bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae
Authors: Mayo-Smith Leslie M. , Simon Jakub K. , Chen Wilbur H. , Haney Douglas , Lock Michael , Lyon Caroline E. , Calderwood Stephen B. , Kirkpatrick Beth D. , Cohen Mitchell , Levine Myron M. , Gurwith Marc , Harris Jason B. 
Published: November 2016

ABSTRACT

One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the
in vivo
-induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to
Vibrio cholerae
O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with
V. cholerae
O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with
V. cholerae
alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed
in vivo
by attenuated
V. cholerae
may have relevance to the maintenance of immunity in areas where cholera is endemic.
An Amino Acid in the Stalk Domain of N1 Neuraminidase Is Critical for Enzymatic Activity
Authors: Zanin Mark , Duan Susu , Wong Sook-San , Kumar Gyanendra , Baviskar Pradyumna , Collin Emily , Russell Charles , Barman Subrata , Hause Benjamin , Webby Richard 
Published: November 2016

ABSTRACT

Neuraminidase (NA) is a sialidase expressed on the surface of influenza A viruses that releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. It is a homotetramer, with each monomer consisting of a transmembrane region, a stalk, and a globular head with sialidase activity. We recently characterized two swine viruses of the pandemic H1N1 lineage, A/swine/Virginia/1814-1/2012 (pH1N1
low
-1) and A/swine/Virginia/1814-2/2012 (pH1N1
low
-2), with almost undetectable NA enzymatic activity compared to that of the highly homologous A/swine/Pennsylvania/2436/2012 (pH1N1-1) and A/swine/Minnesota/2499/2012 (pH1N1-2) viruses. pH1N1-1 transmitted to aerosol contact ferrets, but pH1N1
low
-1 did not. The aim of this study was to identify the molecular determinants associated with low NA activity as potential markers of aerosol transmission. We identified the shared unique substitutions M19V, A232V, D248N, and I436V (N1 numbering) in pH1N1
low
-1 and pH1N1
low
-2. pH1N1
low
-1 also had the unique Y66D substitution in the stalk domain, where 66Y was highly conserved in N1 NAs. Restoration of 66Y was critical for the NA activity of pH1N1
low
-1 NA, although 19M or 248D in conjunction with 66Y was required to recover the level of activity to that of pH1N1 viruses. Studies of NA stability and molecular modeling revealed that 66Y likely stabilized the NA homotetramer. Therefore, 66Y in the stalk domain of N1 NA was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.

IMPORTANCE
Neuraminidase (NA) is a sialidase that is one of the major surface glycoproteins of influenza A viruses and the target for the influenza drugs oseltamivir and zanamivir. NA is important as it releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. Mutations in the globular head domain that decrease enzymatic activity but confer resistance to NA inhibitors have been characterized; however, the importance of specific mutations in the stalk domain is unknown. We identified 66Y (N1 numbering), a highly conserved amino acid that was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.
Replacement of Porcine CD163 Scavenger Receptor Cysteine-Rich Domain 5 with a CD163-Like Homolog Confers Resistance of Pigs to Genotype 1 but Not Genotype 2 Porcine Reproductive and Respiratory Syndrome Virus
Authors: Wells Kevin D. , Bardot Rachel , Whitworth Kristin M. , Trible Benjamin R. , Fang Ying , Mileham Alan , Kerrigan Maureen A. , Samuel Melissa S. , Prather Randall S. , Rowland Raymond R. R. 
Published: November 2016

ABSTRACTCD163 knockout (KO) pigs are resistant to infection with genotype 2 (type 2) porcine reproductive and respiratory syndrome virus (PRRSV). Furthermore, the substitution of CD163 scavenger receptor cysteine-rich (SRCR) domain 5 with a homolog of human CD163-like (hCD163L1) SRCR 8 domain confers resistance of transfected HEK cells to type 1 PRRSV. As a means to understand the role of domain 5 in PRRSV infection with both type 1 and type 2 viruses, pigs were genetically modified (GM) to possess one of the following genotypes: complete knockout (KO) of CD163, deletions within SRCR domain 5, or replacement (domain swap) of SRCR domain 5 with a synthesized exon encoding a homolog of hCD163L1 SRCR domain 8. Immunophenotyping of porcine alveolar macrophages (PAMs) showed that pigs with the KO or SRCR domain 5 deletion did not express CD163. When placed in culture, PAMs from pigs with the CD163 KO phenotype were completely resistant to a panel consisting of six type 1 and nine type 2 isolates. PAMs from pigs that possessed the hCD163L1 domain 8 homolog expressed CD163 and supported the replication of all type 2 isolates, but no type 1 viruses. Infection ofCD163-modified pigs with representative type 1 and type 2 viruses confirmed thein vitroresults. The results confirm that CD163 is the likely receptor for all PRRS viruses. Even though type 1 and type 2 viruses are considered phenotypically similar at several levels, there is a distinct difference between the viral genotypes in the recognition of CD163.IMPORTANCEGenetic modification of theCD163gene creates the opportunity to develop production animals that are resistant to PRRS, the costliest viral disease to ever face the swine industry. The results create further opportunities to develop refinements in the modification ofCD163with the goal of making pigs refractory to infection while retaining important CD163 functions.
Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria
Authors: Chadha Pooja , Sarfo Akua , Zhang Dan , Abraham Thomas , Carmichael Jillian , Han Jun , Wills John W. 
Published: November 2016

ABSTRACT
The UL16 tegument protein of herpes simplex virus 1 (HSV-1) is conserved among all herpesviruses and plays many roles during replication. This protein has an N-terminal domain (NTD) that has been shown to bind to several viral proteins, including UL11, VP22, and glycoprotein E, and these interactions are negatively regulated by a C-terminal domain (CTD). Thus, in pairwise transfections, UL16 binding is enabled only when the CTD is absent or altered. Based on these results, we hypothesized that direct interactions occur between the NTD and the CTD. Here we report that the separated and coexpressed functional domains of UL16 are mutually responsive to each other in transfected cells and form complexes that are stable enough to be captured in coimmunoprecipitation assays. Moreover, we found that the CTD can associate with itself. To our surprise, the CTD was also found to contain a novel and intrinsic ability to localize to specific spots on mitochondria in transfected cells. Subsequent analyses of HSV-infected cells by immunogold electron microscopy and live-cell confocal imaging revealed a population of UL16 that does not merely accumulate on mitochondria but in fact makes dynamic contacts with these organelles in a time-dependent manner. These findings suggest that the domain interactions of UL16 serve to regulate not just the interaction of this tegument protein with its viral binding partners but also its interactions with mitochondria. The purpose of this novel interaction remains to be determined.

IMPORTANCE
The HSV-1-encoded tegument protein UL16 is involved in multiple events of the virus replication cycle, ranging from virus assembly to cell-cell spread of the virus, and hence it can serve as an important drug target. Unfortunately, a lack of both structural and functional information limits our understanding of this protein. The discovery of domain interactions within UL16 and the novel ability of UL16 to interact with mitochondria in HSV-infected cells lays a foundational framework for future investigations aimed at deciphering the structure and function of not just UL16 of HSV-1 but also its homologs in other herpesviruses.
Myeloid Cell Turnover and Clearance
Authors: Janssen William J. , Bratton Donna L. , Jakubzick Claudia V. , Henson Peter M. 
Published: November 2016

ABSTRACTGiven the dual and intrinsically contradictory roles of myeloid cells in both protective and yet also damaging effects of inflammatory and immunological processes, we suggest that it is important to consider the mechanisms and circumstances by which these cells are removed, either in the normal unchallenged state or during inflammation or disease. In this essay we address these subjects from a conceptual perspective, focusing as examples on four main myeloid cell types (neutrophils, monocytes, macrophages, and myeloid dendritic cells) and their clearance from the circulation or from naive and inflamed tissues. While the primary clearance process appears to involve endocytic uptake into macrophages, various tissue cell types can also recognize and remove dying cells, though their overall quantitative contribution is unclear. In fact, surprisingly, given the wealth of study in this area over the last 30 years, our conclusion is that we are still challenged with a substantial lack of mechanistic and regulatory understanding of when, how, and by what mechanisms migratory myeloid cells come to die and are recognized as needing to be removed, and indeed the precise processes of uptake of either the intact or fragmented cells. This reflects the extreme complexity and inherent redundancy of the clearance processes and argues for substantial investigative effort in this arena. In addition, it leads us to a sense that approaches to significant therapeutic modulation of selective myeloid clearance are still a long way off.
Ocular Tuberculosis
Authors: Albert Daniel M. , Raven Meisha L. 
Published: November 2016

ABSTRACTOcular tuberculosis is an extrapulmonary mycobacterial infection with variable manifestations. The reported incidence of ocular involvement varies considerably, depending on the criteria used for diagnosis and the population sampled. However, tuberculosis is thought to affect the lungs in 80% of patients, with the remaining 20% being affected in other organs, such as the eye. It is imperative for physicians to consider this diagnosis in their differential, as ocular tuberculosis can present in a fashion similar to that of more common conditions causing ocular inflammation. In addition, prompt recognition of the clinical signs and symptoms leads to quicker initiation of antituberculosis therapy.
Long shadow of fear in an epidemic: fearonomic effects of Ebola on the private sector in Nigeria
Authors: Bali Sulzhan , Stewart Kearsley A , Pate Muhammad Ali 
Published: November 2016

BackgroundThe already significant impact of the Ebola epidemic on Guinea, Liberia and Sierra Leone, was worsened by a fear of contagion that aggravated the health crisis. However, in contrast to other Ebola-affected countries, Nigeria fared significantly better due to its swift containment of the disease. The objective of our study was to describe the impact of Ebola on the Nigerian private sector. This paper introduces and defines the termfearonomic effectas the direct and indirect economic effects of both misinformation as well as fear-induced aversion behaviour, exhibited by individuals, organisations or countries during an outbreak or an epidemic.MethodsThis study was designed as a cross-sectional mixed-methods study that used semistructured in-depth interviews and a supporting survey to capture the impact of Ebola on the Nigerian private sector after the outbreak. Themes were generated from the interviews on the direct and indirect impact of Ebola on the private sector; the impact of misinformation and fear-based aversion behaviour in the private sector.ResultsOur findings reveal that the fearonomic effects of Ebola included health service outages and reduced healthcare usage as a result of misinformation and aversion behaviour by both patients and providers. Although certain sectors (eg, health sector, aviation sector, hospitality sector) in Nigeria were affected more than others, no business was immune to Ebola's fearonomic effects. We describe how sectors expected to prosper during the outbreak (eg, pharmaceuticals), actually suffered due to the changes in consumption patterns and demand shocks.ConclusionIn a high-stressor epidemic-like setting, altered consumption behaviour due to distorted disease perception, misinformation and fear can trigger short-term economic cascades that can disproportionately affect businesses and lead to financial insecurity of the poorest and the most vulnerable in a society.
The role of intersection and street design on severity of bicycle-motor vehicle crashes
Authors: Asgarzadeh Morteza , Verma Santosh , Mekary Rania A , Courtney Theodore K , Christiani David C 
Published: November 2016

BackgroundSafety concerns are a major barrier to cycling. Intersection and street design variables such as intersection angles and street width might contribute to the severity of crashes and the safety concerns. In this study we examined whether these design variables were associated with bicycle-motor vehicle crashes (BMVC) severity.MethodsUsing the geographical information system and latitudes/longitudes recorded by the police using a global positioning device, we extracted intersection angles, street width, bicycle facilities, posted speed limits and annual average daily traffic from 3266 BMVC data from New York City police records. Additional variables about BMVC, including age and sex of the bicyclist, time of the day, road surface conditions, road character, vehicle type and injury severity, were obtained from police reports. Injury severity was classified as severe (incapacitating or killed) or non-severe (non-incapacitating, possible injury). The associations between injury severity and environment design variables were examined using multivariate log-binomial regression model.FindingsCompared with crashes at orthogonal intersections, crashes at non-orthogonal intersections had 1.37 times (95% CI 1.05 to 1.80) and non-intersection street segments had 1.31 times (95% CI 1.01 to 1.70) higher risk of a severe injury. Crashes that involved a truck or a bus were twice as likely to result in a severe injury outcome; street width was not significantly associated with injury severity.ConclusionCrashes at non-orthogonal intersections and non-intersection segments are more likely to result in higher injury severity. The findings can be used to improve road design and develop effective safety interventions.
Cocaine sensitization increases subthreshold activity in dopamine neurons from the ventral tegmental area
Authors: Arencibia-Albite Francisco , Vázquez-Torres Rafael , Jiménez-Rivera Carlos A. 
Published: November 2016

The progressive escalation of psychomotor responses that results from repeated cocaine administration is termed sensitization. This phenomenon alters the intrinsic properties of dopamine (DA) neurons from the ventral tegmental area (VTA), leading to enhanced dopaminergic transmission in the mesocorticolimbic network. The mechanisms underlying this augmented excitation are nonetheless poorly understood. DA neurons display the hyperpolarization-activated, nonselective cation current, dubbed Ih. We recently demonstrated that Ih and membrane capacitance are substantially reduced in VTA DA cells from cocaine-sensitized rats. The present study shows that 7 days of cocaine withdrawal did not normalize Ih and capacitance. In cells from cocaine-sensitized animals, the amplitude of excitatory synaptic potentials, at −70 mV, was ∼39% larger in contrast to controls. Raise and decay phases of the synaptic signal were faster under cocaine, a result associated with a reduced membrane time constant. Synaptic summation was paradoxically elevated by cocaine exposure, as it consisted of a significantly reduced summation indexed but a considerably increased depolarization. These effects are at least a consequence of the reduced capacitance. Ih attenuation is unlikely to explain such observations, since at −70 mV, no statistical differences exist in Ih or input resistance. The neuronal shrinkage associated with a diminished capacitance may help to understand two fundamental elements of drug addiction: incentive sensitization and negative emotional states. A reduced cell size may lead to substantial enhancement of cue-triggered bursting, which underlies drug craving and reward anticipation, whereas it could also result in DA depletion, as smaller neurons might express low levels of tyrosine hydroxylase. NEW & NOTEWORTHY This work uses a new approach that directly extracts important biophysical parameters from alpha function-evoked synaptic potentials. Two of these parameters are the cell membrane capacitance (Cm) and rate at any time point of the synaptic waveform. The use of such methodology shows that cocaine sensitization reduces Cm and increases the speed of synaptic signaling. Paradoxically, although synaptic potentials show a faster decay under cocaine their temporal summation is substantially elevated.
Context-dependent plasticity in the subcortical encoding of linguistic pitch patterns
Authors: Lau Joseph C. Y. , Wong Patrick C. M. , Chandrasekaran Bharath 
Published: November 2016

We examined the mechanics of online experience-dependent auditory plasticity by assessing the influence of prior context on the frequency-following responses (FFRs), which reflect phase-locked responses from neural ensembles within the subcortical auditory system. FFRs were elicited to a Cantonese falling lexical pitch pattern from 24 native speakers of Cantonese in a variable context, wherein the falling pitch pattern randomly occurred in the context of two other linguistic pitch patterns; in a patterned context, wherein, the falling pitch pattern was presented in a predictable sequence along with two other pitch patterns, and in a repetitive context, wherein the falling pitch pattern was presented with 100% probability. We found that neural tracking of the stimulus pitch contour was most faithful and accurate when listening context was patterned and least faithful when the listening context was variable. The patterned context elicited more robust pitch tracking relative to the repetitive context, suggesting that context-dependent plasticity is most robust when the context is predictable but not repetitive. Our study demonstrates a robust influence of prior listening context that works to enhance online neural encoding of linguistic pitch patterns. We interpret these results as indicative of an interplay between contextual processes that are responsive to predictability as well as novelty in the presentation context. NEW & NOTEWORTHY Human auditory perception in dynamic listening environments requires fine-tuning of sensory signal based on behaviorally relevant regularities in listening context, i.e., online experience-dependent plasticity. Our finding suggests what partly underlie online experience-dependent plasticity are interplaying contextual processes in the subcortical auditory system that are responsive to predictability as well as novelty in listening context. These findings add to the literature that looks to establish the neurophysiological bases of auditory system plasticity, a central issue in auditory neuroscience.
Urinary Melatonin in Relation to Postmenopausal Breast Cancer Risk According to Melatonin 1 Receptor Status
Authors: Devore Elizabeth E. , Warner Erica T. , Eliassen A. Heather , Brown Susan B. , Beck Andrew H. , Hankinson Susan E. , Schernhammer Eva S. 
Published: November 2016

AbstractBackground: Urinary melatonin levels have been associated with a reduced risk of breast cancer in postmenopausal women, but this association might vary according to tumor melatonin 1 receptor (MT1R) expression.Methods: We conducted a nested case–control study among 1,354 postmenopausal women in the Nurses' Health Study, who were cancer free when they provided first-morning spot urine samples in 2000 to 2002; urine samples were assayed for 6-sulfatoxymelatonin (aMT6s, a major metabolite of melatonin). Five-hundred fifty-five of these women developed breast cancer before May 31, 2012, and were matched to 799 control subjects. In a subset of cases, immunohistochemistry was used to determine MT1R status of tumor tissue. We used multivariable-adjusted conditional logistic regression to estimate the relative risk (RR) of breast cancer [with 95% confidence intervals (CI)] across quartiles of creatinine-standardized urinary aMT6s level, including by MT1R subtype.Results: Higher urinary melatonin levels were suggestively associated with a lower overall risk of breast cancer (multivariable-adjusted RR = 0.78; 95% CI = 0.61–0.99, comparing quartile 4 vs. quartile 1; Ptrend = 0.08); this association was similar for invasive vs. in situ tumors (Pheterogeneity = 0.12). There was no evidence that associations differed according to MT1R status of the tumor (e.g., Pheterogeneity for overall breast cancer = 0.88).Conclusions: Higher urinary melatonin levels were associated with reduced breast cancer risk in this cohort of postmenopausal women, and the association was not modified by MT1R subtype.Impact: Urinary melatonin levels appear to predict the risk of breast cancer in postmenopausal women. However, future research should evaluate these associations with longer-term follow-up and among premenopausal women. Cancer Epidemiol Biomarkers Prev; 26(3); 413–9. ©2016 AACR.