bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly
Authors: Cifuentes-Muñoz Nicolás , Sun Weina , Ray Greeshma , Schmitt Phuong Tieu , Webb Stacy , Gibson Kathleen , Dutch Rebecca Ellis , Schmitt Anthony P. 
Published: May 2017

ABSTRACT
Hendra virus (HeV) is a zoonotic paramyxovirus that causes deadly illness in horses and humans. An intriguing feature of HeV is the utilization of endosomal protease for activation of the viral fusion protein (F). Here we investigated how endosomal F trafficking affects HeV assembly. We found that the HeV matrix (M) and F proteins each induced particle release when they were expressed alone but that their coexpression led to coordinated assembly of virus-like particles (VLPs) that were morphologically and physically distinct from M-only or F-only VLPs. Mutations to the F protein transmembrane domain or cytoplasmic tail that disrupted endocytic trafficking led to failure of F to function with M for VLP assembly. Wild-type F functioned normally for VLP assembly even when its cleavage was prevented with a cathepsin inhibitor, indicating that it is endocytic F trafficking that is important for VLP assembly, not proteolytic F cleavage. Under specific conditions of reduced M expression, we found that M could no longer induce significant VLP release but retained the ability to be incorporated as a passenger into F-driven VLPs, provided that the F protein was competent for endocytic trafficking. The F and M proteins were both found to traffic through Rab11-positive recycling endosomes (REs), suggesting a model in which F and M trafficking pathways converge at REs, enabling these proteins to preassemble before arriving at plasma membrane budding sites.

IMPORTANCE
Hendra virus and Nipah virus are zoonotic paramyxoviruses that cause lethal infections in humans. Unlike that for most paramyxoviruses, activation of the henipavirus fusion protein occurs in recycling endosomal compartments. In this study, we demonstrate that the unique endocytic trafficking pathway of Hendra virus F protein is required for proper viral assembly and particle release. These results advance our basic understanding of the henipavirus assembly process and provide a novel model for the interplay between glycoprotein trafficking and paramyxovirus assembly.
Hypervariable Domain of Eastern Equine Encephalitis Virus nsP3 Redundantly Utilizes Multiple Cellular Proteins for Replication Complex Assembly
Authors: Frolov Ilya , Kim Dal Young , Akhrymuk Maryna , Mobley James A. , Frolova Elena I. 
Published: May 2017

ABSTRACT
Eastern equine encephalitis virus (EEEV) is a representative member of the New World alphaviruses. It is pathogenic for a variety of vertebrate hosts, in which EEEV induces a highly debilitating disease, and the outcomes are frequently lethal. Despite a significant public health threat, the molecular mechanism of EEEV replication and interaction with hosts is poorly understood. Our previously published data and those of other teams have demonstrated that hypervariable domains (HVDs) of the alphavirus nsP3 protein interact with virus-specific host factors and play critical roles in assembly of viral replication complexes (vRCs). The most abundantly represented HVD-binding proteins are the FXR and G3BP family members. FXR proteins drive the assembly of vRCs of Venezuelan equine encephalitis virus (VEEV), and G3BPs were shown to function in vRC assembly in the replication of chikungunya and Sindbis viruses. Our new study demonstrates that EEEV exhibits a unique level of redundancy in the use of host factors in RNA replication. EEEV efficiently utilizes both the VEEV-specific FXR protein family and the Old World alphavirus-specific G3BP protein family. A lack of interaction with either FXRs or G3BPs does not affect vRC formation; however, removal of EEEV's ability to interact with both protein families has a deleterious effect on virus growth. Other identified EEEV nsP3 HVD-interacting host proteins are also capable of supporting EEEV replication, albeit with a dramatically lower efficiency. The ability to use a wide range of host factors with redundant functions in vRC assembly and function provides a plausible explanation for the efficient replication of EEEV and may contribute to its highly pathogenic phenotype.

IMPORTANCE
Eastern equine encephalitis virus (EEEV) is one of the most pathogenic New World alphaviruses. Despite the continuous public health threat, to date, the molecular mechanisms of its very efficient replication and high virulence are not sufficiently understood. The results of this new study demonstrate that North American EEEV exhibits a high level of redundancy in using host factors in replication complex assembly and virus replication. The hypervariable domain of the EEEV nsP3 protein interacts with all of the members of the FXR and G3BP protein families, and only a lack of interaction with both protein families strongly affects virus replication rates. Other identified HVD-binding factors are also involved in EEEV replication, but their roles are not as critical as those of FXRs and G3BPs. The new data present a plausible explanation for the exceptionally high replication rates of EEEV and suggest a new means of its attenuation and new targets for screening of antiviral drugs.
Cell Culture Systems To Study Human Herpesvirus 6A/B Chromosomal Integration
Authors: Gravel Annie , Dubuc Isabelle , Wallaschek Nina , Gilbert-Girard Shella , Collin Vanessa , Hall-Sedlak Ruth , Jerome Keith R. , Mori Yasuko , Carbonneau Julie , Boivin Guy , Kaufer Benedikt B. , Flamand Louis 
Published: May 2017

ABSTRACT

Human herpesviruses 6A/B (HHV-6A/B) can integrate their viral genomes in the telomeres of human chromosomes. The viral and cellular factors contributing to HHV-6A/B integration remain largely unknown, mostly due to the lack of efficient and reproducible cell culture models to study HHV-6A/B integration. In this study, we characterized the HHV-6A/B integration efficiencies in several human cell lines using two different approaches. First, after a short-term infection (5 h), cells were processed for single-cell cloning and analyzed for chromosomally integrated HHV-6A/B (ciHHV-6A/B). Second, cells were infected with HHV-6A/B and allowed to grow in bulk for 4 weeks or longer and then analyzed for the presence of ciHHV-6. Using quantitative PCR (qPCR), droplet digital PCR, and fluorescent
in situ
hybridization, we could demonstrate that HHV-6A/B integrated in most human cell lines tested, including telomerase-positive (HeLa, MCF-7, HCT-116, and HEK293T) and telomerase-negative cell lines (U2OS and GM847). Our results also indicate that inhibition of DNA replication, using phosphonoacetic acid, did not affect HHV-6A/B integration. Certain clones harboring ciHHV-6A/B spontaneously express viral genes and proteins. Treatment of cells with phorbol ester or histone deacetylase inhibitors triggered the expression of many viral genes, including
U39
,
U90
, and
U100
, without the production of infectious virus, suggesting that the tested stimuli were not sufficient to trigger full reactivation. In summary, both integration models yielded comparable results and should enable the identification of viral and cellular factors contributing to HHV-6A/B integration and the screening of drugs influencing viral gene expression, as well as the release of infectious HHV-6A/B from the integrated state.

IMPORTANCE
The analysis and understanding of HHV-6A/B genome integration into host DNA is currently limited due to the lack of reproducible and efficient viral integration systems. In the present study, we describe two quantitative cell culture viral integration systems. These systems can be used to define cellular and viral factors that play a role in HHV-6A/B integration. Furthermore, these systems will allow us to decipher the conditions resulting in virus gene expression and excision of the integrated viral genome resulting in reactivation.
Regulation of axonal regeneration following spinal cord injury in the lamprey
Authors: Benes Jessica A. , House Kylie N. , Burks Frank N. , Conaway Kris P. , Julien Donald P. , Donley Jeffrey P. , Iyamu Michael A. , McClellan Andrew D. 
Published: May 2017

Following rostral spinal cord injury (SCI) in larval lampreys, injured descending brain neurons, particularly reticulospinal (RS) neurons, regenerate their axons, and locomotor behavior recovers in a few weeks. However, axonal regeneration of descending brain neurons is mostly limited to relatively short distances, but the mechanisms for incomplete axonal regeneration are unclear. First, lampreys with rostral SCI exhibited greater axonal regeneration of descending brain neurons, including RS neurons, as well as more rapid recovery of locomotor muscle activity right below the lesion site, compared with animals with caudal SCI. In addition, following rostral SCI, most injured RS neurons displayed the “injury phenotype,” whereas following caudal SCI, most injured neurons displayed normal electrical properties. Second, following rostral SCI, at cold temperatures (~4–5°C), axonal transport was suppressed, axonal regeneration and behavioral recovery were blocked, and injured RS neurons displayed normal electrical properties. Cold temperatures appear to prevent injured RS neurons from detecting and/or responding to SCI. It is hypothesized that following rostral SCI, injured descending brain neurons are strongly stimulated to regenerate their axons, presumably because of elimination of spinal synapses and reduced neurotrophic support. However, when these neurons regenerate their axons and make synapses right below the lesion site, restoration of neurotrophic support very likely suppress further axonal regeneration. In contrast, caudal SCI is a weak stimulus for axonal regeneration, presumably because of spared synapses above the lesion site. These results may have implications for mammalian SCI, which can spare synapses above the lesion site for supraspinal descending neurons and propriospinal neurons. NEW & NOTEWORTHY Lampreys with rostral spinal cord injury (SCI) exhibited greater axonal regeneration of descending brain neurons and more rapid recovery of locomotor muscle activity below the lesion site compared with animals with caudal SCI. In addition, following rostral SCI, most injured reticulospinal (RS) neurons displayed the “injury phenotype,” whereas following caudal SCI, most injured neurons had normal electrical properties. We hypothesize that following caudal SCI, the spared synapses of injured RS neurons might limit axonal regeneration and behavioral recovery.
Phase I Trial of Intratumoral Injection ofCCL21Gene–Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T-cell Infiltration
Authors: Lee Jay M. , Lee Mi-Heon , Garon Edward , Goldman Jonathan W. , Salehi-Rad Ramin , Baratelli Felicita E. , Schaue Dörthe , Wang Gerald , Rosen Fran , Yanagawa Jane , Walser Tonya C. , Lin Ying , Park Stacy J. , Adams Sharon , Marincola Francesco M. , Tumeh Paul C. , Abtin Fereidoun , Suh Robert , Reckamp Karen L. , Lee Gina , Wallace William D. , Lee Sarah , Zeng Gang , Elashoff David A. , Sharma Sherven , Dubinett Steven M. 
Published: May 2017

AbstractPurpose: A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non–small cell lung carcinoma (NSCLC) following intratumoral administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen–specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222).Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen–specific peripheral blood lymphocyte induction of IFNγ in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor-associated antigens (TAA). Tumor CD8+ T-cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression.Conclusions: Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen–specific immune responses; (ii) enhanced tumor CD8+ T-cell infiltration; and (iii) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination. Clin Cancer Res; 23(16); 4556–68. ©2017 AACR.
The “Tricky Business” of Identifying Mechanisms of Resistance to Anti–PD-1
Authors: Wilmott James S. , Rizos Helen , Scolyer Richard A. , Long Georgina V. 
Published: May 2017

Abstract
Resistance to immune checkpoint inhibitors can vary between patients and among metastases. Understanding the genomic, transcriptomic, and microenvironmental factors that contribute to this variability will reveal the mechanisms that tumors utilize to evade the therapeutic effects of checkpoint inhibitor immunotherapies and will enable us to develop strategies to overcome them. Clin Cancer Res; 23(12); 2921–3. ©2017 AACR.
See related article by Ascierto et al., p. 3168
Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors
Authors: Lam Lloyd T. , Lin Xiaoyu , Faivre Emily J. , Yang Ziping , Huang Xiaoli , Wilcox Denise M. , Bellin Richard J. , Jin Sha , Tahir Stephen K. , Mitten Michael , Magoc Terry , Bhathena Anahita , Kati Warren M. , Albert Daniel H. , Shen Yu , Uziel Tamar 
Published: May 2017

Abstract
Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as MYC, CCND2, and BCL2L1. Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase-3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2–BIM complex, thus priming the cells for apoptosis. Indeed, strong synergy was observed both in vitro and in vivo when cotreating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199). ABBV-075 interaction with venetoclax positively correlated with BCL2 expression. Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression. Mol Cancer Ther; 16(8); 1511–20. ©2017 AACR.
Synergy between Androgen Receptor Antagonism and Inhibition of mTOR and HER2 in Breast Cancer
Authors: Gordon Michael A. , D'Amato Nicholas C. , Gu Haihua , Babbs Beatrice , Wulfkuhle Julia , Petricoin Emanuel F. , Gallagher Isela , Dong Ting , Torkko Kathleen , Liu Bolin , Elias Anthony , Richer Jennifer K. 
Published: May 2017

Abstract
The androgen receptor (AR) is widely expressed in breast cancer, and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in preclinical models and clinical trials of prostate cancer and are currently being evaluated in breast cancer. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit breast cancer growth. HER2+ and triple-negative breast cancer cell lines were treated with AR antagonist plus anti-HER2 mAb trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation, and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, Western blot, and reverse phase protein array. In vivo, HER2+ breast cancer xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved breast cancer therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ breast cancer cells in vivo. Mol Cancer Ther; 16(7); 1389–400. ©2017 AACR.
Combining DNA Vaccine and AIDA-1 in AttenuatedSalmonellaActivates Tumor-Specific CD4+ and CD8+ T-cell Responses
Authors: Mei Yu , Zhao Lixiang , Liu Yonghao , Gong Huanle , Song Yuan , Lei Lei , Zhu Ying , Jin Ziqi , Ma Shoubao , Hu Bo , Sun Qing , Liu Haiyan 
Published: May 2017

AbstractStimulation of tumor-specific responses in both CD4+ and CD8+ T cells has been a challenge for effective tumor vaccines. We designed a vaccine vector containing the AIDA-1 autotransporter and DNA vaccine elements, generating a murine melanoma vaccine that was delivered by the attenuated Salmonella strain SL7207. Growth of murine subcutaneous melanoma was significantly inhibited by intranasal immunization with the Salmonella tumor vaccine. The vaccine activated tumor-specific CD4+ and CD8+ T-cell responses, with increased T-cell proliferation, tumor antigen–specific Th1 cytokine production, increased percentages of tetramer positive cells, and cytotoxicity. CD4+ or CD8+ T-cell depletion resulted in the loss of antitumor activity of the Salmonella tumor vaccine, suggesting that the efficacy of the vaccine was dependent on both CD4+ and CD8+ T cells. Lung metastasis of the tumor was also inhibited by vaccine treatment. Similarly, the percentages of tumor-specific Th1 cytokine production by CD4+ and CD8+ T cells in the spleen, tumor, and bronchoalveolar lavage were increased after vaccine treatment. Tumor-specific proliferation of CD4+ and CD8+ T cells was also promoted by the vaccine. Tetramer staining and cytotoxicity assay showed enhanced tumor-specific CD8+ T-cell response after vaccine treatment. Therefore, the Salmonella tumor vaccine could activate both tumor-specific CD4+ and CD8+ T-cell responses. This vaccine strategy may be widely applicable to the development of oral or nasal vaccines against tumors. Cancer Immunol Res; 5(6); 503–14. ©2017 AACR.
Speech Processing for Text Independent Amharic Language Dialect Recognition
Authors: Mengistu Abrham Debasu , Alemayehu Dagnachew Melesew 
Published: May 2017

<span style="color: #666666; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 11.2px; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; display: inline !important; float: none;">Dialect is a difference of verbal communication spoken by people from a particular society or geographic area so the paper focuses on Amharic language dialect recognition. In this paper, the authors have used backpropagation artificial neural network, VQ(vector quantization), (Gaussian Mixture Models) and a combination of GMM and backpropagation artificial neural network for classifying dialects of Amharic language speakers. In this research, a total of 100 speakers for each group of dialects are considered each having about 10 seconds duration is collected. The feature vectors of Mel frequency cepstral coefficients (MFCC) had been used to recognize the dialects of speakers. In this research paper the recognition model that uses a tanh activation function have a better result instead of using the Logistic Sigmoid activation function in backpropagation artificial neural network. After conducting the above experiments 95.7% accuracy achieved when GMM and backpropagation artificial neural network with tanh activation function are combined.</span>
Physicians’ and Users’ Perceptions towards Wearable Health Devices
Authors: Seshadri Narassima M , P Anbuudayasankar S , Vasudevan Shriram Kris , J Abhinavaram 
Published: May 2017

<p>Healthcare plays a vital role in economic development of a country, and has a major impact on the entire wellness of humankind. One of the biggest issues of all times, Blood Pressure is prevailing in patients of all countries. In developing countries like India, it is prevalent among people of diverse age groups, which somehow permeates into their wellness, reflecting and slowing down the growth of the country as well as that of an individual. As Blood Pressure is identified as one of the major contributors to Cardio Vascular Diseases, there is an urge to educate people about the consequences. The research focuses on various factors and their levels of impact on acceptance of Mobile Health Management Services. Appropriate tests have been carried out for validating this hypothesis. All the details are presented in the results’ section with clear discussion and description.</p>
Comparative Study on the Effectiveness of UPFC and TCSC for Increasing Power Transfer Capability Applied to Non-linear Load Models
Authors: Al-Mawsawi S.Ali Abbas 
Published: May 2017

<p>In recent years, studies have been investigated the effectiveness of UPFC and TCSC in increasing power transfer capability. However, the effectiveness of these FACTS devices in increasing power transfer capability when the load is non-linear has not been established in a comparative study yet. This paper will explore the steady-state performance of the UPFC and TCSC as impedance compensation models. The effectiveness of both FACTS devices are investigated when they are installed in multi-machine systems with different non-linear load models. Simulation results demonstrate that, upon installing UPFC, more active and reactive powers are received at the sending end bus for different types of non-linear load models. In addition, both active and reactive powers are more sensitive in changing the modulation index of the converters. Furthermore, both the active and reactive powers are less sensitive to the non-linearity of the load model type. However, active and reactive powers in case of installing TCSC are only sensitive in changing the firing angle (α) when it is between 90º to 110º. Therefore, results from this study clearly encourage the effectiveness of UPFC in comparison to TSCS in terms of increasing power transfer capability applied to non-linear load models. </p>