bluuebunny/crossref_metadata_2025_split huggingface dataset:
Origins and Evolutionary Dynamics of H3N2 Canine Influenza Virus
Authors: Zhu Henan , Hughes Joseph , Murcia Pablo R. 
Published: March 2015

ABSTRACT
Influenza A viruses (IAVs) are maintained mainly in wild birds, and despite frequent spillover infections of avian IAVs into mammals, only a small number of viruses have become established in mammalian hosts. A new H3N2 canine influenza virus (CIV) of avian origin emerged in Asia in the mid-2000s and is now circulating in dog populations of China and South Korea, and possibly in Thailand. The emergence of CIV provides new opportunities for zoonotic infections and interspecies transmission. We examined 14,764 complete IAV genomes together with all CIV genomes publicly available since its first isolation until 2013. We show that CIV may have originated as early as 1999 as a result of segment reassortment among Eurasian and North American avian IAV lineages. We also identified amino acid changes that might have played a role in CIV emergence, some of which have not been previously identified in other cross-species jumps. CIV evolves at a lower rate than H3N2 human influenza viruses do, and viral phylogenies exhibit geographical structure compatible with high levels of local transmission. We detected multiple intrasubtypic and heterosubtypic reassortment events, including the acquisition of the NS segment of an H5N1 avian influenza virus that had previously been overlooked. In sum, our results provide insight into the adaptive changes required by avian viruses to establish themselves in mammals and also highlight the potential role of dogs to act as intermediate hosts in which viruses with zoonotic and/or pandemic potential could originate, particularly with an estimated dog population of ∼700 million.

IMPORTANCE
Influenza A viruses circulate in humans and animals. This multihost ecology has important implications, as past pandemics were caused by IAVs carrying gene segments of both human and animal origin. Adaptive evolution is central to cross-species jumps, and this is why understanding the evolutionary processes that shape influenza A virus genomes is key to elucidating the mechanisms underpinning viral emergence. An avian-origin canine influenza virus (CIV) has recently emerged in dogs and is spreading in Asia. We reconstructed the evolutionary history of CIV and show that it originated from both Eurasian and North American avian lineages. We also identified the mutations that might have been responsible for the cross-species jump. Finally, we provide evidence of multiple reassortment events between CIV and other influenza viruses (including an H5N1 avian virus). This is a cause for concern, as there is a large global dog population to which humans are highly exposed.
Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env
Authors: Georgiev Ivelin S. , Joyce M. Gordon , Yang Yongping , Sastry Mallika , Zhang Baoshan , Baxa Ulrich , Chen Rita E. , Druz Aliaksandr , Lees Christopher R. , Narpala Sandeep , Schön Arne , Van Galen Joseph , Chuang Gwo-Yu , Gorman Jason , Harned Adam , Pancera Marie , Stewart-Jones Guillaume B. E. , Cheng Cheng , Freire Ernesto , McDermott Adrian B. , Mascola John R. , Kwong Peter D. 
Published: March 2015

ABSTRACT
Similar to other type I fusion machines, the HIV-1 envelope glycoprotein (Env) requires proteolytic activation; specifically, cleavage of a gp160 precursor into gp120 and gp41 subunits creates an N-terminal gp41 fusion peptide and permits folding from an immature uncleaved state to a mature closed state. While the atomic-level consequences of cleavage for HIV-1 Env are still being determined, the uncleaved state is antigenically distinct from the mature closed state, and cleavage has been reported to be essential for mimicry of the mature viral spike by soluble versions of Env. Here we report the redesign of a current state-of-the-art soluble Env mimic, BG505.SOSIP, to make it cleavage independent. Specifically, we replaced the furin cleavage site between gp120 and gp41 with Gly-Ser linkers of various lengths. The resultant linked gp120-gp41 constructs, termed single-chain gp140 (sc-gp140), exhibited different levels of structural and antigenic mimicry of the parent cleaved BG505.SOSIP. When constructs were subjected to negative selection to remove subspecies recognized by poorly neutralizing antibodies, trimers of high antigenic mimicry of BG505.SOSIP could be obtained; negative-stain electron microscopy indicated these to resemble the mature closed state. Higher proportions of BG505.SOSIP-trimer mimicry were observed in sc-gp140s with linkers of 6 or more residues, with a linker length of 15 residues exhibiting especially promising traits. Overall, flexible linkages between gp120 and gp41 in BG505.SOSIP can thus substitute for cleavage, and sc-gp140s that closely mimicked the vaccine-preferred mature closed state of Env could be obtained.

IMPORTANCE
The trimeric HIV-1 envelope glycoprotein (Env) is the sole target of virus-directed neutralizing antibody responses and a primary focus of vaccine design. Soluble mimics of Env have proven challenging to obtain and have been thought to require proteolytic cleavage into two-component subunits, gp120 and gp41, to achieve structural and antigenic mimicry of mature Env spikes on virions. Here we show that replacement of the cleavage site between gp120 and gp41 in a lead soluble gp140 construct, BG505.SOSIP, with flexible linkers can result in molecules that do not require cleavage to fold efficiently into the mature closed state. Our results provide insights into the impact of cleavage on HIV-1 Env folding. In some contexts such as genetic immunization, optimized cleavage-independent soluble gp140 constructs may have utility over the parental BG505.SOSIP, as they would not require furin cleavage to achieve mimicry of mature Env spikes on virions.
Diversifying Selection Analysis Predicts Antigenic Evolution of 2009 Pandemic H1N1 Influenza A Virus in Humans
Authors: Lee Alexandra J. , Das Suman R. , Wang Wei , Fitzgerald Theresa , Pickett Brett E. , Aevermann Brian D. , Topham David J. , Falsey Ann R. , Scheuermann Richard H. 
Published: March 2015

ABSTRACT

Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified 16 amino acid sites experiencing diversifying selection during the evolution of prepandemic seasonal H1N1 strains and found that 11 sites were located in experimentally determined B-cell/antibody (Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb, and Ca2 [A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417–427, 1982,
http://dx.doi.org/10.1016/0092-8674(82)90135-0
]. We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi-squared goodness-of-fit test, we identified 10 amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions as identified in the analysis of prepandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution.

IMPORTANCE
The WHO estimates that approximately 5 to 10% of adults and 20 to 30% of children in the world are infected by influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza virus infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza virus strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted.
Profiling of Virus-Encoded MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma and Their Roles in Gastric Carcinogenesis
Authors: Shinozaki-Ushiku Aya , Kunita Akiko , Isogai Maya , Hibiya Takashi , Ushiku Tetsuo , Takada Kenzo , Fukayama Masashi 
Published: March 2015

ABSTRACT

Epstein-Barr virus (EBV) is one of the major oncogenic viruses and is found in nearly 10% of gastric carcinomas. EBV is known to encode its own microRNAs (miRNAs); however, their roles have not been fully investigated. The present report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in tissue samples from patients with EBV-associated gastric carcinoma. Several miRNAs were highly expressed in EBV-associated gastric carcinoma, and
in silico
analysis revealed that the target genes of these EBV miRNAs had functions associated with cancer-related pathways, especially the regulation of apoptosis. Apoptosis was reduced in EBV-associated gastric carcinoma tissue samples, and gastric carcinoma cell lines infected with EBV exhibited downregulation of the proapoptotic protein Bid (the BH3-interacting domain death agonist), a member of the Bcl-2 family. The luciferase activity of the reporter vector containing the 3′ untranslated region of BID was inhibited by an ebv-miR-BART4-5p mimic in gastric cancer cell lines. Transfection of an ebv-miR-BART4-5p mimic reduced Bid expression in EBV-negative cell lines, leading to reduced apoptosis under serum deprivation. The inhibition of ebv-miR-BART4-5p expression was associated with partial recovery of Bid levels in EBV-positive cell lines. The results demonstrated the antiapoptotic role of EBV miRNA via regulation of Bid expression in EBV-associated gastric carcinoma. These findings provide novel insights in the roles of EBV miRNAs in gastric carcinogenesis, which would be a potential therapeutic target.

IMPORTANCE
This report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in clinical samples from EBV-associated gastric carcinoma patients. Of the EBV miRNAs, ebv-miR-BART4-5p plays an important role in gastric carcinogenesis via regulation of apoptosis.
Work and non-work stressors, psychological distress and obesity: evidence from a 14-year study on Canadian workers
Authors: Marchand Alain , Beauregard Nancy , Blanc Marie-Eve 
Published: March 2015

ObjectiveThis study aimed to evaluate the contribution of work, non-work and individual factors to obesity with regard to gender-related differences, and to clarify the mediating role that psychological distress plays in these dynamics in Canada from 1994 to 2008 using the Canadian National Population Health Survey (NPHS).DesignLongitudinal.SettingsThe NPHS is a randomised longitudinal cohort study with biennial interviews of the Canadian adult population from 18 to 64.Participants5925 non-obese workers in cycle 1 (49% were women).MeasurementsObesity was measured using the body mass index (BMI), with a threshold of BMI >30 kg/m2. BMI was corrected in accordance with the recommendations of Connor Gorberet alto adjust for gender bias in responses.ResultsOf the work characteristics evaluated, only decision authority was associated with obesity for women but not for men. Living as a couple, child-related strains, psychotropic drug use, hypertension, being physically inactive and low psychological distress were obesity risk factors but were not moderated by gender. Overall, psychological distress did not mediate the associations that work factors have on obesity.ConclusionsOur study suggests that men and women differ little in the extent to which work, non-work and individual factors predict obesity. However, for women, the level of decision authority is associated with a lower obesity risk. In addition, psychological distress did not mediate the contribution of work factors and actually seems, contrary to expectations, to decrease the obesity risk when work, non-work and individual factors are taken into account.
Always tell the truth?
Authors: Rees Gwen 
Published: March 2015

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Always tell the truth?’, was submitted by Richard Brown and is discussed by Gwen Rees. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Emergency exsanguination of working equids’, which was published in the February issue of In Practice, appears on page 151.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.
Preliminary test of the LFA rapid evaluation of activity in lupus (LFA-REAL): an efficient outcome measure correlates with validated instruments
Authors: Askanase Anca , Li Xiaoqing , Pong Avery , Shum Katrina , Kamp Stan , Carthen Fredonna , Aberle Teresa , Hanrahan Leslie , Daly Paola , Giles Jon , Merrill Joan T 
Published: March 2015

ObjectiveCurrent disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in Lupus (REAL) is a pilot application composed of anchored visual analogue scores (0–100 mm each) for each organ affected by lupus. This study evaluated the use of LFA-REAL in capturing SLE disease activity.MethodsIn a preliminary test of LFA-REAL, this simplified, organ-based system was compared with the most widely used outcome measures in clinical trials, the British Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease Activity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The level of agreement was analysed using Spearman rank correlations.Results91 patients with SLE with mild to severe disease activity were evaluated, their median SLEDAI score was 4.0 (range 0–28) and BILAG score 8.0 (0–32). The median SS-PGA was 38 mm (4–92) versus the total REAL 50 mm (0–268), which expands in range by additive organ scores. Thirty-three patients had moderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median SS-PGA score of this group was 66 mm (50–92) versus median REAL score of 100 mm (59–268), confirming ability to detect a wider distribution of scores at higher disease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA (correlation coefficient=0.816, 0.933 and 0.903, respectively; p<0.001 for all). Individual LFA-REAL organ scores for musculoskeletal and mucocutaneous also correlated with corresponding BILAG domain scores (correlation coefficient=0.925 and 0.934, p<0.001).ConclusionsIn this preliminary exercise, there were strong correlations between LFA-REAL and validated lupus disease activity indices. Further development may be valuable for consistent scoring in clinical trials, grading optimal assessment of change in disease activity and reliable monitoring of patients in practice.
Urban land use and geohazards in Itanagar, Arunachal Pradesh, India: the need for geotechnical intervention and geoethical policies in urban disaster resilience programmes in a changing climate
Authors: Acharjee Swapna 
Published: March 2015

Abstract
The capital city, Itanagar in Arunachal Pradesh, India, is exposed to multiple geohazards as it is located both in a region which experiences extreme physical phenomena due to changing climate, and in the tectonically active Eastern Himalaya. The geohazards in Itanagar include landslides, flash floods, soil erosion and earthquakes. Due to rapid and haphazard growth in urban land use, the city’ residents have been increasingly exposed to these geohazards over the past two decades. The high decadal growth rate of just over 111% shown in the 1991–2001 censuses has introduced many challenges with respect to the capital city's development planning, and geoscientists are warning of land suitability and stability in terms of rock types, soil, slope, geomorphology and groundwater conditions in their scientific communications. The present condition of the city has raised issues of immediate concern related to effective hazard management. The vulnerability of existing urban land use to landslides, flash floods and soil erosion is increasing steadily, and Itanagar needs to become a disaster-resilient hill city. Experts agree there is therefore a need for appropriate engineering geology intervention as well as the development of geoethical policies in sustainable development planning of the city, which could be achieved by using a strategic urban plan through community participation and awareness generation under the Itanagar Urban Disaster Risk Reduction (UDRR) programme.
NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia
Authors: Gao Pan , He Fang-Fang , Tang Hui , Lei Chun-Tao , Chen Shan , Meng Xian-Fang , Su Hua , Zhang Chun 
Published: March 2015

Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression ofgp91phox, a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1βproduction and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG-exposed podocytes genetic deletion of TXNIP by shRNA reversedgp91phoxoverexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN.Erratum to “NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia”
NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma
Authors: Cescon David W. , She Desmond , Sakashita Shingo , Zhu Chang-Qi , Pintilie Melania , Shepherd Frances A. , Tsao Ming-Sound 
Published: March 2015

Abstract
Purpose: Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC.
Experimental Design: Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2ACT) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression.
Results: Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway–activated and wild-type (WT) tumors. NRF2ACT was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10-randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2ACT HR 2.28, P = 0.48; interaction P = 0.15). NRF2ACT was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression.
Conclusions: A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway–activating somatic alterations may have reduced benefit from this therapy. Clin Cancer Res; 21(11); 2499–505. ©2015 AACR.
Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300
Authors: Uttarkar Sagar , Dukare Sandeep , Bopp Bertan , Goblirsch Michael , Jose Joachim , Klempnauer Karl-Heinz 
Published: March 2015

Abstract
The transcription factor c-Myb is highly expressed in hematopoietic progenitor cells and controls the transcription of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-Myb has been implicated in the development of leukemia and certain other types of human cancer. c-Myb activity is highly dependent on the interaction of the c-Myb with the KIX domain of the coactivator p300, making the disruption of this interaction a reasonable strategy for the development of Myb inhibitors. Here, we have used bacterial Autodisplay to develop an in vitro binding assay that mimics the interaction of Myb and the KIX domain of p300. We have used this binding assay to investigate the potential of Naphthol AS-E phosphate, a compound known to bind to the KIX domain, to disrupt the interaction between Myb and p300. Our data show that Naphthol AS-E phosphate interferes with the Myb–KIX interaction in vitro and inhibits Myb activity in vivo. By using several human leukemia cell lines, we demonstrate that Naphthol AS-E phosphate suppresses the expression of Myb target genes and induces myeloid differentiation and apoptosis. Our work identifies Naphthol AS-E phosphate as the first low molecular weight compound that inhibits Myb activity by disrupting its interaction with p300, and suggests that inhibition of the Myb–KIX interaction might be a useful strategy for the treatment of leukemia and other tumors caused by deregulated c-Myb. Mol Cancer Ther; 14(6); 1276–85. ©2015 AACR.
See related commentary by Liu et al., p. 1273