bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness
Authors: Mounce Bryan C. , Cesaro Teresa , Vlajnić Lea , Vidiņa Anna , Vallet Thomas , Weger-Lucarelli James , Passoni Gabriella , Stapleford Kenneth A. , Levraud Jean-Pierre , Vignuzzi Marco 
Published: May 2017

ABSTRACT

Polyamines, which are small positively charge molecules present in all cells, play important roles in the replication of DNA and RNA viruses. Chikungunya virus (CHIKV) relies on polyamines for translation of the viral genome upon viral entry, and pharmacological depletion of polyamines limits viral replication. However, the potential development of antiviral resistance necessitates a better understanding of how polyamines function and can be targeted via compounds that alter polyamine levels. We have isolated CHIKV that is resistant to polyamine depletion and contains two mutations in the nonstructural protein 1 (nsP1)-coding region in combination with a mutation to the opal stop codon preceding nsP4. These mutations, in addition to promoting viral replication in polyamine-depleted cells, confer enhanced viral replication
in vitro
and
in vivo
. The nsP1 mutations enhance membrane binding and methyltransferase activities, while the stop codon mutation allows increased downstream translation. These mutations, when combined, enhance viral fitness, but individual mutants are attenuated in mosquitoes. Together, our results suggest that CHIKV can evolve resistance to polyamine depletion and that pharmaceuticals targeting the polyamine biosynthetic pathway may be best used in combination with other established antivirals to mitigate the development of resistance.

IMPORTANCE
Chikungunya virus is a mosquito-borne virus that has infected millions worldwide. Its expansion into the Americas and rapid adaptation to new mosquito hosts present a serious threat to human health, which we can combat with the development of antiviral therapies as well as understanding how these viruses will mutate when exposed to antiviral therapies. Targeting polyamines, small positively charged molecules in the cell, may be a potential strategy against RNA viruses, including chikungunya virus. Here, we have described a virus that is resistant to polyamine depletion and has increased fitness in cells and in full organisms. Mutations in viral genome capping machinery, membrane binding activity, and a stop codon arise, and their altered activities enhance replication in the absence of polyamines. These results highlight strategies by which chikungunya virus can overcome polyamine depletion and emphasize continued research on developing improved antiviral therapies.
Ebola Virus Delta Peptide Is a Viroporin
Authors: He Jing , Melnik Lilia I. , Komin Alexander , Wiedman Gregory , Fuselier Taylor , Morris Cameron F. , Starr Charles G. , Searson Peter C. , Gallaher William R. , Hristova Kalina , Garry Robert F. , Wimley William C. 
Published: May 2017

ABSTRACT
The Ebola virus (EBOV) genome encodes a partly conserved 40-residue nonstructural polypeptide, called the delta peptide, that is produced in abundance during Ebola virus disease (EVD). The function of the delta peptide is unknown, but sequence analysis has suggested that delta peptide could be a viroporin, belonging to a diverse family of membrane-permeabilizing small polypeptides involved in replication and pathogenesis of numerous viruses. Full-length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells of rodent, dog, monkey, and human origin; increase ion permeability across confluent cell monolayers; and permeabilize synthetic lipid bilayers. Permeabilization activity is completely dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity. Taken together, the evidence strongly suggests that Ebola virus delta peptide is a viroporin and that it may be a novel, targetable aspect of Ebola virus disease pathology.

IMPORTANCE
During the unparalleled West African outbreak of Ebola virus disease (EVD) that began in late 2013, the lack of effective countermeasures resulted in chains of serial infection and a high mortality rate among infected patients. A better understanding of disease pathology is desperately needed to develop better countermeasures. We show here that the Ebola virus delta peptide, a conserved nonstructural protein produced in large quantities by infected cells, has the characteristics of a viroporin. This information suggests a critical role for the delta peptide in Ebola virus disease pathology and as a possible target for novel countermeasures.
Heparan Sulfate Proteoglycan Is an Important Attachment Factor for Cell Entry of Akabane and Schmallenberg Viruses
Authors: Murakami Shin , Takenaka-Uema Akiko , Kobayashi Tomoya , Kato Kentaro , Shimojima Masayuki , Palmarini Massimo , Horimoto Taisuke 
Published: May 2017

ABSTRACT

Akabane virus
(AKAV) and Schmallenberg virus (SBV) are members of the genus
Orthobunyavirus
, which are transmitted by arthropod vectors with a broad cellular tropism
in vitro
as well as
in vivo
. Both AKAV and SBV cause arthrogryposis-hydranencephaly syndrome in ruminants. The main cellular receptor and attachment factor for entry of these orthobunyaviruses are unknown. Here, we found that AKAV and SBV infections were inhibited by the addition of heparin or enzymatic removal of cell surface heparan sulfates. To confirm this finding, we prepared heparan sulfate proteoglycan (HSPG)-knockout (KO) cells by using a clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system and measured the quantities of binding of these viruses to cell surfaces. We observed a substantial reduction in AKAV and SBV binding to cells, limiting the infections by these viruses. These data demonstrate that HSPGs are important cellular attachment factors for AKAV and SBV, at least
in vitro
, to promote virus replication in susceptible cells.

IMPORTANCE
AKAV and SBV are the etiological agents of arthrogryposis-hydranencephaly syndrome in ruminants, which causes considerable economic losses in the livestock industry. Here, we identified heparan sulfate proteoglycan as a major cellular attachment factor for the entry of AKAV and SBV. Moreover, we found that heparin is a strong inhibitor of AKAV and SBV infections. Revealing the molecular mechanisms of virus-host interactions is critical in order to understand virus biology and develop novel live attenuated vaccines.
Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption
Authors: Lee Wen Shi , Kristensen Anne B. , Rasmussen Thomas A. , Tolstrup Martin , Østergaard Lars , Søgaard Ole S. , Wines Bruce D. , Hogarth P. Mark , Reynaldi Arnold , Davenport Miles P. , Emery Sean , Amin Janaki , Cooper David A. , Kan Virginia L. , Fox Julie , Gruell Henning , Parsons Matthew S. , Kent Stephen J. 
Published: May 2017

ABSTRACT

There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells
in vitro
. These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells.

IMPORTANCE
The “shock and kill” HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined
in vivo
, but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.
Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+T Cells
Authors: Bolduc Jean-François , Hany Laurent , Barat Corinne , Ouellet Michel , Tremblay Michel J. 
Published: May 2017

ABSTRACTIn this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4+T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4+T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4+T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4+T cells to productive HIV-1 infection.IMPORTANCEAlterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4+T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.
In situ
stress distribution and mechanical stratigraphy in the Bowen and Surat basins, Queensland, Australia
Authors: Tavener Emma , Flottmann Thomas , Brooke-Barnett Sam 
Published: May 2017

Abstract

We present regional
in situ
stress analyses based on publicly available log and pressure data from coal seam gas developments in the Permian Bowen basin, Australia. Together with earlier data from the eastern part of the Jurassic Surat basin, our results show a broad, but systematic, rotation of
S
Hmax
azimuths in this part of eastern Australia as well as systematic changes in stress state with depth. Overall, the geomechanical state of the region appears to reflect the interplay between basin-controlling structures and a complex far-field stress regime. At the reservoir level, within and between Permian coal seams, this stress complexity is reflected in highly variable stress states both vertically and laterally. Stress data, including direct pressure measurements and observations of borehole failure in image logs, have been used to calibrate sonic-derived one-dimensional wellbore stress models that consistently exhibit a change in tectonic stress regime with depth. Shallow depths (<600 m) are characterized by a reverse-thrust stress regime and deeper levels are characterized by a strike-slip regime. Changes in the stress state with depth influence the mechanical stratigraphy of rocks with widely contrasting mechanical attributes (coals and clastic sediments). Our results highlight the interdependency between regional tectonic, local structural and detailed rheological influences on the well scale geomechanical conditions that have to be taken into consideration in drilling and completion designs.

Supplementary material:
Database of additional wells with image log data are available at
https://doi.org/10.6084/m9.figshare.c.3785849
Drilling project at Gamburtsev Subglacial Mountains, East Antarctica: recent progress and plans for the future
Authors: Talalay Pavel , Sun Youhong , Zhao Yue , Li Yuansheng , Cao Pinlu , Markov Alexey , Xu Huiwen , Wang Rusheng , Zhang Nan , Fan Xiaopeng , Yang Yang , Sysoev Mikhail , Liu Yongwen , Liu Yunchen 
Published: May 2017

Abstract
The Gamburtsev Subglacial Mountains (GSM), located in the central part of East Antarctica, have become the subject of great scientific interest because the mechanism driving the uplift of the range, which resembles younger mountain ranges in shape, in the middle of the old Antarctic Plate is unknown. The next step planned in the exploration of the GSM will be focused on direct examination of the ice sheet bed by drilling. The use of cable-suspended drilling technology is proposed. All of the drilling equipment will be installed inside a movable, sledge-mounted, temperature-controlled, and wind-protected drilling shelter and workshop connected by steel pathway. To drill through ice and bedrock, a new version of the cable-suspended ice and bedrock electromechanical drill was designed and tested. During the 2017–18 season, the drilling shelter and workshop will be assembled near the Zhongshan Station and first field tests will be carried out. Drilling for bedrock on the GSM is planned as soon as full financial and logistical support is obtained for the project.
BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma
Authors: Kulkarni Atul , Al-Hraishawi Husam , Simhadri Srilatha , Hirshfield Kim M. , Chen Suzie , Pine Sharon , Jeyamohan Chandrika , Sokol Levi , Ali Siraj , Teo Man Lung , White Eileen , Rodriguez-Rodriguez Lorna , Mehnert Janice M. , Ganesan Shridar 
Published: May 2017

Abstract
Purpose: Many patients with BRAFV600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies.
Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAFV600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3–BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAFV600E melanoma cell lines, and its effect on drug sensitivity was evaluated.
Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAFV600E mutation was associated with acquisition of an AGAP3–BRAF fusion gene. Expression of the AGAP3–BRAF fusion in BRAFV600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of the AGAP3–BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAFV600E and AGAP3–BRAF only have a fitness advantage over parental BRAFV600E cells during active treatment with a BRAF inhibitor.
Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma. Clin Cancer Res; 23(18); 5631–8. ©2017 AACR.
Video Analysis Verification of Head Impact Events Measured by Wearable Sensors
Authors: Cortes Nelson , Lincoln Andrew E. , Myer Gregory D. , Hepburn Lisa , Higgins Michael , Putukian Margot , Caswell Shane V. 
Published: May 2017

Background:Wearable sensors are increasingly used to quantify the frequency and magnitude of head impact events in multiple sports. There is a paucity of evidence that verifies head impact events recorded by wearable sensors.Purpose:To utilize video analysis to verify head impact events recorded by wearable sensors and describe the respective frequency and magnitude.Study Design:Cohort study (diagnosis); Level of evidence, 2.Methods:Thirty male (mean age, 16.6 ± 1.2 years; mean height, 1.77 ± 0.06 m; mean weight, 73.4 ± 12.2 kg) and 35 female (mean age, 16.2 ± 1.3 years; mean height, 1.66 ± 0.05 m; mean weight, 61.2 ± 6.4 kg) players volunteered to participate in this study during the 2014 and 2015 lacrosse seasons. Participants were instrumented with GForceTracker (GFT; boys) and X-Patch sensors (girls). Simultaneous game video was recorded by a trained videographer using a single camera located at the highest midfield location. One-third of the field was framed and panned to follow the ball during games. Videographic and accelerometer data were time synchronized. Head impact counts were compared with video recordings and were deemed valid if (1) the linear acceleration was ≥20 g, (2) the player was identified on the field, (3) the player was in camera view, and (4) the head impact mechanism could be clearly identified. Descriptive statistics of peak linear acceleration (PLA) and peak rotational velocity (PRV) for all verified head impacts ≥20 g were calculated.Results:For the boys, a total recorded 1063 impacts (2014: n = 545; 2015: n = 518) were logged by the GFT between game start and end times (mean PLA, 46 ± 31 g; mean PRV, 1093 ± 661 deg/s) during 368 player-games. Of these impacts, 690 were verified via video analysis (65%; mean PLA, 48 ± 34 g; mean PRV, 1242 ± 617 deg/s). The X-Patch sensors, worn by the girls, recorded a total 180 impacts during the course of the games, and 58 (2014: n = 33; 2015: n = 25) were verified via video analysis (32%; mean PLA, 39 ± 21 g; mean PRV, 1664 ± 619 rad/s).Conclusion:The current data indicate that existing wearable sensor technologies may substantially overestimate head impact events. Further, while the wearable sensors always estimated a head impact location, only 48% of the impacts were a result of direct contact to the head as characterized on video. Using wearable sensors and video to verify head impacts may decrease the inclusion of false-positive impacts during game activity in the analysis.
Medication Adherence in Older Patients With Dementia: A Systematic Literature Review
Authors: El-Saifi Najwan , Moyle Wendy , Jones Cindy , Tuffaha Haitham 
Published: May 2017

Background: Older patients with dementia are often unable to take their medications as prescribed due to cognitive and physical impairment. Objectives: To review the evidence on medication adherence in older patients with dementia in terms of the level of adherence, outcomes, contributing factors, and available interventions. Methods: A systematic literature review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searched databases included CINAHL, Cochrane Library, DARE, MEDLINE, and PubMed. Results: Eighteen studies reported levels of medication adherence or discontinuation and related factors. Medication adherence ranged from 17% to 42%, and medication discontinuation before the end of treatment ranged from 37% to 80%. Nonadherence was associated with an increased risk of hospitalization or death, while increasing age, choice of medication, use of concomitant medications, and medicines’ costs were reported to decrease medication adherence. Telehealth home monitoring and treatment modification were the only interventions reported in the literature to improve medication adherence in this population. Conclusion: Older patients with dementia have a low level of medication adherence. Future research should focus on the development and implementation of interventions to help older patients with dementia and their caregivers make better use of medications.
Magnetic Resonance Imaging Appearance of the Hip Musculature After Arthroscopic Labral-Level Iliopsoas Tenotomies
Authors: Walczak Brian E. , Blankenbaker Donna G. , Tuite Michael R. , Keene James S. 
Published: May 2017

Background: Iliopsoas (IP) muscle atrophy is a known consequence of open IP tenotomy, but the severity of IP muscle atrophy that occurs after arthroscopic labral-level IP tenotomies has not been documented. Purpose: To document the severity of muscle atrophy that occurs in the iliacus, psoas, and adjacent hip musculature after arthroscopic labral-level IP tenotomy. Study Design: Case series; Level of evidence, 4. Methods: Twenty-eight patients who had magnetic resonance arthrograms (MRAs) obtained prior to and 3 months to 5 years after arthroscopic labral-level IP tenotomies are the basis of this report. The pre- and postoperative MRAs of each patient were examined in consensus by 2 musculoskeletal radiologists who graded the postoperative muscle atrophy from 0 (no fatty infiltration) to 4 (>75% fatty infiltration) and noted any compensatory muscle hypertrophy or abnormal IP tendon morphology. Patients also were assessed with the Byrd 100-point modified Harris Hip Scoring system (MHHS) preoperatively and at the time of their postoperative MRA. Results: Postoperative MRAs were obtained on average 1.7 years (range, 3 months to 5 years) after hip arthroscopy. None of the patients had muscle atrophy on their preoperative MRAs. In contrast, 89% of patients had iliacus and psoas muscle atrophy on their postoperative MRAs, but only 2 (7%) developed grade 4 atrophy, and the majority (64%) had either grade 1 (n = 15) or no atrophy (n = 3). In addition, there were no significant differences in the MHHS of the patients with mild (grades 0-1), moderate (grades 2-3), or severe (grade 4) postoperative atrophy. Postoperative MRAs also demonstrated low-grade atrophy (grades 1-2) in the quadratus femoris (n = 5) and rectus femoris (n = 1) muscles, and 16 patients (57%) had distortion of the tendon, but none had a gap in their tendon. Conclusion: A majority of patients (89%) developed IP muscle atrophy after arthroscopic labral-level IP tenotomies, and although this percentage was similar (89% vs 90%) to that reported with lesser trochanteric IP tenotomies, the patients did not (1) develop atrophy of the gluteus maximus and vastus lateralis muscles, (2) have chronic IP tendon disruption, or (3) develop the severity of IP atrophy (55% grade 4 vs 7% grade 4) that has been reported after arthroscopic lesser trochanteric IP tenotomies.