images of lung adenocarcinoma (n=427) and lung squamous cell carcinoma patients (n=457) in The Cancer Genome Atlas. To establish neural networks for quantitative image analyses, we first build convolutional neural network models to identify tumor regions from adjacent dense benign tissues (areas under the receiver operating characteristic curves (AUC) > 0.935) and recapitulated expert pathologists' diagnosis (AUC > 0.88), with the results validated in an independent cohort (n=125; AUC > 0.85). We further demonstrated that quantitative histopathology morphology features identified the major transcriptomic subtypes of both adenocarcinoma and squamous cell carcinoma (P < 0.01). Our study is the first to classify the transcriptomic subtypes of non-small cell lung cancer using fully-automated machine learning methods. Our approach does not rely on prior pathology knowledge and can discover novel clinically-relevant histopathology patterns objectively. The developed procedure is generalizable to other tumor types or diseases.
1,852 downloads pathology
To explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.
1,767 downloads pathology
Rohan Munir, Kjetil Soreide, Rajan Ravindran, James J Powell, Ewen M. Harrison, Anya Adair, Stephen J. Wigmore, Rowan W. Parks, O James Garden, Lorraine Kirkpatrick, Lucy R Wall, Alan Christie, Ian Penman, Norma McAvoy, Vicki Save, Alan Stockman, David Worrall, Hamish Ireland, Graeme Weir, Neil Masson, Chris Hay, James-Gordon Smith, DJ Mole
Introduction: The pattern of recurrence after surgical excision of pancreas cancer may guide alternative pre-operative strategies to either detect occult disease or need for chemotherapy. This study investigated patterns of recurrence after pancreatic surgery. Methods: Recurrence patterns were described in a series of resected pancreas cancers over a 2-year period and recurrence risk expressed as odds ratio (OR) with 95% confidence interval (C.I.). Survival was displayed by Kaplan-Meier curves. Results: Of 107 pancreas resections, 69 (65%) had pancreatic cancer. R0 resection was achieved in 21 of 69 (30.4%). Analysis was based on 66 patients who survived 30 days after surgery with median follow up 21 months. Recurrence developed in 41 (62.1%) patients with median time to first recurrence of 13.3 months (interquartile range 6.9, 20.8 months). Recurrence site was most frequently locoregional (n=28, 42%), followed by liver (n=23, 35%), lymph nodes (n=21, 32%), and lungs (n=13, 19%). In patients with recurrence, 9 of 41 had single site recurrence; the remaining 32 patients had more than one site of recurrence. Locoregional recurrence was associated with R+ resection (53% vs 25% for R+ vs R0, respectively; OR 3.5, 95% C.I. 1.1-11.2; P=0.034). Venous invasion was associated with overall recurrence risk (OR 3.3, 95% C.I. 1.1-9.4; P=0.025). In multivariable analysis, R-stage and adjuvant chemotherapy predicted longer survival. Discussion: The predominant locoregional recurrence pattern, multiple sites of recurrence and a high R+ resection rate reflect the difficulty in achieving initial local disease control.
1,507 downloads pathology
Reliable recognition of malignant white blood cells is a key step in the diagnosis of hematologic malignancies such as Acute Myeloid Leukemia. Microscopic morphological examination of blood cells is usually performed by trained human examiners, making the process tedious, time-consuming and hard to standardise. We compile an annotated image dataset of over 18,000 white blood cells, use it to train a convolutional neural network for leukocyte classification, and evaluate the network's performance. The network classifies the most important cell types with high accuracy. It also allows us to decide two clinically relevant questions with human-level performance, namely (i) if a given cell has blast character, and (ii) if it belongs to the cell types normally present in non-pathological blood smears. Our approach holds the potential to be used as a classification aid for examining much larger numbers of cells in a smear than can usually be done by a human expert. This will allow clinicians to recognize malignant cell populations with lower prevalence at an earlier stage of the disease.
1,443 downloads pathology
Dawn M. Dudley, Matthew T. Aliota, Emma Mohr, Andrea M Weiler, Gabrielle Lehrer-Brey, Kim L Weisgrau, Mariel S. Mohns, Meghan E. Breitbach, Mustafa N Rasheed, Christina M. Newman, Dane D Gellerup, Louise H. Moncla, Jennifer Post, Nancy Schultz-Darken, Michele L. Schotkzo, Jennifer M. Hayes, Josh A Eudailey, M Anthony Moody, Sallie R Permar, Shelby L. O’Connor, Eva G Rakasz, Heather A. Simmons, Saverio Capuano, Thaddeus G. Golos, Jorge E Osorio, Thomas C. Friedrich, David H. O’Connor
Infection with Asian lineage Zika virus has been associated with Guillain-Barre syndrome and fetal abnormalities 1-4, but the mechanisms and risk factors for these outcomes remain unknown. Here we show that rhesus macaques are susceptible to infection by an Asian-lineage virus closely related to strains currently circulating in the Americas. Following subcutaneous inoculation, Zika virus RNA was detected in plasma one day post-infection (dpi) in all animals (N = 8, including 2 animals infected during the first trimester of pregnancy). Plasma viral loads peaked above 1 x 105 viral RNA copies/mL in seven of eight animals. Viral RNA was also present in saliva, urine, and cerebrospinal fluid (CSF), consistent with case reports from infected humans. Viral RNA was cleared from plasma and urine by 21 dpi in non-pregnant animals. In contrast, both pregnant animals remained viremic longer, up to 57 days. In all animals, infection was associated with transient increases in proliferating natural killer cells, CD8+ T cells, CD4+ T cells, and plasmablasts. Neutralizing antibodies were detected in all animals by 21 dpi. Rechallenge of three non-pregnant animals with the Asian-lineage Zika virus 10 weeks after the initial challenge resulted in no detectable virus replication, suggesting that primary Zika virus infection elicits protective immunity against homologous virus strains. These data establish that Asian-lineage Zika virus infection of rhesus macaques provides a relevant animal model for studying pathogenesis in pregnant and non-pregnant individuals and evaluating potential interventions against human infection, including during pregnancy.
1,409 downloads pathology
Idiopathic pulmonary fibrosis (IPF) is an intractable interstitial lung disease for which no curative treatment is available except for lung transplantation. Its pathogenesis is unclear, but a role for injury to type 2 alveolar epithelial cells is hypothesized. Recessive mutations in some, but not all genes implicated in Hermansky-Pudlak Syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity similar to IPF. We previously reported that mutation in HPS1 in embryonic stem cells-derived 3D lung organoids caused fibrotic changes. Here we show that introduction of all HPS mutations associated with HPSIP (HPS1, 2 and 4) promote fibrosis in lung organoids, while mutation in HSP8, which is not associated with HPSIP, does not. Furthermore, genome-expression analysis of epithelial cells derived from these organoids revealed significant overlap with similar analyses of both affected and unaffected lung tissue of non-HPS IPF patients. Importantly, this analysis showed upregulation of interleukin-11 in HPS-mutant fibrotic organoids and in fibrotic and unaffected lung tissue from IPF patients. Furthermore, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in fibrotic HPS4-mutant organoids, suggesting IL-11 as a therapeutic target in IPF and HPSIP. hPSC-derived 3D lung organoids are therefore a valuable resource to model fibrotic lung disease.
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