bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells
Authors: Montefusco Francesco , Pedersen Morten Gram 
Published: July 2015

Key points
The control of glucagon secretion from pancreatic alpha‐cells is still unclear and, when defective, is involved in the development of diabetes.
We propose a mathematical model of Ca2+ dynamics and exocytosis to understand better the intracellular mechanisms downstream of electrical activity that control glucagon secretion.
The model exploits compartmental modelling of Ca2+ levels near open and closed high voltage‐activated Ca2+ channels involved in exocytosis, in the sub‐membrane Ca2+ compartment, in the bulk cytosol and in the endoplasmic reticulum.
The model reproduces the effects of glucose, glucagon‐like peptide 1 (GLP‐1) and adrenaline, providing insight into the relative contributions of the various subcellular Ca2+ compartments in the control of glucagon secretion.
Our results highlight that the number of open Ca2+ channels is a dominant factor in glucagon release, and clarify why cytosolic Ca2+ is a poor read‐out of alpha‐cell secretion.
AbstractGlucagon secretion from pancreatic alpha‐cells is dysregulated in diabetes. Despite decades of investigations of the control of glucagon release by glucose and hormones, the underlying mechanisms are still debated. Recently, mathematical models have been applied to investigate the modification of electrical activity in alpha‐cells as a result of glucose application. However, recent studies have shown that paracrine effects such as inhibition of glucagon secretion by glucagon‐like peptide 1 (GLP‐1) or stimulation of release by adrenaline involve cAMP‐mediated effects downstream of electrical activity. In particular, depending of the intracellular cAMP concentration, specific types of Ca2+ channels are inhibited or activated, which interacts with mobilization of secretory granules. To investigate these aspects of alpha‐cell function theoretically, we carefully developed a mathematical model of Ca2+ levels near open or closed Ca2+ channels of various types, which was linked to a description of Ca2+ below the plasma membrane, in the bulk cytosol and in the endoplasmic reticulum. We investigated how the various subcellular Ca2+ compartments contribute to control of glucagon‐exocytosis in response to glucose, GLP‐1 or adrenaline. Our studies refine previous modelling studies of alpha‐cell function, and provide deeper insight into the control of glucagon secretion.
Contrast invariance of orientation tuning in cat primary visual cortex neurons depends on stimulus size
Authors: Liu Yong‐Jun , Hashemi‐Nezhad Maziar , Lyon David C. 
Published: July 2015

Key points
The process of orientation tuning is an important and well‐characterized feature of neurons in primary visual cortex.
The combination of ascending and descending circuits involved is not only relevant to understanding visual processing but the function of neocortex in general.
The classic feed‐forward model of orientation tuning predicts a broadening effect due to increasing contrast; yet, experimental results consistently report contrast invariance.
We show here that contrast invariance actually depends on stimulus size such that large stimuli extending beyond the neuron's receptive field engage circuits that promote invariance, whereas optimally sized, smaller stimuli result in contrast variance that is more in line with the classical orientation tuning model.
These results illustrate the importance of optimizing stimulus parameters to best reflect the sensory pathways under study and provide new clues about different circuits that may be involved in variant and invariant response properties.
AbstractSelective response to stimulus orientation is a key feature of neurons in primary visual cortex, yet the underlying mechanisms generating orientation tuning are not fully understood. The combination of feed‐forward and cortical mechanisms involved is not only relevant to understanding visual processing but the function of neocortex in general. The classic feed‐forward model predicts that orientation tuning should broaden considerably with increasing contrast; however, experimental results consistently report contrast invariance. We show here, in primary visual cortex of anaesthetized cats under neuromuscular blockade, that contrast invariance occurs when visual stimuli are large enough to include the extraclassical surround (ECS), which is likely to involve circuits of suppression that may not be entirely feed‐forward in origin. On the other hand, when stimulus size is optimized to the classical receptive field of each neuron, the population average shows a statistically significant 40% increase in tuning width at high contrast, demonstrating that contrast variance of orientation tuning can occur. Conversely, our results also suggest that the phenomenon of contrast invariance relies in part on the presence of the ECS. Moreover, these results illustrate the importance of optimizing stimulus parameters to best reflect the neural pathways under study.
External validation of a publicly available computer assisted diagnostic tool for mammographic mass lesions with two high prevalence research datasets
Authors: Benndorf Matthias , Burnside Elizabeth S. , Herda Christoph , Langer Mathias , Kotter Elmar 
Published: July 2015

Purpose:Lesions detected at mammography are described with a highly standardized terminology: the breast imaging‐reporting and data system (BI‐RADS) lexicon. Up to now, no validated semantic computer assisted classification algorithm exists to interactively link combinations of morphological descriptors from the lexicon to a probabilistic risk estimate of malignancy. The authors therefore aim at the external validation of the mammographic mass diagnosis (MMassDx) algorithm. A classification algorithm like MMassDx must perform well in a variety of clinical circumstances and in datasets that were not used to generate the algorithm in order to ultimately become accepted in clinical routine.Methods:The MMassDx algorithm uses a naïve Bayes network and calculates post‐test probabilities of malignancy based on two distinct sets of variables, (a) BI‐RADS descriptors and age (“descriptor model”) and (b) BI‐RADS descriptors, age, and BI‐RADS assessment categories (“inclusive model”). The authors evaluate both the MMassDx (descriptor) and MMassDx (inclusive) models using two large publicly available datasets of mammographic mass lesions: the digital database for screening mammography (DDSM) dataset, which contains two subsets from the same examinations—a medio–lateral oblique (MLO) view and cranio–caudal (CC) view dataset—and the mammographic mass (MM) dataset. The DDSM contains 1220 mass lesions and the MM dataset contains 961 mass lesions. The authors evaluate discriminative performance using area under the receiver‐operating‐characteristic curve (AUC) and compare this to the BI‐RADS assessment categories alone (i.e., the clinical performance) using the DeLong method. The authors also evaluate whether assigned probabilistic risk estimates reflect the lesions’ true risk of malignancy using calibration curves.Results:The authors demonstrate that the MMassDx algorithms show good discriminatory performance. AUC for the MMassDx (descriptor) model in the DDSM data is 0.876/0.895 (MLO/CC view) and AUC for the MMassDx (inclusive) model in the DDSM data is 0.891/0.900 (MLO/CC view). AUC for the MMassDx (descriptor) model in the MM data is 0.862 and AUC for the MMassDx (inclusive) model in the MM data is 0.900. In all scenarios, MMassDx performs significantly better than clinical performance, P < 0.05 each. The authors furthermore demonstrate that the MMassDx algorithm systematically underestimates the risk of malignancy in the DDSM and MM datasets, especially when low probabilities of malignancy are assigned.Conclusions:The authors’ results reveal that the MMassDx algorithms have good discriminatory performance but less accurate calibration when tested on two independent validation datasets. Improvement in calibration and testing in a prospective clinical population will be important steps in the pursuit of translation of these algorithms to the clinic.
Comparative Analysis of Whole-Genome Sequences of Influenza A(H1N1)pdm09 Viruses Isolated from Hospitalized and Nonhospitalized Patients Identifies Missense Mutations That Might Be Associated with Patient Hospital Admissions in Finland during 2009 to 2014
Authors: Mishel Polina , Ojala Teija , Benner Christian , Lakspere Triin , Bychkov Dmitrii , Jalovaara Petri , Kakkola Laura , Kallio-Kokko Hannimari , Kantele Anu , Kankainen Matti , Ikonen Niina , Ripatti Samuli , Julkunen Ilkka , Kainov Denis E. 
Published: July 2015

ABSTRACT
Here, we report 40 new whole-genome sequences of influenza A(H1N1)pdm09 viruses isolated from Finnish patients during 2009 to 2014. A preliminary analysis of these and 186 other whole genomes of influenza A(H1N1)pdm09 viruses isolated from hospitalized and nonhospitalized patients during 2009 to 2014 in Finland revealed several viral mutations that might be associated with patient hospitalizations.
Draft Genome Sequence of
Lactobacillus
sp. Strain TCF032-E4, Isolated from Fermented Radish
Authors: Mao Yuejian , Chen Meng , Horvath Philippe 
Published: July 2015

ABSTRACT

Here, we report the draft genome sequence of
Lactobacillus
sp. strain TCF032-E4 (= CCTCC AB2015090 = DSM 100358), isolated from a Chinese fermented radish. The total length of the 57 contigs is about 2.9 Mb, with a G+C content of 43.5 mol% and 2,797 predicted coding sequences (CDSs).
Mitochondrial Genome Sequence of the Glass Sponge
Oopsacas minuta
Authors: Jourda Cyril , Santini Sébastien , Rocher Caroline , Le Bivic André , Claverie Jean-Michel 
Published: July 2015

ABSTRACT

We report the complete mitochondrial genome sequence of the Mediterranean glass sponge
Oopsacas minuta
. This 19-kb mitochondrial genome has 24 noncoding genes (22 tRNAs and 2 rRNAs) and 14 protein-encoding genes coding for 11 subunits of respiratory chain complexes and 3 ATP synthase subunits.
LavaSIM: its physical basis and applicability
Authors: Fujita Eisuke , Nagai Masashi 
Published: July 2015

Abstract
LavaSIM is a lava -flow simulator to carry out three-dimensional (3D) analysis of solid–liquid two-phase lava flows. Heat transfer between molten lava and solidified crust into the air, water and ground is calculated using radiation equations, so we can simulate not only the lava-flow distribution but also its physical characteristics: for instance, the internal convectional structure. Lava viscosity can be treated as a function of temperature, and is associated with the percentage of crystallization. The stop condition for the lava flow is determined by calculating the minimum spreading thickness, taking into consideration the yield strength. This paper also discusses whether LavaSIM, the deterministic lava-flow simulation, can be applied to basaltic lava flows and allow lava-flow characteristics, such as inundated area, temperature distribution, crust–melt distribution, velocity and pressure field, to be quantitatively evaluated.
Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis
Authors: Ebos John M.L. 
Published: July 2015

Abstract
The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits. The paradox of treatment-induced metastasis (TIM) is not new. Supporting preclinical studies span decades, but are often overlooked. With recent evidence of prometastatic effects following treatment with targeted agents blocking the tumor microenvironment, a closer inspection of this literature is warranted. The TIM phenomena may diminish the impact of effective therapies and play a critical role in eventual resistance. Alternatively, it may simply exemplify the gap between animal and human studies, and therefore have little impact for patient disease and treatment. This review will focus on the preclinical model systems used to evaluate TIM and explore the mechanisms that influence overall treatment efficacy. Understanding the role of TIM in established and emerging drug treatment strategies may help provide rationales for future drug combination approaches with antimetastatic agents to improve outcomes and reduce resistance. Cancer Res; 75(17); 3427–35. ©2015 AACR.
Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer
Authors: Labanca Estefanía , De Luca Paola , Gueron Geraldine , Paez Alejandra , Moiola Cristian P. , Massillo Cintia , Porretti Juliana , Giudice Jimena , Zalazar Florencia , Navone Nora , Vazquez Elba , De Siervi Adriana 
Published: July 2015

Abstract
Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1–negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1–NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer.
Implications: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2. Mol Cancer Res; 13(11); 1455–64. ©2015 AACR.
BMP9 Induces Cord Blood–Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1
Authors: Kim Jihye , Kim Minhyung , Jeong Yoonjeong , Lee Wook-bin , Park Hyojin , Kwon Ja-Young , Kim Young-Myeong , Hwang Daehee , Kwon Young-Guen 
Published: July 2015

Objective—
Modulating endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis, and thus various clinical trials involving EPCs are ongoing. However, the identification of environmental conditions and development of optimal methods are required to accelerate EPC-driven vasculogenesis.

Approach and Results—
We evaluated gene expression profiles of cord blood–derived EPCs and endothelial cells to identify the key factors in EPC→endothelial cell differentiation and to show that transforming growth factor-β family members contribute to EPC differentiation. The expression levels of activin receptor-like kinase 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9) were markedly changed in EPC→endothelial cell differentiation. Interestingly, BMP9 induced EPC→endothelial cell differentiation and EPC incorporation into vessel-like structures by acting on ALK1 expressed on EPCs in vitro. BMP9 also induced neovascularization in mice with hindlimb ischemia by increasing vessel formation and the incorporation of EPCs into vessels. Conversely, neovascularization was impaired when ALK1 signaling was blocked. Furthermore, EPCs exposed to either short- or long-term BMP9 stimulation demonstrated these functions in EPC-mediated neovascularization.

Conclusions—
Collectively, our results indicated that BMP9/ALK1 augmented vasculogenesis and angiogenesis, and thereby enhanced neovascularization. Thus, we suggest that BMP9/ALK1 may improve the efficacy of EPC-based therapies for treating ischemic diseases.
The HARMONY Trial
Authors: Reiffel James A. , Camm A. John , Belardinelli Luiz , Zeng Dewan , Karwatowska-Prokopczuk Ewa , Olmsted Ann , Zareba Wojciech , Rosero Spencer , Kowey Peter 
Published: July 2015

Background—
Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety.

Methods and Results—

HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone’s negative inotropic effect—see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (
P
=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (
P
=0.072). Both combinations were well tolerated.

Conclusions—
HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled.

Clinical Trial Registration—

ClinicalTrials.gov
; Unique identifier: NCT01522651.
Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis
Authors: Findlay Mark D. , Thomson Peter C. , Fulton Rachael L. , Solbu Marit D. , Jardine Alan G. , Patel Rajan K. , Stevens Kathryn K. , Geddes Colin C. , Dawson Jesse , Mark Patrick B. 
Published: July 2015

Background and Purpose—
End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke.

Methods—
All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 2012, were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging, and dialysis-related variables were assessed, and case-fatality was determined. Follow-up was until December 31, 2013.

Results—
A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke.

Conclusions—
Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving hemodialysis.
Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Asian Patients With Nonvalvular Atrial Fibrillation
Authors: Wang Kang-Ling , Lip Gregory Y.H. , Lin Shing-Jong , Chiang Chern-En 
Published: July 2015

Background and Purpose—
The use of vitamin K antagonists (VKAs), the cornerstone treatment for stroke prevention in patients with atrial fibrillation, is limited by the perceived risk of serious bleeding in Asia. Non-VKA oral anticoagulants (NOACs) are safer alternatives. Here, we evaluate performance differences of NOACs between Asians and non-Asians.

Methods—
We compared efficacy and safety of NOACs between patients enrolled in Asian and non-Asian countries using aggregative data from phase III clinical trials. The odds ratios (ORs [95% confidence interval]) were calculated by a random effects model.

Results—

Comparing with VKAs, standard-dose NOACs reduced stroke or systemic embolism (OR=0.65 [0.52–0.83] versus 0.85 [0.77–0.93],
P
interaction= 0.045) more in Asians than in non-Asians and were safer in Asians than in non-Asians about major bleeding (OR=0.57 [0.44–0.74] versus 0.89 [0.76–1.04],
P
interaction=0.004), hemorrhagic stroke (OR=0.32 [0.19–0.52] versus 0.56 [0.44–0.70],
P
interaction=0.046) in particular, whereas gastrointestinal bleeding was significantly increased in non-Asians (OR=0.79 [0.48–1.32] versus 1.44 [1.12–1.85],
P
interaction=0.041). Generally, low-dose NOACs were safer than VKAs without heterogeneity in efficacy and safety between Asians and non-Asians, except for ischemic stroke, major, and gastrointestinal bleeding.

Conclusions—
Our findings suggest that standard-dose NOACs were more effective and safer in Asians than in non-Asians, whereas low-dose NOACs performed similarly in both populations.