bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements
Authors: Iyer Lakshminarayan M. , Burroughs A. Maxwell , Anand Swadha , de Souza Robson F. , Aravind L. 
Published: May 2017

ABSTRACT
Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular “weaponry” deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, we term them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid-binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.

IMPORTANCE
This is the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems.
Functional Interaction between the N and C Termini of NhaD Antiporters from Halomonas sp. Strain Y2
Authors: Meng Yiwei , Yang Zhou , Cheng Bin , Nie Xinyu , Li Shannan , Yin Huijia , Xu Ping , Yang Chunyu 
Published: May 2017

ABSTRACT

Two NhaD-type antiporters, NhaD1 and NhaD2, from the halotolerant and alkaliphilic
Halomonas
sp. strain Y2, exhibit different physiological functions in regard to Na
+
and Li
+
resistance, although they share high sequence identity. In the present study, the truncation of an additional 4 C-terminal residues from NhaD2 or an exchange of 39 N-terminal residues between these proteins resulted in the complete loss of antiporter activity. Interestingly, combining 39 N-terminal residues and 7 C-terminal residues of NhaD2 (N39D2-C7) partially recovered the activity for Na
+
and Li
+
expulsion, as well as complementary growth following exposure to 300 mM Na
+
and 100 mM Li
+
stress. The recovered activity of chimera N39D2-C7 indicated that the N and C termini are structurally dependent on each other and function synergistically. Furthermore, fluorescence resonance energy transfer (FRET) analysis suggested that the N and C termini are relatively close in proximity which may account for their synergistic function in ion translocation. In the N-terminal region of N39D2-C7, the replacement of Glu
38
with Pro abolished the recovered complementary and transport activities. In addition, this amino acid substitution in NhaD2 resulted in a drastically decreased complementation ability in
Escherichia coli
KNabc (level identical to that of NhaD1), as well as decreased activity and an altered pH profile.

IMPORTANCE
Limited information on NhaD antiporters supports speculation that these antiporters are important for resistance to high salinity and alkalinity. Moreover, only a few functional residues have been identified in NhaD antiporters, and there is limited literature on the molecular mechanisms of NhaD antiporter activity. The altered antiporter abilities of chimeras and mutants in this study implicate the functions of the N and C termini, especially Glu
38
, in pH regulation and ion translocation, and, most importantly, the essential roles of this negatively charged residue in maintaining the physiological function of NhaD2. These findings further our understanding of the molecular mechanism of NhaD antiporters for ion transport.
A Toxin Involved in
Salmonella
Persistence Regulates Its Activity by Acetylating Its Cognate Antitoxin, a Modification Reversed by CobB Sirtuin Deacetylase
Authors: VanDrisse Chelsey M. , Parks Anastacia R. , Escalante-Semerena Jorge C. 
Published: May 2017

ABSTRACT

Bacterial toxin-antitoxin systems trigger the onset of a persister state by inhibiting essential cellular processes. The TacT toxin of
Salmonella enterica
is known to induce a persister state in macrophages through the acetylation of aminoacyl-tRNAs. Here, we show that the TacT toxin and the TacA antitoxin work as a complex that modulates TacT activity via the acetylation state of TacA. TacT acetylates TacA at residue K44, a modification that is removed by the NAD
+
-dependent CobB sirtuin deacetylase. TacA acetylation increases the activity of TacT, downregulating protein synthesis. TacA acetylation altered binding to its own promoter, although this did not change
tacAT
expression levels. These claims are supported by results from
in vitro
protein synthesis experiments used to monitor TacT activity,
in vivo
growth analyses, electrophoretic mobility shift assays, and quantitative reverse transcription-PCR (RT-qPCR) analysis. TacT is the first example of a Gcn5-related
N-
acetyltransferase that modifies nonprotein and protein substrates.

IMPORTANCE
During host infection, pathogenic bacteria can modulate their physiology to evade host defenses. Some pathogens use toxin-antitoxin systems to modulate a state of self-toxicity that can decrease their cellular activity, triggering the onset of a persister state. The lower metabolic activity of persister cells allows them to escape host defenses and antibiotic treatments. Hence a better understanding of the mechanisms used by pathogens to ingress and egress the persister state is of relevance to human health.
Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
Authors: Singh Jogender , Aballay Alejandro 
Published: May 2017

ABSTRACT

The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode
Caenorhabditis elegans
, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins.

IMPORTANCE
Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode
C. elegans
, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity.
Chalk reservoir of the Ockley accumulation, North Sea:
in situ
stresses, geology and implications for stimulation
Authors: Wynn T. J. , Kumar R. , Jones R. , Howell K. , Maxwell D. , Bailey P. 
Published: May 2017

Abstract

The Ockley discovery is a gas condensate accumulation contained within tight chalks of the Hod Formation. The observed faults and fractures are a combination of features radial to the main periclinal structure and parallel to the local structural grain 100° from north. Most natural fractures appear to be healed or cemented. The pore pressure gradient at Ockley is
c.
0.199 bar/m. The
in situ
stresses are estimated to all be within
c.
46 bar of each other, indicating a near-isotropic
in situ
stress system. Therefore the orientation of
S
Hmax
is hard to define and drilling optimally oriented wells to create transverse hydraulic fractures is difficult. The estimated intact rock fracture initiation pressure in a horizontal well would exceed all the
in situ
stress gradients. Therefore, even if a vertical planar induced fracture were created at the wellbore wall, it would probably exploit natural fractures and bedding planes, leading to complex fracture geometries. Acid fracture stimulations are plugged by the insoluble clay residue within the clay-rich Hod chalk, so this is not an optimal strategy. Proppant fracturing has more merit, but complex fracture geometries present significant challenges for successful treatment design while trying to avoid or minimize extremely costly early screen-outs.
Efficient Kernel Management on GPUs
Authors: Liang Yun , Li Xiuhong 
Published: May 2017

Graphics Processing Units (GPUs) have been widely adopted as accelerators for compute-intensive applications due to its tremendous computational power and high memory bandwidth. As the complexity of applications continues to grow, each new generation of GPUs has been equipped with advanced architectural features and more resources to sustain its performance acceleration capability. Recent GPUs have been featured with concurrent kernel execution, which is designed to improve the resource utilization by executing multiple kernels simultaneously. However, it is still a challenge to find a way to manage the resources on GPUs for concurrent kernel execution. Prior works only achieve limited performance improvement as they do not optimize the thread-level parallelism (TLP) and model the resource contention for the concurrently executing kernels.
In this article, we design an efficient kernel management framework that optimizes the performance for concurrent kernel execution on GPUs. Our kernel management framework contains two key components: TLP modulation and cache bypassing. The TLP modulation is employed to adjust the TLP for the concurrently executing kernels. It consists of three parts: kernel categorization, static TLP modulation, and dynamic TLP modulation. The cache bypassing is proposed to mitigate the cache contention by only allowing a subset of a kernel’s blocks to access the L1 data cache. Experiments indicate that our framework can improve the performance by 1.51 × on average (energy-efficiency by 1.39 × on average), compared with the default concurrent kernel execution framework.
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Authors: Cascone Tina , Xu Li , Lin Heather Y. , Liu Wenbin , Tran Hai T. , Liu Yuan , Howells Kathryn , Haddad Vincent , Hanrahan Emer , Nilsson Monique B. , Cortez Maria A. , Giri Uma , Kadara Humam , Saigal Babita , Park Yun-Yong , Peng Weiyi , Lee Ju-Seog , Ryan Anderson J. , Jüergensmeier Juliane M. , Herbst Roy S. , Wang Jing , Langley Robert R. , Wistuba Ignacio I. , Lee Jack J. , Heymach John V. 
Published: May 2017

Abstract
Purpose: Resistance to VEGFR inhibitors is a major obstacle in the treatment of non–small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors.
Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes.
Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival.
Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. Clin Cancer Res; 23(18); 5489–501. ©2017 AACR.
Incremental Prognostic Use of Left Ventricular Global Longitudinal Strain in Asymptomatic/Minimally Symptomatic Patients With Severe Bioprosthetic Aortic Stenosis Undergoing Redo Aortic Valve Replacement
Authors: Naji Peyman , Shah Shailee , Svensson Lars G. , Gillinov A. Marc , Johnston Douglas R. , Rodriguez L. Leonardo , Grimm Richard A. , Griffin Brian P. , Desai Milind Y. 
Published: May 2017

Background—
With improved survival of patients undergoing primary bioprosthetic aortic valve replacement (AVR), reoperation to relieve severe prosthetic aortic stenosis (PAS) is increasing. Timing of redo surgery in asymptomatic/minimally symptomatic patients remains controversial. Left ventricular (LV) global longitudinal strain (GLS) is a marker of subclinical LV dysfunction. In asymptomatic/minimally symptomatic patients with severe PAS undergoing redo AVR, we sought to determine whether LV-GLS provides incremental prognostic use.

Methods and Results—

We studied 191 patients with severe bioprosthetic PAS (63±16 years, 58% men) who underwent redo AVR between 2000 and 2012 (excluding mechanical PAS, severe other valve disease transcatheter AVR, and LV ejection fraction <50%). Society of Thoracic Surgeons score was calculated. Standard echocardiography data were obtained. LV-GLS was measured on 2-, 3-, and 4-chamber views using velocity vector imaging. Severe PAS was defined as aortic valve area <0.8 cm
2
, mean aortic valve gradient ≥40 mm Hg, and dimensionless index <0.25. A composite outcome of death and congestive heart failure admission was recorded. At baseline, mean Society of Thoracic Surgeons score, LV ejection fraction, mean aortic valve gradients, and right ventricular systolic pressure were 7±6, 58±6%, 54±10 mm Hg and 40±14 mm Hg, whereas 50% had >2+ aortic regurgitation. Median LV-GLS was −14.2% (−11.4, −17.1%). At 4.2±3 years, 41 (22%) patients met the composite end point (2.5% deaths and 1% strokes at 30 days postoperatively). On multivariable Cox survival analysis, LV-GLS was independently associated with longer-term composite events (hazard ratio, 1.21; 95% confidence interval, 1.10–1.33),
P
<0.01. The C statistic for the clinical model (Society of Thoracic Surgeons score, degree of aortic regurgitation, and right ventricular systolic pressure) was 0.64 (95% confidence interval 0.54–0.79),
P
<0.001. Addition of LV-GLS to the clinical model increased the C statistic significantly to 0.71 (95% confidence interval 0.58–0.81),
P
<0.001.

Conclusions—
In asymptomatic/minimally symptomatic patients with severe bioprosthetic PAS undergoing redo AVR, baseline LV-GLS provides incremental prognostic use over established predictors and could potentially aid in surgical timing and risk stratification.
Changing Attitudes and Knowledge Toward SNAP Application
Authors: Bird Carolyn L. , McClelland Jacquelyn W. 
Published: May 2017

Purpose: To examine effectiveness of an educational intervention on attitude and knowledge related to accessing and qualifying for the Supplemental Nutrition Assistance Program (SNAP). Design: Cross-sectional survey. Setting: Community sites (38) in North Carolina. Participants: Low-income adult participants who provided data (n = 558). Intervention: Participants completed pre- and postsurveys for the 45-minute program. Measures: Theoretically based surveys measured knowledge requisite to the decision to apply for SNAP benefits. Analysis: Paired sample t tests tested the hypothesis of “no difference” in postintervention knowledge. Results: Knowledge gains were statistically significant on all questions ( P < .01) including the amount of food a minimum benefit could purchase, how to apply for SNAP, how the electronic benefit transfer card and benefits work, eligibility restrictions, and how to receive application assistance. Subsequent percentage change analyses revealed the strongest intervention effects to be how to apply and accessing application assistance. Conclusion: Effective theory-based programs can improve knowledge and dispel myths concerning SNAP participation among low-income participants.
Anesthesia Duration as an Independent Risk Factor for Early Postoperative Complications in Adults Undergoing Elective ACDF
Authors: Phan Kevin , Kim Jun S. , Kim Joung Heon , Somani Sulaiman , Di’Capua John , Dowdell James E. , Cho Samuel K. 
Published: May 2017

Study Design: Retrospective study. Objective: To determine the presence of any potential associations between anesthesia time with postoperative outcome and complications following elective anterior cervical discectomy and fusion (ACDF). Methods: Patients who underwent elective ACDF were identified in the American College of Surgeons National Quality Improvement Program database. Patient demographics, medical comorbidities, and perioperative and postoperative complications up to 30 days were analyzed by univariate and multivariate analysis. Results: A total of 3801 patients undergoing elective ACDF were identified. Patients were subdivided into quintiles of anesthesia time: Group 1, 48 to 129 minutes (n = 761, 20%); Group 2, 129 to 156 minutes (n = 760, 20%); Group 3, 156 to 190 minutes (n = 760, 20%); Group 4, 190 to 245 minutes (n = 760, 20%); and Group 5, 245 to 1025 minutes (n = 760, 20%). Univariate analysis showed significantly higher rates of any complication ( P < .0001), pulmonary complication ( P < .0001), intra-/postoperative blood transfusions ( P < .0001), sepsis ( P = .017), wound complications ( P = .002), total length of stay >5 days ( P < .0001), and return to operating room ( P = .006) in the highest quintile compared to those of other groups. Multivariate regression analysis revealed that prolonged anesthesia was an independent factor for increased odds of overall complications (odds ratio [OR] = 2.71, P = .012), venous thromboembolism (OR = 2.69, P = .011), and return to the operating room (OR = 2.92, P = .004). The 2 groups with the longest anesthesia durations (quintiles 4 and 5) had increased total length of stay more than 5 days (for quintile 4, OR = 3.10, P = .0004; for quintile 5, OR = 3.61, P < .0001). Conclusion: Prolonged anesthesia duration is associated with increased odds of complication, venous thromboembolism, increased length of stay, and return to the operating room.
20 Year Outcomes of ACL Reconstruction with Hamstring Tendon Autograft. Does Age Matter?
Authors: Roe Justin , Shah Feisal , Fitzgibbon Emma , Salmon Lucy , Linklater James , Pinczewski Leo 
Published: May 2017

Introduction: The purpose of this study was to document the prospective longitudinal outcome of ‘isolated’ anterior cruciate ligament (ACL) ruptures treated with anatomical endoscopic reconstruction using hamstring tendon autograft over 20 years. Long term outcomes were compared between those undergoing ACL reconstruction age 18 or less and those >18 years the time of surgery. Methods: A total of 100 consecutive men and 100 consecutive women with ‘isolated’ ACL rupture underwent four-strand hamstring tendon reconstruction with anteromedial portal femoral tunnel drilling and interference screw fixation by a single surgeon. At the time of ACL reconstruction 39 participants were aged 18 or less, 81 were aged 19 to 25 and 80 were over 25. Reviews were performed pre-operatively and at 1, 2, 7, 15 and 20 years post-operatively. Outcomes included further ACL injury, clinical examination, subjective and objective scoring systems, and radiological assessment. Results: Further ACL injury occurred in 55 of the 200 patients (28%), 37 ruptured the ACL graft and 22 ruptured the contralateral ACL. ACL graft rupture was significantly increased in the young; 39% in those aged 18 or less, 21% of those aged 19-25 and 6% of those over 25 years (p=0.001). Participants with a posterior tibial slope of 12 degrees or more sustained a further ACL injury in 65% of cases. Moderate to severe radiological degenerative change was evident in 14% at 20 years. Outcomes were not statistically different between those aged 18 or less and those >18 years for the variables of IKDC subjective score (p=0.98), rate of return to preinjury activity level (p=0.32), current activity level, or degree of radiological degenerative change at 20 years (p=0.65). Conclusions: ACL reconstructive surgery in patients with an ‘isolated’ rupture using this technique was associated with good long term outcomes and does not appear to cause osteoarthritis, regardless of age. However further ACL injury after ACL reconstruction is significantly more common in the young and those with a high posterior tibial slope. **This study was performed with support from AOA Research Foundation