Faculty Bibliography

Products derived from bacterial members of the gut microbiota evoke immune signalling pathways of the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. We recently demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities following depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and interleukin (IL)-22-producing innate lymphoid cells, which in turn promote pSTAT3 signalling in intestinal epithelial cells and protection from intestinal injury. In addition, we demonstrate that MNV provides a striking IL-22-dependent protection against early-life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.

Motivation/UNASSIGNED:Shotgun DNA sequencing provides sensitive detection of all 182 HPV types in tissue and body fluid. However, existing computational methods either produce false positives misidentifying HPV types due to shared sequences among HPV, human, and prokaryotes, or produce false negative since they identify HPV by assembled contigs requiring large abundant of HPV reads. Results/UNASSIGNED:We designed HPViewer with two custom HPV reference databases masking simple repeats and homology sequences respectively and one homology distance matrix to hybridize these two databases. It directly identified HPV from short DNA reads rather than assembled contigs. Using 100,100 simulated samples, we revealed that HPViewer was robust for samples containing either high or low number of HPV reads. Using 12 shotgun sequencing samples from respiratory papillomatosis, HPViewer was equal to VirusTAP, and Vipie and better than HPVDetector with the respect to specificity and was the most sensitive method in the detection of HPV types 6 and 11. We demonstrated that contigs-based approaches had disadvantages of detection of HPV. In 1,573 sets of metagenomic data from 18 human body sites, HPViewer identified 104 types of HPV in a body-site associated pattern and 89 types of HPV co-occurring in one sample with other types of HPV. We demonstrated HPViewer was sensitive and specific for HPV detection in metagenomic data. Availability/UNASSIGNED:HPViewer can be accessed at https://github.com/yuhanH/HPViewer/. Contact/UNASSIGNED:Zhiheng.pei@nyumc.org. Supplementary information/UNASSIGNED:Supplementary data are available at Bioinformatics online.

Mixed carcinomas in the esophagus are highly uncommon neoplasms that represent a diagnostic challenge on small tissue biopsies. We present a case of a primary mixed sarcomatoid-small cell carcinoma of the esophagus that was diagnosed after repeat sampling of the lesion. The components were morphologically distinct and could be further classified by immunohistochemistry. Next-generation sequencing identified mutations in PIK3CA and CDKN2A. The small cell component morphology was also identified in brain metastasis.

Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci. Apart from an ESC-specific factor, we demonstrate that Phf5a controls differentiation of adult myoblasts. Our findings suggest a potent mode of regulation by Phf5a in stem cells, which directs their transcriptional programme, ultimately regulating maintenance of pluripotency and cellular reprogramming.

Colorectal carcinoma (CRC), as the third most common new cancer diagnosis, poses a significant health risk to the population. Interval CRCs are those that appear after a negative screening test or examination. The development of interval CRCs has been shown to be multifactorial: location of exam-academic institution versus community hospital, experience of the endoscopist, quality of the procedure, age of the patient, flat versus polypoid neoplasia, genetics, hereditary gastrointestinal neoplasia, and most significantly missed or incompletely excised lesions. The rate of interval CRCs has decreased in the last decade, which has been ascribed to an increased understanding of interval disease and technological advances in the screening of high risk individuals. In this article, we aim to review the literature with regard to the multifactorial nature of interval CRCs and provide the most recent developments regarding this important gastrointestinal entity.

Traditional Chinese medicines are readily available without prescription from herbal drug stores. One such Chinese medicine, Chan Su, which is prepared from the skin gland of toads, has cardiotonic effect due to bufadienolides. Here we report rapid detection of the presence of Chan Su in blood using the fluorescence polarization immunoassay for digitoxin. In our study mice were fed with a dose of 75 mg/kg of Chan Su and blood was drawn before, and 1 and 2 h after feeding. We observed significant digitoxin-like immunoreactivity in the sera. For example in one mouse the digitoxin-like immunoreactivity was undetectable before feeding with Chan Su, but was 19.7 ng/ml 1 h and 8.8 ng/ml 2 h afterwards. The apparent half-life of Chan Su is approximately 1 h in mice. In another experiment, we studied protein binding of Chan Su by measuring total and free Chan Su concentrations (ultrafiltrate prepared by using Centrifree Micropartition Filter, molecular weight cutoff: 30000 Da). Chan Su was strongly bound to serum proteins. We observed higher free fraction in uremic sera and sera from patients with liver disease. We identified albumin as one of the proteins that bind Chan Su in serum.