bluuebunny/crossref_metadata_2025_split huggingface dataset:
ArcD1 and ArcD2 Arginine/Ornithine Exchangers Encoded in the Arginine Deiminase Pathway Gene Cluster of Lactococcus lactis
Authors: Noens Elke E. E. , Kaczmarek Michał B. , Żygo Monika , Lolkema Juke S. 
Published: September 2015

ABSTRACT

The arginine deiminase (ADI) pathway gene cluster in
Lactococcus lactis
contains two copies of a gene encoding an
l
-arginine/
l
-ornithine exchanger, the
arcD1
and
arcD2
genes. The physiological function of ArcD1 and ArcD2 was studied by deleting the two genes. Deletion of
arcD1
resulted in loss of the growth advantage observed in the presence of high
l
-arginine in different growth media. Uptake of
l
-arginine and
l
-ornithine by resting cells was reduced to the low level observed for an ArcD1/ArcD2 double deletion mutant. Deletion of the
arcD2
gene did not affect the growth enhancement, and uptake activities were slightly reduced. Nevertheless, recombinant expression of ArcD2 in the ArcD1/ArcD2 double mutant did recover the growth advantage. Kinetic characterization of ArcD1 and ArcD2 showed high affinities for both
l
-arginine and
l
-ornithine (

K
m

in the micromolar range). A difference between the two transporters was the significantly lower affinity of ArcD2 for the cationic amino acids
l
-ornithine,
l
-lysine, and
l
-histidine. In contrast, the affinity of ArcD2 was higher for the neutral amino acid
l
-alanine. Moreover, ArcD2 efficiently translocated
l
-alanine, while ArcD1 did not. Both transporters revealed affinities in the mM range for agmatine, cadaverine, histamine, and putrescine. These amines bind but are not translocated. It is concluded that ArcD1 is the main
l
-arginine/
l
-ornithine exchanger in the ADI pathway and that ArcD2 is not functionally expressed in the media used. ArcD2 is proposed to function together with the
arcT
gene that encodes a putative transaminase and is found adjacent to the
arcD2
gene.

IMPORTANCE
The arginine deiminase (ADI) pathway gene cluster in
Lactococcus lactis
contains two copies of a gene encoding an
l
-arginine/
l
-ornithine exchanger, the
arcD1
and
arcD2
genes. The physiological function of ArcD1 and ArcD2 was studied by deleting the two genes. It is concluded that ArcD1 is the main
l
-arginine/
l
-ornithine exchanger in the ADI pathway. ArcD2 is proposed to function as a
l
-arginine/
l
-alanine exchanger in a pathway together with the
arcT
gene, which is found adjacent to the
arcD2
gene in the ADI gene cluster.
A Matter of Timing: Contrasting Effects of Hydrogen Sulfide on Oxidative Stress Response in Shewanella oneidensis
Authors: Wu Genfu , Wan Fen , Fu Huihui , Li Ning , Gao Haichun 
Published: September 2015

ABSTRACT

Hydrogen sulfide (H
2
S), well known for its toxic properties, has recently become a research focus in bacteria, in part because it has been found to prevent oxidative stress caused by treatment with some antibiotics. H
2
S has the ability to scavenge reactive oxygen species (ROS), thus preventing oxidative stress, but it is also toxic, leading to conflicting reports of its effects in different organisms. Here, with
Shewanella oneidensis
as a model, we report that the effects of H
2
S on the response to oxidative stress are time dependent. When added simultaneously with H
2
O
2
, H
2
S promoted H
2
O
2
toxicity by inactivating catalase, KatB, a heme-containing enzyme involved in H
2
O
2
degradation. Such an inhibitory effect may apply to other heme-containing proteins, such as cytochrome
cbb
3
oxidase. When H
2
O
2
was supplied 20 min or later after the addition of H
2
S, the oxidative-stress-responding regulator OxyR was activated, resulting in increased resistance to H
2
O
2
. The activation of OxyR was likely triggered by the influx of iron, a response to lowered intracellular iron due to the iron-sequestering property of H
2
S. Given that
Shewanella
bacteria thrive in redox-stratified environments that have abundant sulfur and iron species, our results imply that H
2
S is more important for bacterial survival in such environmental niches than previously believed.

IMPORTANCE
Previous studies have demonstrated that H
2
S is either detrimental or beneficial to bacterial cells. While it can act as a growth-inhibiting molecule by damaging DNA and denaturing proteins, it helps cells to combat oxidative stress. Here we report that H
2
S indeed has these contrasting biological functions and that its effects are time dependent. Immediately after H
2
S treatment, there is growth inhibition due to damage of heme-containing proteins, at least to catalase and cytochrome
c
oxidase. In contrast, when added a certain time later, H
2
S confers an enhanced ability to combat oxidative stress by activating the H
2
O
2
-responding regulator OxyR. Our data reconcile conflicting observations about the functions of H
2
S.
A critical appraisal of clinical trials conducted and subsequent drug approvals in India and South Africa
Authors: Limaye Dnyanesh , Langer Janka Marisa , Rühling Tjorben , Fortwengel Gerhard 
Published: September 2015

ObjectivesTo assess the relation between the number of clinical trials conducted and respective new drug approvals in India and South Africa.DesignConstruction and analysis of a comprehensive database of completed randomised controlled clinical trials based on clinicaltrials.gov from 1 January 2005 to 31 December 2010 and drug approval data from 2006 until 2013 for India and South Africa.SettingUSA, the EU, India and South Africa.Main outcome measuresPercentage of completed randomised clinical trials for an Investigational Medicinal Product (IMP) leading to new drug approval in India and South Africa.ResultsA total of 622 eligible randomised controlled trials were identified as per search criteria for India and South Africa. Clustering them for the same sponsor and the same Investigational New Drug (IND) resulted in 453 eligible trials, that is, 224 for India and 229 for South Africa. The distribution of the market application approvals between the EU/USA as well as India and South Africa revealed that out of clinical trials with the participation of test centres in India and/or South Africa, 39.6% (India) clinical trials and 60.1% (South Africa) clinical trials led to market authorisation in the EU/USA without a New Drug Application (NDA) approval in India or South Africa.ConclusionsDespite an increase in clinical trial activities, there is a clear gap between the number of trials conducted and market availability of these new drugs in India and South Africa. Drug regulatory authorities, investigators, institutional review boards and patient groups should direct their efforts to ensuring availability of new drugs in the market that have been tested and researched on their population.
Can we influence the epidemiology of dementia? Perspectives from population-based studies
Authors: Birdi Ratika , Stephan Blossom Christa Maree , Robinson Louise , Davis Daniel 
Published: September 2015

ABSTRACT
The worldwide prevalence of dementia is predicted to rise significantly in the next three decades. However, these projections have not taken into account the role of modifiable risk factors and whether any prevention strategies might influence the predicted trend. Attempts at pharmacological disease modification have largely been disappointing, and the difficulties in conducting dementia trials are reviewed here. In contrast, recent population studies in high-income countries suggest that the epidemiology may be changing with a possible decline in incident dementia, or even a reduction in age-specific prevalence. Therefore, efforts to develop public health interventions may prove to be the more successful approach to addressing dementia at a societal level.
Magnetic field, frequency and temperature dependence of complex conductance of ultrathin La1.65Sr0.45CuO4∕La2CuO4 films and the organic superconductors κ-(BEDT-TTF)2Cu[N(CN)2]Br
Authors: Gasparov V. A. , He Xi , Dubuis G. , Pavuna D. , Kushch N. D. , Yagubskii E. B. , Schlueter J. A. , Bozovic I. 
Published: September 2015

We used atomic-layer molecular beam epitaxy (ALL-MBE) to synthesize bilayer films of a cuprate metal ([Formula: see text], LSCO) and a cuprate insulator ([Formula: see text], LCO), in which interface superconductivity occurs in a layer that is just one-half unit cell thick. We have studied the magnetic field and temperature dependence of the complex sheet conductance, [Formula: see text], of these films, and compared them to [Formula: see text]-(BEDT-TTF)[Formula: see text] single crystals. The magnetic field [Formula: see text] was applied both parallel and perpendicular to the 2D conducting layers. Experiments have been carried out at frequencies between 23 kHz and 50 MHz using either two-coil mutual inductance technique, or the LC resonators with spiral or rectangular coils. The real and the imaginary parts of the mutual-inductance [Formula: see text] between the coil and the sample were measured and converted to complex conductivity. For [Formula: see text] perpendicular to the conducting layers, we observed almost identical behavior in both films and [Formula: see text]-Br single crystals: (i) the transition onset in the inductive response, [Formula: see text](T) occurs at a temperature lower by 2 K than in [Formula: see text], (ii) this shift is almost constant with magnetic field up to 8 T; (iii) the vortex diffusion constant [Formula: see text] is exponential due to pinning of vortex cores. These results can be described by the extended dynamic theory of the Berezinski–Kosterlitz–Thouless (BKT) transition and dynamics of bound vortex–antivortex pairs with short separation lengths.
Revisiting Clustered Microarchitecture for Future Superscalar Cores
Authors: Michaud Pierre , Mondelli Andrea , Seznec André 
Published: September 2015

During the past 10 years, the clock frequency of high-end superscalar processors has not increased. Performance keeps growing mainly by integrating more cores on the same chip and by introducing new instruction set extensions. However, this benefits only some applications and requires rewriting and/or recompiling these applications. A more general way to accelerate applications is to increase the IPC, the number of instructions executed per cycle. Although the focus of academic microarchitecture research moved away from IPC techniques, the IPC of commercial processors was continuously improved during these years.
We argue that some of the benefits of technology scaling should be used to raise the IPC of future superscalar cores further. Starting from microarchitecture parameters similar to recent commercial high-end cores, we show that an effective way to increase the IPC is to allow the out-of-order engine to issue more micro-ops per cycle. But this must be done without impacting the clock cycle. We propose combining two techniques: clustering and register write specialization. Past research on clustered microarchitectures focused on narrow issue clusters, as the emphasis at that time was on allowing high clock frequencies.
Instead, in this study, we consider wide issue clusters, with the goal of increasing the IPC under a constant clock frequency. We show that on a wide issue dual cluster, a very simple steering policy that sends 64 consecutive instructions to the same cluster, the next 64 instructions to the other cluster, and so forth, permits tolerating an intercluster delay of three cycles. We also propose a method for decreasing the energy cost of sending results from one cluster to the other cluster.
Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling
Authors: Roy Ishan , McAllister Donna M. , Gorse Egal , Dixon Kate , Piper Clinton T. , Zimmerman Noah P. , Getschman Anthony E. , Tsai Susan , Engle Dannielle D. , Evans Douglas B. , Volkman Brian F. , Kalyanaraman Balaraman , Dwinell Michael B. 
Published: September 2015

Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis. Cancer Res; 75(17); 3529–42. ©2015 AACR.
Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity
Authors: Caruso Hillary G. , Hurton Lenka V. , Najjar Amer , Rushworth David , Ang Sonny , Olivares Simon , Mi Tiejuan , Switzer Kirsten , Singh Harjeet , Huls Helen , Lee Dean A. , Heimberger Amy B. , Champlin Richard E. , Cooper Laurence J.N. 
Published: September 2015

Abstract
Many tumors overexpress tumor-associated antigens relative to normal tissue, such as EGFR. This limits targeting by human T cells modified to express chimeric antigen receptors (CAR) due to potential for deleterious recognition of normal cells. We sought to generate CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate density of EGFR expression by generating two CARs from monoclonal antibodies that differ in affinity. T cells with low-affinity nimotuzumab-CAR selectively targeted cells overexpressing EGFR, but exhibited diminished effector function as the density of EGFR decreased. In contrast, the activation of T cells bearing high-affinity cetuximab-CAR was not affected by the density of EGFR. In summary, we describe the generation of CARs able to tune T-cell activity to the level of EGFR expression in which a CAR with reduced affinity enabled T cells to distinguish malignant from nonmalignant cells. Cancer Res; 75(17); 3505–18. ©2015 AACR.
Childhood Determination of Hodgkin Lymphoma among U.S. Servicemen
Authors: Mack Thomas M. , Norman James E. , Rappaport Edward , Cozen Wendy 
Published: September 2015

AbstractBackground: Hodgkin lymphoma in young adults is inexplicably linked to economic development.Methods: We conducted a nested case–control study of the 656 servicemen with Hodgkin lymphoma diagnosed between ages 17 to 32 while on active duty in the U.S. military during 1950–68. Controls, chosen randomly from the servicemen on duty at the time, were matched on service, birth year, and induction date. Information came from preinduction records and military records for the period ending at onset or the equivalent date.Results: Risk was independently increased with small sib-ship size [OR, 2.3; confidence interval (CI), 1.6–3.5], low birth order (OR, 1.9; CI, 1.4–2.6), and an interval of at least 5 years between birth and that of a previous or subsequent sibling (OR, 2.1; CI, 1.5–3.1). Other factors independently and significantly associated with elevated risk of Hodgkin lymphoma were: tallness, high body mass index, more education (but not higher income) in the county of birth, BB or AB blood type, and past infectious mononucleosis (but a deficit of other childhood viral infections). Early fatherhood conveyed high risk (OR, 2.6; CI, 1.4–4.8), especially if with a high-risk sibling configuration. Factors unrelated to risk included personal education, preinduction or military occupation, induction test score, and rank. Findings were similar for nodular sclerosis and mixed cell histologic subtypes.Conclusions: Protection from the environment in childhood, but not in adulthood, increases the likelihood of young adult Hodgkin lymphoma, which may result from nonspecific isolation from early infections and/or exposure to late infection by a specific but unidentified ubiquitous childhood virus.Impact: Events in childhood protect against later Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev; 24(11); 1707–15. ©2015 AACR.
New Strategies in Human Papillomavirus–Related Oropharynx Cancer: Effecting Advances in Treatment for a Growing Epidemic
Authors: Massarelli Erminia , Ferrarotto Renata , Glisson Bonnie S. 
Published: September 2015

Abstract
The past two decades have been witness to a steadily increasing incidence of oropharynx cancer, specifically related to human papillomavirus (HPV), primarily affecting middle-aged Caucasian men, in North America and Europe. The ever-increasing incidence, now clearly an epidemic, of this unique clinicopathologic entity demands new perspectives in diagnosis and staging and presents unique challenges in clinical research, given the excellent prognosis afforded by chemoradiation for the majority of these patients. To reduce the morbidity of late toxicity in survivors without compromising the high rates of survival currently enjoyed, and simultaneously address the poor prognosis of those with recurrence, it is critical to capitalize on the viral etiology and translate discoveries in genomics, target/drug discovery, viral oncogenesis, and immunbiology to improved outcomes for patients. Herein, we review ongoing and planned clinical research for HPV-related oropharynx cancer, the basis for which is constituted by prior clinical observations, knowledge of the genomic alterations and altered biology associated with HPV-related oncogenesis, and hope that molecularly targeted and immunomodulatory therapies can be harnessed. Clin Cancer Res; 21(17); 3821–8. ©2015 AACR.
Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer
Authors: Moon Edmund K. , Ranganathan Raghuveer , Eruslanov Evgeniy , Kim Soyeon , Newick Kheng , O'Brien Shaun , Lo Albert , Liu Xiaojun , Zhao Yangbing , Albelda Steven M. 
Published: September 2015

AbstractPurpose: Tumor-infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study mechanisms and to test anti-human therapeutics.Experimental Design: We transduced human T cells with a published, optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen, NY-ESO-1. After demonstrating antigen-specific in vitro activity, these cells were used to target a human lung cancer line that expressed NY-ESO-1 in the appropriate HLA context growing in immunodeficient mice. The ability of anti-PD1 antibody to augment efficacy was tested.Results: Injection of transgenic T cells had some antitumor activity, but did not eliminate the tumors. The injected T cells became profoundly hypofunctional accompanied by upregulation of PD1, Tim3, and Lag3 with coexpression of multiple inhibitory receptors in a high percentage of cells. This model allowed us to test reagents targeted specifically to human T cells. We found that injections of an anti-PD1 antibody in combination with T cells led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells.Conclusions: This model offers a platform for preclinical testing of adjuvant immunotherapeutics targeted to human T cells prior to transition to the bedside. Because the model employs engineering of human T cells with a TCR clone instead of a CAR, it allows for study of the biology of tumor-reactive TILs that signal through an endogenous TCR. The lessons learned from TCR-engineered TILs can thus be applied to tumor-reactive TILs. Clin Cancer Res; 22(2); 436–47. ©2015 AACR.See related commentary by Yang, p. 275
Incidence of Major Cardiovascular Events in Immigrants to Ontario, Canada
Authors: Tu Jack V. , Chu Anna , Rezai Mohammad R. , Guo Helen , Maclagan Laura C. , Austin Peter C. , Booth Gillian L. , Manuel Douglas G. , Chiu Maria , Ko Dennis T. , Lee Douglas S. , Shah Baiju R. , Donovan Linda R. , Sohail Qazi Zain , Alter David A. 
Published: September 2015

Background—
Immigrants from ethnic minority groups represent an increasing proportion of the population in many high-income countries, but little is known about the causes and amount of variation between various immigrant groups in the incidence of major cardiovascular events.

Methods and Results—
We conducted the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) Immigrant Study, a big data initiative, linking information from Citizenship and Immigration Canada’s Permanent Resident database to 9 population-based health databases. A cohort of 824 662 first-generation immigrants aged 30 to 74 as of January 2002 from 8 major ethnic groups and 201 countries of birth who immigrated to Ontario, Canada between 1985 and 2000 were compared with a reference group of 5.2 million long-term residents. The overall 10-year age-standardized incidence of major cardiovascular events was 30% lower among immigrants than among long-term residents. East Asian immigrants (predominantly ethnic Chinese) had the lowest incidence overall (2.4 in males, 1.1 in females per 1000 person-years), but this increased with greater duration of stay in Canada. South Asian immigrants, including those born in Guyana, had the highest event rates (8.9 in males, 3.6 in females per 1000 person-years), along with immigrants born in Iraq and Afghanistan. Adjustment for traditional risk factors reduced but did not eliminate the differences in cardiovascular risk between various ethnic groups and long-term residents.

Conclusions—
Striking differences in the incidence of cardiovascular events exist among immigrants to Canada from different ethnic backgrounds. Traditional risk factors explain a part but not all of these differences.