Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein

The glycoproteins of hepatitis C virus, E1E2, are unlike any other viral fusion machinery yet described, and are the current focus of immunogen design in HCV vaccine development; thus, making E1E2 both scientifically and medically important. We used pre-existing, but fragmentary, structures to model a complete ectodomain of the major glycoprotein E2 from three strains of HCV. We then performed molecular dynamic simulations to explore the conformational landscape of E2, revealing a number of important features. Despite high sequence divergence, and subtle differences in the models, E2 from different strains behave similarly, possessing a stable core flanked by highly flexible regions, some of which perform essential functions such as receptor binding. Comparison with sequence data suggest that this consistent behaviour is conferred by a network of conserved residues that act as hinge and anchor points throughout E2. The variable regions (HVR-1, HVR-2 and VR-3) exhibit particularly high flexibility, and bioinformatic analysis suggests that HVR-1 is a putative intrinsically disordered protein region. Dynamic cross-correlation analyses demonstrate intramolecular communication and suggest that specific regions, such as HVR-1, can exert influence throughout E2. To support our computational approach we performed small-angle X-ray scattering with purified E2 ectodomain; this data was consistent with our MD experiments, suggesting a compact globular core with peripheral flexible regions. This work captures the dynamic behaviour of E2 and has direct relevance to the interaction of HCV with cell-surface receptors and neutralising antibodies

Serological Survey and Pathogen Exposure of Adult Female White-tailed Deer in the Western Dakotas

Establishing baseline values for pathogen exposure and nutritional indices is necessary to monitor population health. However, little is known about white-tailed deer (Odocoileus virginianus) pathogen exposure and nutritional condition in the Northern Great Plains. Our objective was to assess pathogen exposure and establish nutritional indices for female white-tailed deer in Dunn and Grant counties, North Dakota and Perkins County, South Dakota. During 2014, we collected blood serum from 150 adult female white-tailed deer. Pathogens with the highest antibody prevalence included West Nile Virus (WNV; 85%), epizootic hemorrhagic disease (48%), and malignant catarrhal fever (32%). Serum values for creatine kinase, globulin, glucose, potassium, and lactate dehydrogenase in all three study areas were higher than reference ranges while sodium was low in Grant County relative to Dunn and Perkins counties. We speculate that high exposure of WNV and high potassium values combined with low sodium values may affect neonate survival in Grant County. However, regional differences in pathogen exposure, their connection to serum values, and their potential interactive effects on survival are not well understood

Serological Survey and Pathogen Exposure of Adult Female White-tailed Deer in the Western Dakotas

Establishing baseline values for pathogen exposure and nutritional indices is necessary to monitor population health. However, little is known about white-tailed deer (Odocoileus virginianus) pathogen exposure and nutritional condition in the Northern Great Plains. Our objective was to assess pathogen exposure and establish nutritional indices for female white-tailed deer in Dunn and Grant counties, North Dakota and Perkins County, South Dakota. During 2014, we collected blood serum from 150 adult female white-tailed deer. Pathogens with the highest antibody prevalence included West Nile Virus (WNV; 85%), epizootic hemorrhagic disease (48%), and malignant catarrhal fever (32%). Serum values for creatine kinase, globulin, glucose, potassium, and lactate dehydrogenase in all three study areas were higher than reference ranges while sodium was low in Grant County relative to Dunn and Perkins counties. We speculate that high exposure of WNV and high potassium values combined with low sodium values may affect neonate survival in Grant County. However, regional differences in pathogen exposure, their connection to serum values, and their potential interactive effects on survival are not well understood

Ursinus College Alumni Journal, Winter 1950

A good investment • Locally speaking • To the ladies • President\u27s page • Alumni Association appoints committees • Dr. Lentz attends church unification conference • Nine Ursinus hockey stars in national tourney • York County alumni only slightly winded after vigorous square dance opener • Ursinus Women\u27s Club holds yuletide luncheon • Woman dead, returns to life as result of Dr. Valloti\u27s diagnosis • College establishes new placement bureau • So Much to Be Done filmed on Ursinus campus • Dr. John Mauchly invents new computing machine • McClure elected president of St. Andrew\u27s Society • Bailey elected officer of athletic conference • Art catalogue prepared for Lachman paintings • Chandler reelected to museum board • Necrology • News about town: Coed wins magazine post; Francis heads school board; Hartzell wins DeMolay honor; Sewage plant in service • Sports review: Bruin wrestlers take eighth straight meet; Basketball team compiles 2-4 record at midseason; Pattison to captain girls\u27 swimming team; Jayvee hockey team\u27s 3-year record broken; JV courtmen rack up six wins in eight tilts; Lone victory closes poor grid season; Hockeyites win five, tie one, lose one; College hockey star to play in Europe; Soccermen beat alumni for season\u27s only win • News about ourselveshttps://digitalcommons.ursinus.edu/alumnijournal/1037/thumbnail.jp

Ursinus College Alumni Journal, Fall 1950

President\u27s page • Titus addresses largest class; 247 graduated at 80th commencement • The 1950 graduating class • Black succeeds Blum as alumni president • McClures entertain class of 1915 • Class of 1925 publishes biographical booklet • Bears tackle Swarthmore; Old Timers\u27 Day, Oct. 21 • Alumni Day 1950 • York County association holds annual banquet; McClure, Helfferich, and Frosberg address group • Barbara Dietz elected associate director of SCF • Necrology • New honors bestowed on Dr. G. E. Pfahler • Name three alumni to Board of Directors • 1950-51 academic year sees five faculty changes • E. and R. General Synod convenes at Ursinus • Bomberger: Founder of Ursinus • Gurzynski predicts improved grid season • Eight seniors spark nine to 10-4 record • New training room aids injured athletes • Two losses in ten years for girls\u27 softball teams • Golf team wins one • News about ourselveshttps://digitalcommons.ursinus.edu/alumnijournal/1039/thumbnail.jp

Ursinus College Alumni Journal, Spring 1950

Constitutional amendments proposed extending terms of office to two years • President\u27s page • Alumni Day set for June third • Ursinus Woman\u27s Club entertains senior girls • Lloyd Wood, candidate for lieutenant-governor • Kenneth Fink directs opinion survey service • Frank Tornetta named assistant anesthesiologist • Dr. Charles Dotterer heads hospital staff • Alpha Sigma Nu alumnae will meet June third • Woman\u27s Club will hear Captain John Graf • Salinger hits movies • 15 at Glenwood reunion • Phi Psi alumnae meet • Ray Gurzynski appointed head coach of football • Viewbook becomes new Ursinus agent • 246 to receive degrees at 80th commencement • Dean Stahr and alumnae meet at convention • Eugene Miller lectures on world affairs • Church synod to meet at Ursinus in June • Necrology • Coeds trip the light fantastic on Ursinus greensward since 1905 • Whence Ursinus? • Sports review: Baseball team opens with 3 straight wins; Men\u27s tennis team wins, 8-1; loses, 9-0; 1950 football schedule includes Adelphi College; Cumpstone opens season with record javelin toss; Bronson, Young named cage co-captains; Helfferich wins title as matmen close season; Freshman Joan Compton wins breaststroke title • News about ourselveshttps://digitalcommons.ursinus.edu/alumnijournal/1038/thumbnail.jp

Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications

A number of drug-specific and host-related factors contribute to the development of drug-induced liver injury (DILI). Investigations focused on genetic susceptibility to DILI have advanced our understanding of the pathogenesis of this rare, yet potentially life-threatening adverse reaction. Candidate gene studies involving well-characterized patients with DILI and drug-exposed controls have identified single nucleotide polymorphisms (SNPs) affecting the metabolism and clearance of specific drugs and hence, influencing individual’s susceptibility to DILI. On the other hand, a series of genome-wide association studies (GWASs) have revealed a number of Human Leucocyte Antigen (HLA) alleles that are associated with DILI secondary to compounds with dissimilar chemical structures, highlighting the role of adaptive immune responses in the development of liver damage. These risk alleles, such as HLA-DRB1*15:02 illustrated by the example presented in the clinical vignette, determine the physicochemical properties of the peptide-binding grooves of the HLA molecules and increase the likelihood of DILI in a susceptible individual by altering the nature or the magnitude of immune-mediated liver injury. Associations of HLA alleles with DILI secondary to specific drugs can be translated into genetic tests, and when performed selectively, can improve the accuracy of diagnosis of DILI as well as assist in identifying the correct causal agent when the event could be attributed to more than one drug

A Case for Humans-in-the-Loop: Decisions in the Presence of Erroneous Algorithmic Scores

The increased use of algorithmic predictions in sensitive domains has been accompanied by both enthusiasm and concern. To understand the opportunities and risks of these technologies, it is key to study how experts alter their decisions when using such tools. In this paper, we study the adoption of an algorithmic tool used to assist child maltreatment hotline screening decisions. We focus on the question: Are humans capable of identifying cases in which the machine is wrong, and of overriding those recommendations? We first show that humans do alter their behavior when the tool is deployed. Then, we show that humans are less likely to adhere to the machine's recommendation when the score displayed is an incorrect estimate of risk, even when overriding the recommendation requires supervisory approval. These results highlight the risks of full automation and the importance of designing decision pipelines that provide humans with autonomy.Comment: Accepted at ACM Conference on Human Factors in Computing Systems (ACM CHI), 202

Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate-cancer patients

Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be obtained from bone-marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer alterations reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTCs). We also demonstrate that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and variation in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation of the relationship between DTC genomic alterations and progressive prostate cancer