Publications by authors named "Jessica Clark"

69 Publications

Reconciling egg- and antigen-based estimates of Schistosoma mansoni clearance and reinfection: a modelling study.

Clin Infect Dis 2021 Aug 6. Epub 2021 Aug 6.

Wellcome Centre for Integrative Parasitology, Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, Glasgow, UK.

Background: 240-million people have schistosomiasis despite decades of interventions. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, impacting treatment efficacy and reinfection rate estimates. The Point-of-Care Circulating Cathodic Antigen test (POC-CCA) is advocated as an improvement upon the Kato-Katz, however improved estimates are limited by ambiguities in the interpretation of Trace results.

Method: We collected repeated Kato-Katz counts from 210 school-aged children and scored POC-CCAs according to manufacturer's guidelines (POC-CCA+) and the externally developed G-Score. We used Hidden Markov Models parameterised with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding Trace interpretations.

Results: Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79-92%), 99% (POC-CCA+; 97-100%) and 98% (G-Score; 95-100%). Post-treatment, 93% (Kato-Katz; 88-96%), 72% (POC-CCA+; 64-79%) and 65% (G-Score; 57-73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27-42%), 51% (POC-CCA+; 41-62%) and 44% (G-Score; 33-55%) were estimated to have been reinfected by nine-weeks.

Conclusion: Treatment impact was shorter-lived than only Kato-Katz-based estimates suggested, with lower clearance and rapid reinfection. Three-weeks-post-treatment captured longer-term clearance dynamics. Nine-weeks-post-treatment captured reinfection, but alone could not discern between failed clearance and rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.
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http://dx.doi.org/10.1093/cid/ciab679DOI Listing
August 2021

'Case of the Month' from Thomas Jefferson University, Philadelphia, PA, USA: a large renal pseudoaneurysm masquerading as advanced renal cell carcinoma.

BJU Int 2021 Aug;128(2):158-161

Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/bju.15407DOI Listing
August 2021

Veterinary Professions Advising Center: an innovative approach to preveterinary advising for Animal Science students.

Transl Anim Sci 2021 Apr 7;5(2):txab064. Epub 2021 Apr 7.

Department of Animal Science, North Carolina State University, NC, USA.

Veterinary Professions Advising Center (VetPAC) is a unique undergraduate advising center that combines Career Center services with preprofessional advising for preveterinary students at North Carolina State University (NCSU). During the past 10 years, VetPAC has created five distinct internships, three annual study abroad courses, and a competitive annual high school summer camp, provided holistic advising, and hosted large-scale advising events that consistently provide resources to more than 800 students annually. The VetPAC provided outreach to an average of 13 local high schools per academic year and educated over 300 visiting students about VetPAC and preveterinary life at NCSU since 2015. NCSU College of Veterinary Medicine has had a minimum of 26% and a maximum of 45% DVM students in the incoming classes who accessed VetPAC resources and advising. This article presents the impact VetPAC has had on preveterinary student success at NCSU and provides an outline of VetPAC's first 10 years of development as a model of combined career services and preprofessional advising for peer institutions.
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http://dx.doi.org/10.1093/tas/txab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191483PMC
April 2021

The Impact of COVID-19 on Pre-Veterinary Opportunities and Recommendations for DVM Admissions.

J Vet Med Educ 2021 May 17:e20200145. Epub 2021 May 17.

During the summer of 2020, a survey-based study was conducted at North Carolina State University, a land-grant university, to evaluate the impact of COVID-19 on pre-veterinary students' ability to gain experience hours for Doctor of Veterinary Medicine (DVM) admissions. Of the 286 respondents (47% of the respondent pool), 92% reported losing at least one animal, veterinary, research, extracurricular, or work opportunity due to COVID-19, and 59% were not able to find a replacement. Of the lost experiences, 74 (20.8%) were for academic credit, resulting in 131 total academic credit hours lost, while only 12 credit hours were gained via alternative experiences. Of respondents, 30% (29.7%) identified as applicants of the 2020-2021 Veterinary Medical College Application Service (VMCAS) cycle. More than half (52.6%) of the sample identified being concerned about the strength of their VMCAS experiences due to these lost opportunities. Many respondents reported considering delaying application submissions by taking a gap year (17.5%) or have had their intended graduation timeline affected (14.8%). Since the majority of veterinary colleges utilize a holistic review process, this study provides a basis for understanding the effects of COVID-19 on the duration, depth, and diversity of experiences gained by future DVM applicants. This article also provides recommendations for DVM admissions adaptations based on the outcomes of the data.
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http://dx.doi.org/10.3138/jvme-2020-0145DOI Listing
May 2021

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Cancer Cell 2021 Mar 4;39(3):407-422.e13. Epub 2021 Feb 4.

Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany. Electronic address:

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.
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http://dx.doi.org/10.1016/j.ccell.2021.01.005DOI Listing
March 2021

Pathogen Dynamics across the Diversity of Aging.

Am Nat 2021 02 8;197(2):203-215. Epub 2021 Jan 8.

AbstractReproduction, mortality, and immune function often change with age but do not invariably deteriorate. Across the tree of life, there is extensive variation in age-specific performance and changes to key life-history traits. These changes occur on a spectrum from classic senescence, where performance declines with age, to juvenescence, where performance improves with age. Reproduction, mortality, and immune function are also important factors influencing the spread of infectious disease, yet there exists no comprehensive investigation into how the aging spectrum of these traits impacts epidemics. We used a model laboratory infection system to compile an aging profile of a single organism, including traits directly linked to pathogen susceptibility and those that should indirectly alter pathogen transmission by influencing demography. We then developed generalizable epidemiological models demonstrating that different patterns of aging produce dramatically different transmission landscapes: in many cases, aging can reduce the probability of epidemics, but it can also promote severity. This work provides context and tools for use across taxa by empiricists, demographers, and epidemiologists, advancing our ability to accurately predict factors contributing to epidemics or the potential repercussions of senescence manipulation.
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http://dx.doi.org/10.1086/712380DOI Listing
February 2021

Functionally non-redundant paralogs spe-47 and spe-50 encode FB-MO associated proteins and interact with him-8.

PLoS One 2020 31;15(12):e0230939. Epub 2020 Dec 31.

Department of Biological Sciences, Cal Poly Pomona, Pomona, California, United States of America.

The activation of C. elegans spermatids to crawling spermatozoa is affected by a number of genes including spe-47. Here, we investigate a paralog to spe-47: spe-50, which has a highly conserved sequence and expression, but which is not functionally redundant to spe-47. Phylogenetic analysis indicates that the duplication event that produced the paralogs occurred prior to the radiation of the Caenorhabditis species included in the analysis, allowing a long period for the paralogs to diverge in function. Furthermore, we observed that knockout mutations in both genes, either alone or together, have little effect on sperm function. However, hermaphrodites harboring both knockout mutations combined with a third mutation in the him-8 gene are nearly self-sterile due to a sperm defect, even though they have numerous apparently normal sperm within their spermathecae. We suggest that the sperm in these triple mutants are defective in fusing with oocytes, and that the effect of the him-8 mutation is unclear but likely due to its direct or indirect effect on local chromatin structure and function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774929PMC
January 2021

Increased glucose metabolism in Arid5b skeletal muscle is associated with the down-regulation of TBC1 domain family member 1 (TBC1D1).

Biol Res 2020 Oct 6;53(1):45. Epub 2020 Oct 6.

Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.

Background: Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role of Arid5b in energy metabolism has been suggested in adipocytes and hepatocytes, the role of Arid5b in skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered in Arid5b skeletal muscle.

Results: Arid5b skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated in Arid5b mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed in Arid5b skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane in Arid5b muscle.

Conclusions: The current study showed that the knockout of Arid5b enhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.
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http://dx.doi.org/10.1186/s40659-020-00313-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542134PMC
October 2020

Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.

Genes Dev 2020 09 20;34(17-18):1161-1176. Epub 2020 Aug 20.

Hopp-Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.

Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor are recurrent and enriched in SHH medulloblastoma. To investigate as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of ( ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCOR). While alone did not promote tumorigenesis or affect GNP differentiation, combined with loss of the SHH receptor gene resulted in fully penetrant medulloblastomas. In ; tumors, the growth factor gene was aberrantly up-regulated, and ectopic overexpression was sufficient to drive tumorigenesis in GNPs. BCOR directly regulates , likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the promoter in ; tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to overexpression, which transforms preneoplastic cells to malignant tumors.
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http://dx.doi.org/10.1101/gad.337584.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462063PMC
September 2020

Daphnia magna modifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference.

Mol Ecol 2020 09 30;29(17):3261-3276. Epub 2020 Jul 30.

Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustacean Daphnia magna. We have previously established that micro-RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6,000 genes were differentially expressed between CR and well-fed D. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three haem-binding erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia in Daphnia, which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of superoxide dismutase (SOD) in normally fed individuals, which contrasts with observations of high SOD levels under CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between haemoglobin and CR occurs in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.
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http://dx.doi.org/10.1111/mec.15557DOI Listing
September 2020

Atypical Genotypes for Canine Suggest Novel Chromosomal Rearrangement.

Genes (Basel) 2020 07 3;11(7). Epub 2020 Jul 3.

Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA.

Canine coat color is a readily observed phenotype of great interest to dog enthusiasts; it is also an excellent avenue to explore the mechanisms of genetics and inheritance. As such, multiple commercial testing laboratories include basic color alleles in their popular screening panels, allowing for the creation of genotyped datasets at a scale not before appreciated in canine genetic research. These vast datasets have revealed rare genotype anomalies that encourage further exploration of color and pattern inheritance. We previously reported the simultaneous presence of greater than two allele variants at the locus in a commercial genotype cohort of 11,790 canids. Here we present additional data to characterize the occurrence of anomalous genotypes. We document the detection of combinations of three or four allele variants in 17 dog breeds and Dingoes, at within-breed frequencies of 1.32-63.34%. We analyze the potential impact on phenotype that these allele combinations present, and propose mechanisms that could account for the findings, including: gene recombination, duplication, and incorrect causal variant identification. These findings speak to the accuracy of industry-wide protocols for commercial genotyping and imply that should be analyzed via haplotype, rather than using only the existing allele hierarchy, in the future.
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http://dx.doi.org/10.3390/genes11070739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397341PMC
July 2020

Zoonotic transmission of intestinal helminths in southeast Asia: Implications for control and elimination.

Adv Parasitol 2020 27;108:47-131. Epub 2020 Feb 27.

University of the Philippines Los Baños, Laguna, Philippines. Electronic address:

Intestinal helminths are extremely widespread and highly prevalent infections of humans, particularly in rural and poor urban areas of low and middle-income countries. These parasites have chronic and often insidious effects on human health and child development including abdominal problems, anaemia, stunting and wasting. Certain animals play a fundamental role in the transmission of many intestinal helminths to humans. However, the contribution of zoonotic transmission to the overall burden of human intestinal helminth infection and the relative importance of different animal reservoirs remains incomplete. Moreover, control programmes and transmission models for intestinal helminths often do not consider the role of zoonotic reservoirs of infection. Such reservoirs will become increasingly important as control is scaled up and there is a move towards interruption and even elimination of parasite transmission. With a focus on southeast Asia, and the Philippines in particular, this review summarises the major zoonotic intestinal helminths, risk factors for infection and highlights knowledge gaps related to their epidemiology and transmission. Various methodologies are discussed, including parasite genomics, mathematical modelling and socio-economic analysis, that could be employed to improve understanding of intestinal helminth spread, reservoir attribution and the burden associated with infection, as well as assess effectiveness of interventions. For sustainable control and ultimately elimination of intestinal helminths, there is a need to move beyond scheduled mass deworming and to consider animal and environmental reservoirs. A One Health approach to control of intestinal helminths is proposed, integrating interventions targeting humans, animals and the environment, including improved access to water, hygiene and sanitation. This will require coordination and collaboration across different sectors to achieve best health outcomes for all.
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http://dx.doi.org/10.1016/bs.apar.2020.01.036DOI Listing
July 2020

Prescription of High-Dose Opioids Among People Living with HIV in British Columbia, Canada.

AIDS Behav 2019 Dec;23(12):3331-3339

Department of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada.

People living with HIV (PLHIV) often experience pain for which opioid medications may be prescribed. Thus, these individuals are particularly vulnerable to opioid-related harms, including overdose, misuse, and addiction, particularly when prescribed at high doses. We used a comprehensive linked population-level database of PLHIV in British Columbia (BC) to identify demographic and clinical characteristics associated with being prescribed any high-dose opioid analgesic, defined as > 90 daily morphine milligram equivalents (MME/day). Among PLHIV who were prescribed opioids between 1996 and 2015 (n = 10,780), 28.2% received prescriptions of > 90 MME/day at least once during the study period. Factors positively associated with being prescribed high-dose opioid analgesics included: co-prescription of benzodiazepines (adjusted odds ratio [AOR] = 1.14; 95% confidence interval 1.11-1.17); presence of an AIDS-defining illness (ADI; AOR = 1.78; 95% CI 1.57-2.02); seen by an HIV specialist (AOR = 1.24; 95% CI 1.20-1.29); substance use disorder (AOR = 1.46; 95% CI 1.25-1.71); and more recent calendar year (AOR = 1.05; 95% CI 1.04-1.06). Given the known risks associated with high-dose opioid prescribing, future research efforts should focus on the clinical indication and outcomes associated with these prescribing practices.
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http://dx.doi.org/10.1007/s10461-019-02589-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062387PMC
December 2019

Successful treatment of a intra-articular infection.

Emerg Microbes Infect 2019 ;8(1):866-868

a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.

A 78-year-old woman with a long-term ankle spacer with antibacterials developed an intra-articular infection. Treatment with systemic antifungal therapy plus an amphotericin B moulded cement spacer was successful.
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http://dx.doi.org/10.1080/22221751.2019.1625287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566482PMC
September 2019

Reconsidering Requests-Futility in IR.

J Vasc Interv Radiol 2019 Jun;30(6):961-962

Department of Radiology, Santa Clara Valley Medical Center, 300 Pasteur Dr, Stanford, CA 94305. Electronic address:

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http://dx.doi.org/10.1016/j.jvir.2019.01.025DOI Listing
June 2019

Donor site morbidity following radial forearm free flap reconstruction with split thickness skin grafts using negative pressure wound therapy.

J Otolaryngol Head Neck Surg 2019 May 21;48(1):21. Epub 2019 May 21.

Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alberta, 8440-112 St, 1E4 Walter Mackenzie Centre, Edmonton, Alberta, T6G 2B7, Canada.

Background: Donor site complications secondary to radial forearm free flap (RFFF) reconstruction can limit recovery. Optimizing hand and wrist function in the post-operative period may allow more efficient self-care and return to activities of daily living. Negative pressure wound dressings (NPD) may increase blood flow and perfusion as compared to static pressure dressings (SPD) designed to minimize shear forces during the healing period. This study aims to compare subjective and objective hand and wrist functional outcomes following RFFF reconstruction with split thickness skin grafts (STSG) in patients treated with NPD and SPD.

Methods: Adult patients undergoing RFFF with STSG were identified preoperatively and randomized to receive NPD or SPD following their RFFF reconstruction. NPD involved a single-use, portable device capable of applying 80 mmHg of negative pressure to the forearm donor site. SPD involved a volar splint. Dressings were left in place for seven days with subjective and objective function assessed at seven days, one month and three months postoperatively. The primary outcome was self-reported hand function as measured with the function subscale of the Michigan Hand Questionnaire (MHQ). Secondary outcomes included hand and wrist strength, range of motion, sensation, scar aesthetics, and skin graft complications.

Results: Twenty-four patients undergoing RFFF were randomized to NPD or SPD. Patients treated with NPD had improved MHQ self-reported functional scores as compared to those treated with SPD at seven days postoperatively (P = 0.016). Flexion at seven days was improved in NPD group (P = 0.031); however, all other strength and range of motion outcomes were similar between groups. There were no differences in rates of graft complications, scar aesthetics, or sensation.

Conclusions: In the immediate post-operative period, NPD was associated with improved patient-reported hand and wrist function. Wound care to optimize hand and wrist function could allow for improved patient outcomes in the immediate postoperative period.
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http://dx.doi.org/10.1186/s40463-019-0344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528371PMC
May 2019

Understanding Bias: A Look at Conflicts of Interest in IR.

J Vasc Interv Radiol 2019 May;30(5):765-766

Department of Medicine, Santa Clara Valley Medical Center, 751 S Bascom Ave, San Jose, CA 95128.

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http://dx.doi.org/10.1016/j.jvir.2019.01.002DOI Listing
May 2019

Sodium-powered stators of the bacterial flagellar motor can generate torque in the presence of phenamil with mutations near the peptidoglycan-binding region.

Mol Microbiol 2019 06 17;111(6):1689-1699. Epub 2019 Apr 17.

School of Biotechnology and Biomolecular Science, University of New South Wales, Kensington, NSW, Australia.

The bacterial flagellar motor powers the rotation that propels the swimming bacteria. Rotational torque is generated by harnessing the flow of ions through ion channels known as stators which couple the energy from the ion gradient across the inner membrane to rotation of the rotor. Here, we used error-prone PCR to introduce single point mutations into the sodium-powered Vibrio alginolyticus/Escherichia coli chimeric stator PotB and selected for motors that exhibited motility in the presence of the sodium-channel inhibitor phenamil. We found single mutations that enable motility under phenamil occurred at two sites: (i) the transmembrane domain of PotB, corresponding to the TM region of the PomB stator from V. alginolyticus and (ii) near the peptidoglycan binding region that corresponds to the C-terminal region of the MotB stator from E. coli. Single cell rotation assays confirmed that individual flagellar motors could rotate in up to 100 µM phenamil. Using phylogenetic logistic regression, we found correlation between natural residue variation and ion source at positions corresponding to PotB F22Y, but not at other sites. Our results demonstrate that it is not only the pore region of the stator that moderates motility in the presence of ion-channel blockers.
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http://dx.doi.org/10.1111/mmi.14246DOI Listing
June 2019

Complement C4 Prevents Viral Infection through Capsid Inactivation.

Cell Host Microbe 2019 Apr 26;25(4):617-629.e7. Epub 2019 Mar 26.

Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address:

The complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1rC1s) that initiates a cleavage cascade involving C2, C3, C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.
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http://dx.doi.org/10.1016/j.chom.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461443PMC
April 2019

Acute effects of hyperglycemia on the peripheral nervous system in zebrafish ( Danio rerio) following nitroreductase-mediated β-cell ablation.

Am J Physiol Regul Integr Comp Physiol 2019 04 6;316(4):R395-R405. Epub 2019 Feb 6.

Department of Biological Sciences, Salisbury University , Salisbury, Maryland.

Diabetic peripheral neuropathy (DPN) is estimated to affect 50% of diabetic patients. Although DPN is highly prevalent, molecular mechanisms remain unknown and treatment is limited to pain relief and glycemic control. We provide a novel model of acute DPN in zebrafish ( Danio rerio) larvae. Beginning 5 days postfertilization (dpf), zebrafish expressing nitroreductase in their pancreatic β-cells were treated with metronidazole (MTZ) for 48 h and checked for β-cell ablation 7 dpf. In experimental design, this was meant to serve as proof of concept that β-cell ablation and hyperglycemia are possible at this time point, but we were surprised to find changes in both sensory and motor nerve components. Compared with controls, neurod sensory neurons were often observed outside the dorsal root ganglia in MTZ-treated fish. Fewer motor nerves were properly ensheathed by nkx2.2a perineurial cells, and tight junctions were disrupted along the motor nerve in MTZ-treated fish compared with controls. Not surprisingly, the motor axons of the MTZ-treated group were defasciculated compared with the control group, myelination was attenuated, and there was a subtle difference in Schwann cell number between the MTZ-treated and control group. All structural changes occurred in the absence of behavioral changes in the larvae at this time point, suggesting that peripheral nerves are influenced by acute hyperglycemia before becoming symptomatic. Moving forward, this novel animal model of DPN will allow us to access the molecular mechanisms associated with the acute changes in the hyperglycemic peripheral nervous system, which may help direct therapeutic approaches.
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http://dx.doi.org/10.1152/ajpregu.00258.2018DOI Listing
April 2019

Long-term survival and swallowing outcomes in advanced stage oropharyngeal squamous cell carcinomas.

Papillomavirus Res 2019 06 26;7:1-10. Epub 2018 Sep 26.

Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Alberta, 8440-112 st, Edmonton, Alberta, Canada T6G 2B7; Alberta Head & Neck Centre for Oncology and Reconstruction, 8440-112 st, Edmonton, Alberta, Canada T6G 2B7. Electronic address:

Background: There is a paucity of studies reporting long-term survival outcomes for HPV/p16 positive oropharyngeal squamous cell carcinoma (OPSCC). This study aims to compare long-term outcomes of advanced stage p16 positive and negative OPSCCs, treated by surgical and non-surgical modalities.

Methods: OPSCC patients from 1998 to 2012 were identified through a prospectively collected cancer registry. P16 immunohistochemistry was used as a surrogate marker for HPV-OPSCC. Overall survival (OS) and aspiration free survival (AFS) comparisons were made between patients treated with chemoradiation (CRT) versus primary surgery and radiation/chemoradiation (S+RT/CRT) at 5, 10 and 15 years post-treatment.

Results: A total of 319 patients were included. P16 positive patients and non-smokers had significantly higher long-term (5, 10 and 15-year) OS. Smokers and p16 negative patients treated with S+RT/CRT had improved long-term OS compared to patients who received CRT. Smokers and p16 negative patients had lower long-term AFS. Multivariate analysis showed improved OS was associated with p16 positivity (HR 0.42, 0.28-0.61) and surgery (HR 0.47, 0.32-0.69), whereas lower OS was associated with ECOG ≥ 2 (HR 2.46, 1.61-3.77), smoking (HR 2.37, 1.41-3.99) and higher stage (HR 1.68, 1.05-2.68).

Conclusions: In smokers and p16-negative OPSCC patients, primary surgery may be associated with improved long-term survival and dysphagia-related outcomes.
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http://dx.doi.org/10.1016/j.pvr.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258135PMC
June 2019

TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination.

Proc Natl Acad Sci U S A 2018 10 12;115(41):10440-10445. Epub 2018 Sep 12.

Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.
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http://dx.doi.org/10.1073/pnas.1806314115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187179PMC
October 2018

A General Model of Sensitized Luminescence in Lanthanide-Based Coordination Polymers and Metal-Organic Framework Materials.

Inorg Chem 2017 May 2;56(10):5544-5552. Epub 2017 May 2.

Department of Chemistry & Biochemistry, Florida Atlantic University , 777 Glades Road, Boca Raton, Florida 33431, United States.

Luminescent lanthanides containing coordination polymers and metal-organic frameworks hold great potential in many applications due to their distinctive spectroscopic properties. While the ability to design coordination polymers for specific functions is often mentioned as a major benefit bestowed on these compounds, the lack of a meaningful understanding of the luminescence in lanthanide coordination polymers remains a significant challenge toward functional design. Currently, the study of these compounds is based on the antenna effect as derived from molecular systems, where organic antennae are used to facilitate lanthanide-centered luminescence. This molecular-based approach does not take into account the unique features of extended network solids, particularly the formation of band structure. While guidelines for the antenna effect are well established, they require modification before being applied to coordination polymers. A series of nine coordination polymers with varying topologies and organic linkers were studied to investigate the accuracy of the antenna effect in coordination polymer systems. By comparing a molecular-based approach to a band-based one, it was determined that the band structure that occurs in aggregated organic solids needs to be considered when evaluating the luminescence of lanthanide coordination polymers.
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http://dx.doi.org/10.1021/acs.inorgchem.6b02838DOI Listing
May 2017

Transoral robotic surgery with radial forearm free flap reconstruction: case control analysis.

J Otolaryngol Head Neck Surg 2017 Mar 14;46(1):20. Epub 2017 Mar 14.

Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Alberta, 8440-112 st, 1E4 Walter Mackenzie Centre, Edmonton, AB, T6G 2B7, Canada.

Background: The resection of large oropharyngeal tumors traditionally involves a lip-splitting mandibulotomy for adequate margin visualization and free flap reconstruction of the surgical defect. Transoral robotic surgery (TORS) has emerged as a technique that can resect large and complex oropharyngeal tumors, avoiding a lip-splitting approach. The aim of this study is to compare the lip-splitting mandibulotomy approach versus TORS for the management of advanced stage oropharyngeal carcinomas.

Methods: Prospectively collected data from 18 patients with advanced stage oropharyngeal squamous cell carcinoma (OPSCC) who received TORS with radial forearm free flap reconstruction (RFFF) was compared to a matched cohort of 39 patients who received a lip-splitting mandibulotomy and RFFF. Patients were matched for stage, p16 positivity, smoking, age and gender. Length of hospital stay (LOHS), tracheostomy decanulation time, operative time, surgical margin status, and post-operative complications were compared between groups.

Results: Patients who received TORS with RFFF had a significantly lower mean LOHS, compared to patients who were treated by lip-splitting mandibulotomy and RFFF (14.4 vs 19.7 days, p = 0.03). No significant differences were seen between groups in terms of operative time, tracheostomy decannulation time, margin positivity and post-operative complications.

Conclusion: TORS with radial forearm free flap reconstruction is a safe, effective and cost-saving alternative to the lip-splitting mandibulotomy approach for the treatment of advanced stage OPSCC.
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http://dx.doi.org/10.1186/s40463-017-0196-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351107PMC
March 2017

Disease spread in age structured populations with maternal age effects.

Ecol Lett 2017 04 7;20(4):445-451. Epub 2017 Mar 7.

Institute of Evolutionary Biology, The University of Edinburgh, Ashworth Laboratories, Kings Buildings, Charlotte Auerbach Road, Edinburgh, EH9 3FL, Scotland.

Fundamental ecological processes, such as extrinsic mortality, determine population age structure. This influences disease spread when individuals of different ages differ in susceptibility or when maternal age determines offspring susceptibility. We show that Daphnia magna offspring born to young mothers are more susceptible than those born to older mothers, and consider this alongside previous observations that susceptibility declines with age in this system. We used a susceptible-infected compartmental model to investigate how age-specific susceptibility and maternal age effects on offspring susceptibility interact with demographic factors affecting disease spread. Our results show a scenario where an increase in extrinsic mortality drives an increase in transmission potential. Thus, we identify a realistic context in which age effects and maternal effects produce conditions favouring disease transmission.
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http://dx.doi.org/10.1111/ele.12745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849612PMC
April 2017

Differential recruitment of co-regulatory proteins to the human estrogen receptor 1 in response to xenoestrogens.

Comp Biochem Physiol Part D Genomics Proteomics 2016 09 20;19:159-173. Epub 2016 Apr 20.

Department of Environmental and Global Health and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611, USA. Electronic address:

The diverse biological effects of xenoestrogens may be explained by their ability to differentially recruit co-regulatory proteins to the estrogen receptor (ER). We employed high-throughput receptor affinity binding and co-regulatory protein recruitment screening assays based on fluorescence polarization and time resolved florescence resonance energy transfer (TR-FRET), respectively, to assess xenoestrogen-specific binding and co-regulatory protein recruitment to the ER. Then we used a functional proteomic assay based on co-immunoprecipitation of ER-bound proteins to isolate and identify intact co-regulatory proteins recruited to a ligand-activated ER. Through these approaches, we revealed differential binding affinity of bisphenol-A (BPA) and genistein (GEN) to the human ERα (ESR1) and ligand-dependent recruitment of SRC-1 and SRC-3 peptides. Recruitment profiles were variable for each ligand and in some cases were distinct compared to 17β-estradiol (E2). For example, E2 and GEN recruited both SRC-1 and -3 peptides whereas BPA recruited only SRC-1 peptides. Results of the functional proteomic assay showed differential recruitment between ligands where E2 recruited the greatest number of proteins followed by BPA then GEN. A number of proteins share previously identified relationships with ESR1 as determined by STRING analysis. Although there was limited overlap in proteins identified between treatments, all ligands recruited proteins involved in cell growth as determined by subnetwork enrichment analysis (p<0.05). A comparative, in silico analysis revealed that fewer interactions exist between zebrafish (Danio rerio) esr1 and zebrafish orthologs of proteins identified in our functional proteomic analysis. Taken together these results identify recruitment of known and previously unknown co-regulatory proteins to ESR1 and highlight new methods to assay recruitment of low abundant and intact, endogenous co-regulatory proteins to ESR1 or other nuclear receptors, in both human and aquatic species.
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http://dx.doi.org/10.1016/j.cbd.2016.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987164PMC
September 2016

Validation of the Questionnaire to Identify Knee Symptoms (QuIKS) using Rasch analysis.

Health Qual Life Outcomes 2015 Sep 29;13:157. Epub 2015 Sep 29.

School of Physical Therapy and Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, N6G1H1, Canada.

Background: The Questionnaire to Identify Knee Symptoms (QuIKS) was recently developed to promote activity by screening for experiences related to early symptoms in people with emergent chronic knee pain problems, such as osteoarthritis (OA) - like knee pain. The main purpose of the current study was to evaluate measurement properties of the QuIKS using Rasch analysis in a sample of people with knee symptoms consistent with symptomatic knee OA.

Method: This study used cross-sectional data. The sample was 200 subjects along the following knee health continuum: pain-free healthy knees (n = 55) from a university community, knee pain with no knee OA diagnosis (n = 111) from a university-affiliated medical clinic, and patients with surgeon-diagnosed symptomatic knee OA awaiting high tibial osteotomy (n = 34) from a sports medicine surgical clinic. The 13-item QuIKS was evaluated for its factor structure, item- and person-fit, item's category response structure, differential item functioning by sex and obesity status, local item dependency, unidimensionality, and test precision. Subsequently, the QuIKS underwent known-groups analysis and convergent validity with the Knee injury and Osteoarthritis Outcome Score (KOOS).

Results: In the QuIKS, each item's category response structure was modified. No differential item functioning was observed. Local item dependency informed the formation of four testlets. This refined QuIKS obtained summary fit to the Rasch measurement model, unidimensionality, reliability (person separation index = 0.82), and interval-level scoring. Subsequently, the Rasch-validated QuIKS (QuIKS-R) demonstrated excellent known-groups validity and good convergent validity with the KOOS (Spearman's rho = 0.45 to 0.77).

Conclusions: The QuIKS-R provides interval-level quantification of knee symptoms-related experiences in people with knee symptoms consistent with symptomatic knee OA. Its scores might be useful for clinicians for promoting activity in individuals with early symptoms consistent with symptomatic knee OA.
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http://dx.doi.org/10.1186/s12955-015-0358-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587900PMC
September 2015

Correlation of PET-CT nodal SUVmax with p16 positivity in oropharyngeal squamous cell carcinoma.

J Otolaryngol Head Neck Surg 2015 Sep 15;44:37. Epub 2015 Sep 15.

Faculty of Medicine and Dentistry, Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been rising in recent years. Given the clinical impact of HPV/p16 positivity in OPSCC, identifying surrogate markers of this disease early in the diagnostic work-up of these patients could improve patient care.

Methods: Demographic, pathologic, staging and PET-CT data from patients diagnosed with OPSCC from 2009-2014 were obtained from a prospectively collected provincial cancer registry. Tumor HPV/p16 status was correlated to the maximum standard uptake value (SUVmax) of the primary tumor and cervical nodes. Comparisons of means and multinomial regression models were used to determine associations between p16 status and SUVmax. A diagnostic odds ratio was calculated using a cut off value for predicting HPV/p16 positivity based on nodal SUVmax.

Results: PET-CT and HPV/p16 data was obtained for 65 patients treated surgically for OPSCC. Significantly higher nodal SUVmax was associated with HPV/p16 positive nodes (SUVmax 10.8 vs 7.9). No significant differences were seen between HPV/p16 positive vs negative primary tumor SUVmax (10.3 vs 13.7). In combination with other clinical parameters, higher nodal SUVmax was highly correlated with HPV/p16 positivity.

Conclusion: Elevated nodal SUVmax is a significant predictor of HPV/p16 positive disease.
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http://dx.doi.org/10.1186/s40463-015-0091-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570692PMC
September 2015

A New Player in the Spermiogenesis Pathway of Caenorhabditis elegans.

Genetics 2015 Nov 2;201(3):1103-16. Epub 2015 Sep 2.

Department of Biological Science, California State Polytechnic University, Pomona, California 91768.

Precise timing of sperm activation ensures the greatest likelihood of fertilization. Precision in Caenorhabditis elegans sperm activation is ensured by external signaling, which induces the spherical spermatid to reorganize and extend a pseudopod for motility. Spermatid activation, also called spermiogenesis, is prevented from occurring prematurely by the activity of SPE-6 and perhaps other proteins, termed "the brake model." Here, we identify the spe-47 gene from the hc198 mutation that causes premature spermiogenesis. The mutation was isolated in a suppressor screen of spe-27(it132ts), which normally renders worms sterile, due to defective transduction of the activation signal. In a spe-27(+) background, spe-47(hc198) causes a temperature-sensitive reduction of fertility, and in addition to premature spermiogenesis, many mutant sperm fail to activate altogether. The hc198 mutation is semidominant, inducing a more severe loss of fertility than do null alleles generated by CRISPR-associated protein 9 (Cas9) technology. The hc198 mutation affects an major sperm protein (MSP) domain, altering a conserved amino acid residue in a β-strand that mediates MSP-MSP dimerization. Both N- and C-terminal SPE-47 reporters associate with the forming fibrous body (FB)-membranous organelle, a specialized sperm organelle that packages MSP and other components during spermatogenesis. Once the FB is fully formed, the SPE-47 reporters dissociate and disappear. SPE-47 reporter localization is not altered by either the hc198 mutation or a C-terminal truncation deleting the MSP domain. The disappearance of SPE-47 reporters prior to the formation of spermatids requires a reevaluation of the brake model for prevention of premature spermatid activation.
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http://dx.doi.org/10.1534/genetics.115.181172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649638PMC
November 2015

Cux2 activity defines a subpopulation of perinatal neurogenic progenitors in the hippocampus.

Hippocampus 2015 Feb 3;25(2):253-67. Epub 2014 Oct 3.

Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Life Science Research Institute, Halifax, Nova Scotia, Canada.

The hippocampus arises from the medial region of the subventricular (SVZ) within the telencephalon. It is one of two regions in the postnatal brain that harbors neural progenitors (NPs) capable of giving rise to new neurons. Neurogenesis in the hippocampus is restricted to the subgranular zone (SGZ) of the dentate gyrus (DG) where it contributes to the generation of granule cell layer (gcl) neurons. It is thought that SGZ progenitors are heterogeneous, differing in their morphology, expression profiles, and developmental potential, however it is currently unknown whether they display differences in their developmental origins and cell fate-restriction in the DG. Here we demonstrate that Cux2 is a marker for SGZ progenitors and nascent granule cell neurons in the perinatal brain. Cux2 was expressed in the presumptive hippocampal forming region of the embryonic forebrain from E14.5 onwards. At fetal stages, Cux2 was expressed in early-forming Prox1(+) granule cell neurons as well as the SVZ of the DG germinal matrix. In the postnatal brain, Cux2 was expressed in several types of progenitors in the SGZ of the DG, including Nestin/Sox2 double-positive radial glia, Sox2(+) cells that lacked a radial glial process, DCX(+) neuroblasts, and Calretinin-expressing nascent neurons. Another domain characterized by a low level of Cux2 expression emerged in Calbindin(+) neurons of the developing DG blades. We used Cux2-Cre mice in genetic fate-mapping studies and showed almost exclusive labeling of Calbindin-positive gcl neurons, but not in any progenitor cell types or astroglia. This suggests that Cux2(+) progenitors directly differentiate into gcl neurons and do not self-renew. Interestingly, developmental profiling of cell fate revealed an outside-in formation of gcl neurons in the DG, likely reflecting the activity of Cux2 in the germinative matrices during DG formation and maturation. However, DG morphogenesis proceeded largely normally in hypomorphic Cux2 mutants lacking Cux2 expression. Taken together we conclude that Cux2 expression reflects hippocampal neurogenesis and identifies non-self-renewing NPs in the SGZ.
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http://dx.doi.org/10.1002/hipo.22370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312975PMC
February 2015
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