bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coxsackievirus A9 Infects Cells via Nonacidic Multivesicular Bodies
Authors: Huttunen Moona , Waris Matti , Kajander Ritva , Hyypiä Timo , Marjomäki Varpu 
Published: February 2014

ABSTRACT

Coxsackievirus
A9 (CVA9) is a member of the human enterovirus B species in the
Enterovirus
genus of the family
Picornaviridae
. According to earlier studies, CVA9 binds to αVβ3 and αVβ6 integrins on the cell surface and utilizes β2-microglobulin, dynamin, and Arf6 for internalization. However, the structures utilized by the virus for internalization and uncoating are less well understood. We show here, based on electron microscopy, that CVA9 is found in multivesicular structures 2 h postinfection (p.i.). A neutral red labeling assay revealed that uncoating occurs mainly around 2 h p.i., while double-stranded RNA is found in the cytoplasm after 3 h p.i. The biogenesis of multivesicular bodies (MVBs) is crucial for promoting infection, as judged by the strong inhibitory effect of the wild-type form of Hrs and dominant negative form of VPS4 in CVA9 infection. CVA9 infection is dependent on phospholipase C at the start of infection, whereas Rac1 is especially important between 1 and 3 h p.i., when the virus is in endosomes. Several lines of evidence implicate that low pH does not play a role in CVA9 infection. The infection is not affected by Bafilomycin A1. In addition, CVA9 is not targeted to acidic late endosomes or lysosomes, and the MVBs accumulating CVA9 have a neutral pH. Thus, CVA9 is the second enterovirus demonstrated so far, after echovirus 1, that can trigger neutral MVBs, which are important for virus infection.

IMPORTANCE
We demonstrate here that the enterovirus coxsackievirus A9 (CVA9) uses a nonclathrin and nonacidic pathway to infect cells. CVA9 does not accumulate in conventional late endosomes or lysosomes. We found that inhibitors of phospholipase C (PLC), Rac1, and the Na
+
/H
+
exchanger decreased CVA9 infection. The PLC inhibitor acts on early entry, the Rac1 inhibitor acts between 1 and 3 h, when the virus is in endosomes, and the Na
+
/H
+
exchange inhibitor acts during various steps during the virus life cycle. The infection depends on the formation of novel neutral multivesicular bodies (MVBs), which accumulate CVA9 during the first hours of entry. Thus, CVA9 is the second enterovirus demonstrated so far, after echovirus 1, that can trigger formation of neutral MVBs. The data show that these enteroviruses favor nonacidic conditions and complex MVBs to promote virus infection.
Activities of Transmitted/Founder and Chronic Clade B HIV-1 Vpu and a C-Terminal Polymorphism Specifically Affecting Virion Release
Authors: Jafari Moein , Guatelli John , Lewinski Mary K. 
Published: February 2014

ABSTRACT

Acute HIV-1 infection is characterized by a type I interferon response, resulting in the induction of host restriction factors. HIV-1 has evolved to counteract these factors, and one such adaptation, the ability of Vpu to counteract BST2/tetherin, is associated with the evolution of simian immunodeficiency virus (SIV
cpz
) into pandemic group M human immunodeficiency virus type 1 (HIV-1). During transmission between individuals, very few viruses or even a single virus, the “transmitted/founder” (T/F) virus, gives rise to the new infection, but in the new host the selective pressure of the immune response yields the diverse “quasispecies” of chronic infection. Here we examine the functional characteristics of Vpu proteins encoded by T/F viruses compared to acute and chronic viruses from longitudinally sampled subjects. The studied T/F Vpu proteins showed a trend toward optimized CD4 downregulation compared to chronic Vpu proteins but did not differ substantially in their ability to downregulate BST2 or enhance virion release, although individual clones from each group were impaired in these activities. Analysis of the functionally impaired clones identified a C-terminal residue, W76, as important specifically for Vpu enhancement of virion release. Primary Vpu clones encoding a W76G polymorphism, or site-directed mutants encoding a W76G substitution, were impaired in their ability to enhance virion release, but they were not defective for BST2 surface downregulation. Conversely, the virion release function of impaired primary clones was restored by creating a G76W substitution. The identification of W76 as important for virion release enhancement that is independent of BST2 surface downregulation supports the potential to mechanistically separate these functions of Vpu.

IMPORTANCE
To establish infection in a host, HIV-1 must evade the host's immune response, including the production of antiviral factors. HIV-1 encodes proteins that antagonize these defenses, including Vpu. Vpu counteracts the host protein BST2, which blocks the release of progeny viruses from the host cell. To determine the importance of Vpu activity to HIV-1 transmission, this study assessed the functionality of Vpu from viruses isolated soon after transmission (“transmitted/founder” viruses) compared to isolates from chronic infection. Although the anti-BST2 activity of Vpu proteins from the tested transmitted/founder viruses did not differ from the activity of the chronic Vpu proteins, the transmitted/founder Vpu proteins trended toward having superior activity against another host protein, CD4. Further, this study identified an amino acid near the C terminus of Vpu that is specifically important for Vpu's ability to enhance the release of progeny virus from the host cell, supporting the notion of a new mechanism for this function of Vpu.
Crystal Structure of Marburg Virus VP24
Authors: Zhang Adrianna P. P. , Bornholdt Zachary A. , Abelson Dafna M. , Saphire Erica Ollmann 
Published: February 2014

ABSTRACT
The VP24 protein plays an essential, albeit poorly understood role in the filovirus life cycle. VP24 is only 30% identical between Marburg virus and the ebolaviruses. Furthermore, VP24 from the ebolaviruses is immunosuppressive, while that of Marburg virus is not. The crystal structure of Marburg virus VP24, presented here, reveals that although the core is similar between the viral genera, Marburg VP24 is distinguished by a projecting β-shelf and an alternate conformation of the N-terminal polypeptide.
Role of Poultry in the Spread of Novel H7N9 Influenza Virus in China
Authors: Pantin-Jackwood Mary J. , Miller Patti J. , Spackman Erica , Swayne David E. , Susta Leonardo , Costa-Hurtado Mar , Suarez David L. 
Published: February 2014

ABSTRACT

The recent outbreak of H7N9 influenza in China has resulted in many human cases with a high fatality rate. Poultry are the likely source of infection for humans on the basis of sequence analysis and virus isolations from live bird markets, but it is not clear which species of birds are most likely to be infected and shedding levels of virus sufficient to infect humans. Intranasal inoculation of chickens, Japanese quail, pigeons, Pekin ducks, Mallard ducks, Muscovy ducks, and Embden geese with 10
6
50% egg infective doses of the A/Anhui/1/2013 virus resulted in infection but no clinical disease signs. Virus shedding was much higher and prolonged in quail and chickens than in the other species. Quail effectively transmitted the virus to direct contacts, but pigeons and Pekin ducks did not. In all species, virus was detected at much higher titers from oropharyngeal swabs than cloacal swabs. The hemagglutinin gene from samples collected from selected experimentally infected birds was sequenced, and three amino acid differences were commonly observed when the sequence was compared to the sequence of A/Anhui/1/2013: N123D, N149D, and L217Q. Leucine at position 217 is highly conserved for human isolates and is associated with α2,6-sialic acid binding. Different amino acid combinations were observed, suggesting that the inoculum had viral subpopulations that were selected after passage in birds. These experimental studies corroborate the finding that certain poultry species are reservoirs of the H7N9 influenza virus and that the virus is highly tropic for the upper respiratory tract, so testing of bird species should preferentially be conducted with oropharyngeal swabs for the best sensitivity.

IMPORTANCE
The recent outbreak of H7N9 influenza in China has resulted in a number of human infections with a high case fatality rate. The source of the viral outbreak is suspected to be poultry, but definitive data on the source of the infection are not available. This study provides experimental data to show that quail and chickens are susceptible to infection, shed large amounts of virus, and are likely important in the spread of the virus to humans. Other poultry species can be infected and shed virus but are less likely to play a role of transmitting the virus to humans. Pigeons were previously suggested to be a possible source of the virus because of isolation of the virus from several pigeons in poultry markets in China, but experimental studies show that they are generally resistant to infection and are unlikely to play a role in the spread of the virus.
Mitophagy Enhances Oncolytic Measles Virus Replication by Mitigating DDX58/RIG-I-Like Receptor Signaling
Authors: Xia Mao , Gonzalez Patrick , Li Chunyan , Meng Gang , Jiang Aiqin , Wang Hongwei , Gao Qian , Debatin Klaus-Michael , Beltinger Christian , Wei Jiwu 
Published: February 2014

ABSTRACT
The success of future clinical trials with oncolytic viruses depends on the identification and the control of mechanisms that modulate their therapeutic efficacy. In particular, little is known about the role of autophagy in infection by attenuated measles virus of the Edmonston strain (MV-Edm). We investigated the interaction between autophagy, innate immune response, and oncolytic activity of MV-Edm, since the antiviral immune response is a known factor limiting virotherapies. We report that MV-Edm exploits selective autophagy to mitigate the innate immune response mediated by DDX58/RIG-I like receptors (RLRs) in non-small cell lung cancer (NSCLC) cells. Both RNA interference (RNAi) and overexpression approaches demonstrate that autophagy enhances viral replication and inhibits the production of type I interferons regulated by RLRs. We show that MV-Edm unexpectedly triggers SQSTM1/p62-mediated mitophagy, resulting in decreased mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and subsequently weakening the innate immune response. These results unveil a novel infectious strategy based on the usurpation of mitophagy leading to mitigation of the innate immune response. This finding provides a rationale to modulate autophagy in oncolytic virotherapy.

IMPORTANCE
In vitro
studies, preclinical experiments
in vivo
, and clinical trials with humans all indicate that oncolytic viruses hold promise for cancer therapy. Measles virus of the Edmonston strain (MV-Edm), which is an attenuated virus derived from the common wild-type measles virus, is paradigmatic for therapeutic oncolytic viruses. MV-Edm replicates preferentially in and kills cancer cells. The efficiency of MV-Edm is limited by the immune response of the host against viruses. In our study, we revealed that MV-Edm usurps a homeostatic mechanism of intracellular degradation of mitochondria, coined mitophagy, to attenuate the innate immune response in cancer cells. This strategy might provide a replicative advantage for the virus against the development of antiviral immune responses by the host. These findings are important since they may not only indicate that inducers of autophagy could enhance the efficacy of oncolytic therapies but also provide clues for antiviral therapy by targeting SQSTM1/p62-mediated mitophagy.
Teen dating violence perpetration and relation to STI and sexual risk behaviours among adolescent males
Authors: Reed Elizabeth , Miller Elizabeth , Raj Anita , Decker Michele R , Silverman Jay G 
Published: February 2014

ObjectivesTo investigate teen dating violence (TDV) perpetration (physical, sexual or psychological violence) and association with STI and related sexual risk behaviours among urban male adolescents.MethodsAdolescent male survey participants (N=134) were aged 14–20 years, recruited from urban health centres. Using crude and adjusted logistic regression, TDV perpetration was examined in relation to self-reported: STI, having sex with another person when they were only supposed to have sex with their main partner, and consistent condom use.ResultsOver one-third of males (45%) reported any TDV; 42% reported sexual violence perpetration, 13% reported perpetrating physical violence against a dating/sexual partner and 11% reported psychological violence, including threats of physical or sexual violence. Approximately 15% of males reported having ever had an STI, one quarter reported having sex with another person when they were only supposed to have sex with their main partner and 36% reported consistent condom use (past 3 months). In adjusted logistic regression models, TDV perpetration was significantly associated with self-reports of an STI (OR=3.3; 95% CI 1.2 to 9.2) and having sex with another person when they were supposed to be only having sex with their main partner (OR=4.8; 95% CI 2.0 to 11.4). There was no significant association between TDV perpetration and consistent condom use.ConclusionsCurrent study findings are the first within the literature on adolescents to suggest that greater STI and sexual risk behaviours among male adolescents perpetrating TDV may be one mechanism explaining increased STI among female adolescents reporting TDV victimisation.
Pathogen presence in feral pigs and their movement around two commercial piggeries in Queensland, Australia
Authors: Pearson H. E. , Toribio J‐A. L. M. L. , Hernandez‐Jover M. , Marshall D. , Lapidge S. J. 
Published: February 2014

Feral pigs are wild animal reservoirs of infectious pathogens transmissible to other species, all of which are transmissible to domestic pigs. The objective of this study was to detect the presence of harmful production‐limiting pathogens; Brucella suis, Leptospira species, Lawsonia intracellularis, Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae in a feral pig population within a 10 km radius of two large‐scale commercial piggeries in Southern Queensland, Australia. The movement pattern of six pigs within the feral population was also investigated using geographic positioning system collars. All pathogens were present in the feral pig population except for A pleuropneumoniae. The true seroprevalence (TP) from 83 serum samples was 10.5 per cent for B suis, 48.6 per cent for Leptospira species, 100 per cent for L intracellularis and 42.1 per cent for M hyopneumoniae. Of 72 lung samples, 27.6 per cent were positive for M hyopneumoniae. Serum samples from 86 domestic sows within the study region were positive for Leptospira species (TP 2.1 per cent), L intracellularis (TP 100 per cent) and M hyopneumoniae (TP 100 per cent). The majority of feral pig movement was within 5 km of the piggeries, with one approaching to 100 m of the free‐range piggery. The presence of pathogens in feral pigs in such close proximity to commercial piggeries could pose a biosecurity risk.
The Park Hotels: Designing Communications
Authors: Gupta Seema , Ramachandran J. 
Published: February 2014

The case describes how Priya Paul, the Chairperson of The Park Hotel (TPH), and her team created a uniquely Indian boutique hotel network — infusing each property with local ethos and a charming distinction, emphasizing intimate and personalized service, and positioning each hotel as an entertainment destination for customers. The case invites students to consider the communication choices open to the TPH management in 2010 as they cope with growing competition from the entry of international majors (Hyatt, Starwood Hotels and JW Marriott) and the expansion plans of domestic giants (The Taj, Oberoi and ITC Welcomgroup) while seeking to retain the distinctiveness and individuality of each of the properties in the network. The case describes the communication strategy adopted by TPH and elaborates on the various channels of communication used such as personal selling, advertising, public relations, and social media. The rich exhibits of the case allow for analysis of creative as well as media strategy. The case will enable participants to understand the challenges in integrating the different elements of marketing communications and the challenges in communicating experiences as opposed to products or services.
GAZI and the Shock Absorber Market in Thailand
Authors: Koojaroenpaisan Rawiporn , Patterson Paul 
Published: February 2014

Siam Suspension Innovation Co. Ltd. (SSI) in 2004 manufactured the first local brand of shock absorber for motor cycles (GAZI brand) in Thailand. This case documents how several entrepreneurs with a passion for motorcycles grasped an opportunity to invent, manufacture and successfully brand a decorative shock absorber for the ubiquitous motorcycle riders of Thailand. Prior to the development of the GAZI brand, shock absorbers were simply just another OEM (original equipment manufacturer) component on a motor bike that was typically only replaced when it was worn out. Shock absorbers were differentiated on their performance characteristics of smoothness of ride. Siam Suspension Company (SSI) changed all that with their decorative GAZI brand that had a mass appeal to consumers under 25 years who possessed a 125–150cc motorcycle (by far the largest segment) who simply wanted their motorcycles to look attractive. Rather than compete in the high volume, low margin standard shock absorber segment, SSI positioned GAZI as a decorative shock absorber. However, because GAZI used a new innovative gas filled technology (all other brands used oil filled cylinders) it also gave a much smoother ride on the rough roads of Thailand. GAZI's management initially created a “first-mover” advantage by targeting Gen Y consumers and convincing them to use shock absorbers to decorate their motorcycles. Hence a replacement market was born for decorative shock absorbers, with many riders replacing the OEM shocks as soon as they purchased a new motorcycle. Sales grew at a rapid pace until other manufacturers of standard shocks saw the success of GAZI. At this time the barriers to entry were quite low. As a SME (small to medium size enterprise) with limited capital, the challenge for SSI in 2012 is how to regroup and stay one step ahead of the competition and protect its market share from further erosion.
Bajaj Auto Limited: Synergizing Product Engineering and Market Engineering Initiatives
Authors: Mishra Manit , Sahoo S. C. 
Published: February 2014

The case chronicles the rise-fall-rise saga of the Indian two-wheeler major Bajaj Auto Limited from the perspective of product engineering and market engineering initiatives. The Indian two-wheeler industry went through a metamorphosis over the last two decades as consumer preference shifted from inconspicuous scooter to elegant motorcycle. Even as Bajaj implemented product and market engineering initiatives to satisfy changing consumer tastes, its market share was not a reflection of its efforts until it integrated these two vital domains. The case elucidates upon the decision situations encountered by the top management of Bajaj in its quest to attain consumer centricity through synergistic assimilation of product engineering skills and market engineering acumen. The case is divided into eight sections. The introduction section traces the history of Indian two-wheeler industry from the product and market engineering perspective and elucidates upon the challenge of creating a customer-centred company through synergistic assimilation of both these vital domains. The second section offers a view of the present two-wheeler industry landscape; critically evaluates the consumer value system to reveal the different benefit-based customer segments; and, documents the shifting loyalty of Indian consumers from archaic scooters to aesthetic motorcycles. The third section maps the industry in terms of price and engine capacity so as to sketch out the competitive scenario. The fourth section highlights the trials and tribulations that the organization has undergone on its way to learning the ropes towards better integration of product engineering and market engineering initiatives. The fifth section provides a description of the various product innovation measures taken by Bajaj in the decade gone by to win back its lost glory. The sixth section delineates Bajaj's endeavour in the last decade to harness latent consumer needs, wants and desires to its advantage. The section on competitors' product and market engineering strategies puts into perspective the product engineering and market engineering strategies of Bajaj's key competitors — Hero Honda and TVS. The case culminates with the conclusion section wherein the authors have discussed how the synergy achieved between the product engineering and market engineering initiatives in the last decade has catapulted Bajaj back into reckoning as a proactive player in the Indian two-wheeler industry.
Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition
Authors: Wang Yanping , Sparwasser Tim , Figlin Robert , Kim Hyung L. 
Published: February 2014

Abstract
Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3+ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3+ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. Cancer Res; 74(8); 2217–28. ©2014 AACR.