bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐sedating antihistamines block G‐protein‐gated inwardly rectifying K+ channels
Authors: Chen I‐Shan , Liu Chang , Tateyama Michihiro , Karbat Izhar , Uesugi Motonari , Reuveny Eitan , Kubo Yoshihiro 
Published: May 2019

Background and PurposeA second‐generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the activity of G‐protein‐gated inwardly rectifying K+ (GIRK) channels, which regulate the excitability of neurons and cardiomyocytes. To clarify the underlying mechanism(s), we examined the effects of several antihistamines on GIRK channels and identified the structural determinant for the inhibition.Experimental ApproachElectrophysiological recordings were made in Xenopus oocytes and rat atrial myocytes to analyse the effects of antihistamines on various GIRK subunits (Kir3.x). Mutagenesis analyses identified the residues critical for inhibition by terfenadine and the regulation of ion selectivity. The potential docking site of terfenadine was analysed by molecular docking.Key ResultsGIRK channels containing Kir3.1 subunits heterologously expressed in oocytes and native GIRK channels in atrial myocytes were inhibited by terfenadine and other non‐sedating antihistamines. In Kir3.1 subunits, mutation of Phe137, located in the centre of the pore helix, to the corresponding Ser in Kir3.2 subunits reduced the inhibition by terfenadine. Introduction of an amino acid with a large side chain in Kir3.2 subunits at Ser148 increased the inhibition. When this residue was mutated to a non‐polar amino acid, the channel became permeable to Na+. Phosphoinositide‐mediated activity was also decreased by terfenadine.Conclusion and ImplicationsThe Phe137 residue in Kir3.1 subunits is critical for inhibition by terfenadine. This study provides novel insights into the regulation of GIRK channels by the pore helix and information for drug design.
L‐type voltage‐gated calcium channels in stem cells and tissue engineering
Authors: Tan Yi‐zhou , Fei Dong‐dong , He Xiao‐ning , Dai Ji‐min , Xu Rong‐chen , Xu Xin‐yue , Wu Jun‐jie , Li Bei 
Published: May 2019

AbstractL‐type voltage‐gated calcium ion channels (L‐VGCCs) have been demonstrated to be the mediator of several significant intracellular activities in excitable cells, such as neurons, chromaffin cells and myocytes. Recently, an increasing number of studies have investigated the function of L‐VGCCs in non‐excitable cells, particularly stem cells. However, there appear to be no systematic reviews of the relationship between L‐VGCCs and stem cells, and filling this gap is prescient considering the contribution of L‐VGCCs to the proliferation and differentiation of several types of stem cells. This review will discuss the possible involvement of L‐VGCCs in stem cells, mainly focusing on osteogenesis mediated by mesenchymal stem cells (MSCs) from different tissues and neurogenesis mediated by neural stem/progenitor cells (NSCs). Additionally, advanced applications that use these channels as the target for tissue engineering, which may offer the hope of tissue regeneration in the future, will also be explored.
Non‐infectious granulomatous dermatoses
Authors: Schmitt Andrea , Volz Andreas 
Published: May 2019

SummaryGranulomatous dermatoses comprise a wide range of etiologically and clinically distinct skin diseases that share a common histology characterized by the accumulation of histiocytes include macrophages.While the pathogenesis of these disorders is not fully understood, the underlying mechanism is thought to involve a reaction pattern caused by an immunogenic stimulus. Antigen‐presenting cells and the effect of various cytokines play a key role. Our understanding of granulomatous reaction patterns has been advanced by insights drawn from observations of such reactions in patients on immunomodulatory therapy and in individuals with genetic immunodeficiency.Traditionally, a distinction is made between infectious and non‐infectious granulomatous dermatoses. The present CME article addresses granulomatous skin diseases for which there is no evidence of a causative infectious agent. Common representatives include granuloma annulare, necrobiosis lipoidica and cutaneous sarcoidosis.Granulomatous dermatoses may be part of the clinical spectrum of various systemic disorders or may be associated therewith. Some neoplastic disorders may mimic granulomatous dermatoses histologically.Given the pathogenetic diversity involved, the clinical presentation, too, is quite varied. Overall, however, each disorder is characterized by typical clinical features. The diagnosis always requires thorough clinicopathologic correlation.Treatment is preferably based on the underlying pathogenesis and frequently involves anti‐inflammatory agents. In most cases, however, there is insufficient study data. The dermal nature of these disorders frequently poses a therapeutic challenge, especially with respect to topical treatment.
Understanding mortality in multiple myeloma: Findings of a European retrospective chart review
Authors: Mohty Mohamad , Cavo Michele , Fink Leah , Gonzalez‐McQuire Sebastian , Leleu Henri , Mateos Maria‐Victoria , Raab Marc S. , Schoen Paul , Yong Kwee 
Published: May 2019

AbstractObjectivesThis study aimed to provide real‐world data on the characteristics and treatment of patients with multiple myeloma (MM) at the time of death.MethodsThe study was a retrospective patient chart review across France, Germany, Italy, Spain and the UK during 2016, and included patients who had died in the 3 months before the index date.ResultsData from 786 patients were reviewed. At the time of death, 37% of patients were receiving active treatment, 12% were in a treatment‐free interval and 51% were receiving only supportive care. Death before and during active first‐line treatment was not uncommon (6% and 24% of patients, respectively) but these deaths were often not solely due to disease progression; factors such as renal failure and infection frequently played a role (in 30% and 20% of patients at first‐line, respectively). Most deaths at later lines were due to progressive disease. Cox model results suggested that early deaths were associated with advanced disease stage, high‐risk cytogenetics and poor response and relapse profiles.ConclusionsThese real‐world data could be used to help develop strategies for improving survival in patients with MM and to support management tailored to the stage of disease.
Structural and functional studies on Salmonella typhimurium pyridoxal kinase: the first structural evidence for the formation of Schiff base with the substrate
Authors: Deka Geeta , Kalyani Josyula N. , Jahangir Fathima Benazir , Sabharwal Pallavi , Savithri Handanahal S. , Murthy Mathur R. N. 
Published: May 2019

A large number of enzymes depend on the ubiquitous cofactor pyridoxal 5′ phosphate (PLP) for their activity. Pyridoxal kinase (PLK) is the key enzyme involved in the synthesis of PLP from the three forms of vitamin B6 via the salvage pathway. In the present work, we determined the unliganded structure of StPLK in a monoclinic form and its ternary complex with bound pyridoxal (PL), ADP and Mg2+ in two different tetragonal crystal forms (Form I and Form II). We found that, in the ternary complex structure of StPLK, the active site Lys233 forms a Schiff base linkage with the substrate (PL). Although formation of a Schiff base with the active site Lys229 was demonstrated in the Escherichia coli enzyme based on biochemical studies, the ternary complex of StPLK represents the first crystal structure where the Schiff bond formation has been observed. We also identified an additional site for PLP binding away from the active site in one of the ternary complexes (crystal Form I), suggesting a probable route for the product release. This is the first ternary complex structure where the modeled γ‐phosphate of ATP is close enough to PL for the phosphorylation of the substrate. StPLK prefers PL over pyridoxamine as its substrate and follows a sequential mechanism of catalysis. Surface plasmon resonance studies suggest that StPLK interacts with apo‐PLP–dependent enzymes with μm affinity supporting the earlier proposed direct transfer mechanism of PLP from PLK to PLP‐dependent enzymes.
Creep‐fatigue deformation micromechanisms of a directionally solidified nickel‐base superalloy at 850°C
Authors: Rai R.K. , Sahu J.K. , Das S.K. , Paulose N. , Fernando C. 
Published: May 2019

AbstractIn the present exploration, it was attempted to understand the creep‐fatigue (CF) deformation micromechanisms of alloy CM 247 DS LC by conducting low‐cycle fatigue (LCF) and CF tests employing strain amplitude ranging from 0.6% to 1.0% at T = 850°C in the air and performing extensive electron microscopic examinations. The cyclic life of the alloy lessens for all CF tests conducted at 1 and 5 minute dwell time in comparison to LCF tests. Transmission electron microscopy (TEM) examinations confirmed that during CF tests substructure consists of dislocation loop, mixed dislocations, and γ' rafting, a typical creep deformation signature of nickel‐base superalloys, it also consists of features observed during fatigue deformation such as anti‐phase boundary (APB)‐coupled dislocations inside γ' precipitates and local tangles of dislocations. This confirms that the deformation of CF‐tested specimens is ascribed to the synergistic effect of both creep and fatigue. This fact was further verified by scanning electron microscopic (SEM) examinations.
In‐situ microscopic analysis of ferritic ductile iron during tensile loading: Relation between matrix heterogeneities and damage mechanisms
Authors: Fernandino Diego O. , Boeri Roberto E. 
Published: May 2019

AbstractAn in‐situ microscopic analysis of the damage mechanisms of ferritic ductile iron under uniaxial tensile testing is carried out in this work. The experimental methodology combines specialized metallography techniques, in‐situ optical microscopy observation during loading, and digital image correlation analysis to obtain the strain values at the microscopic level. The results show that the crack initiation is preferentially located at matrix‐nodule interface and ferritic grain boundaries. The propagation of multiple cracks across the internodular ligaments that later coalesce into a single dominant crack is responsible for the final fracture. Noticeably, despite the heterogeneous nature of the Last‐to‐Freeze zones, the cracks propagate avoiding these microsegregated areas. The results provide new insights for the better understanding of the influence of ferritic ductile iron heterogeneities on the fracture process for quasistatic uniaxial loading.
Current status of intensity‐modulated radiation therapy for prostate cancer: History, clinical results and future directions
Authors: Hatano Kazuo , Tohyama Naoki , Kodama Takashi , Okabe Naoyuki , Sakai Mitsuhiro , Konoeda Koichi 
Published: May 2019

AbstractExternal beam radiotherapy has changed dramatically over several decades with the improvement of computer hardware and software, and machinery developments. Intensity‐modulated radiation therapy is the most sophisticated technique for all cancer treatment with radiation therapy, and is widely disseminated and available for daily use in many countries. Several retrospective and prospective studies have shown that intensity‐modulated radiation therapy reduces the radiation dose in the organs at risk with diminished rates of acute and late toxicity, even with higher doses (>74 Gy). An important technique for the clinical use of intensity‐modulated radiation therapy is image‐guided radiation therapy. The clinical benefit for prostate image‐guided radiation therapy has been assessed by comparing the outcomes of patients with either the image‐guided radiation therapy or non‐image‐guided radiation therapy technique. These studies have shown that image‐guided radiation therapy significantly decreases acute and late rectal and bladder toxicities. Randomized trials and meta‐analysis have shown that higher doses result in better biochemical control. More recently, hypofractionated radiation therapy comparing hypofractionated radiation therapy versus conventional fractionated radiation therapy have shown that hypofractionated radiation therapy produces biochemical control and toxicity rated similar to those produced by conventional fractionated radiation therapy. The clinical use of ultrahypofractionated radiation therapy and simultaneous integrated boost technique is necessary to evaluate its further safety and benefits. Intensity‐modulated radiation therapy is also widely accepted in the field of salvage therapy and for the patients with distant oligometastases. The purpose of the present review is to summarize the history of intensity‐modulated radiation therapy, new techniques for intensity‐modulated radiation therapy, hypofractionation and future directions for prostate cancer.
Memory regulatory T cells home to the lung and control influenza A virus infection
Authors: Lu Chunni , Zanker Damien , Lock Peter , Jiang Xiangrui , Deng Jieru , Duan Mubing , Liu Chuanxin , Faou Pierre , Hickey Michael J , Chen Weisan 
Published: May 2019

AbstractMemory regulatory T cells (mTregs) have been demonstrated to persist long‐term in hosts after the resolution of primary influenza A virus (IAV) infection. However, whether such IAV infection‐experienced (IAV‐experienced) mTregs differentiate into a phenotypically and functionally distinct Treg subset and what function they play at the infection site remains poorly defined. In this study, we characterized the phenotype, examined the responsiveness and assessed the suppressive function of IAV‐experienced memory Tregs (mTregs). In comparison with inexperienced naïve Tregs (nTregs), mTregs exhibited elevated expression of CD39, CD69, CD103, cytotoxic T lymphocyte‐associated antigen‐4, leukocyte function‐associated antigen‐1 and programmed cell death‐1 and could be activated in an antigen‐specific manner in vitro and in vivo. When mTregs and nTregs were adoptively cotransferred into recipient mice, mTregs had a competitive advantage in migrating to the IAV‐infected lungs. mTregs were more capable of controlling in vitro proliferation of CD4+ and CD8+ T cells and suppressed CD40 and CD86 upregulation on bone marrow‐derived dendritic cells. Adoptively transferred mTregs, but not adoptively transferred nTregs, significantly attenuated body weight loss, lung pathology and immune cell infiltration into the infected lungs after IAV infection. These results suggest that mTregs generated after IAV infection differentiate into a phenotypically distinct and functionally enhanced Treg subset that can be activated in an antigen‐specific manner to exert immunosuppression. We propose vaccination to induce such mTregs as a potential novel strategy to protect against severe IAV infection.
Exploring Differentiated Disintegration in a Post‐Brexit European Union
Authors: Leruth Benjamin , Gänzle Stefan , Trondal Jarle 
Published: May 2019

AbstractIn the aftermath of the British referendum to leave the European Union and the European Commission's ‘White Paper on the Future of Europe’, it is not only time to take stock of the existing literature on differentiated integration, but also to rethink the perimeters of disintegration. We argue that phenomena such as Brexit embrace forms of differentiation which trigger the need for conceptualizing differentiated disintegration altogether. This article first sketches the path of the scholarly debate in a chronological way to grasp the breadth of existing literature. Second, it discusses differentiated disintegration as a potentially new area for research. Mapping several scenarios for future research, we propose that differentiated (dis)integration needs to be conceived as a negotiated, but profoundly path‐dependent process, which is structurally locked‐in, and deeply conditioned by pre‐existing organizations and institutions of European integration.
Cardiovascular outcomes of vildagliptin in patients with type 2 diabetes mellitus after acute coronary syndrome or acute ischemic stroke
Authors: Chen Dong‐Yi , Li Yan‐Rong , Mao Chun‐Tai , Tseng Chi‐Nan , Hsieh I‐Chang , Hung Ming‐Jui , Chu Pao‐Hsien , Wang Chao‐Hung , Wen Ming‐Shien , Cherng Wen‐Jin , Chen Tien‐Hsing 
Published: May 2019

AbstractAims/IntroductionThe cardiovascular (CV) outcomes of vildagliptin – a dipeptidyl peptidase‐4 inhibitor – in patients with type 2 diabetes mellitus after acute coronary syndrome or acute ischemic stroke are unclear.Materials and MethodsWe analyzed data from the Taiwan National Health Insurance Research Database on 3,750 type 2 diabetes mellitus patients with acute coronary syndrome or acute ischemic stroke within 3 months between 1 August 2011 and 31 December 2013. Clinical outcomes were evaluated by comparing 1,250 participants receiving vildagliptin with 2,500 propensity score‐matched participants. The primary composite outcome included CV death, non‐fatal myocardial infarction and non‐fatal stroke.ResultsThe primary composite outcome occurred in 122 patients (9.8%) in the vildagliptin group and 263 patients (10.5%) in the control group (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.72–1.11) with a mean follow‐up period of 9.9 months. No significant between‐group differences were observed for CV death (HR 0.93, 95% CI 0.56–1.52), non‐fatal myocardial infarction (HR 0.79, 95% CI 0.46–1.36) and non‐fatal stroke (HR 0.96, 95% CI 0.74–1.24). The vildagliptin group was at similar risks of hospitalization for heart failure (HF) or coronary intervention to the control group (P = 0.312 and 0.430, respectively). For patients with HF at baseline, the risk of hospitalization for HF was similar between the vildagliptin and control groups (HR 1.04, 95% CI 0.57–1.88).ConclusionsAmong patients with type 2 diabetes mellitus after a recent acute coronary syndrome or acute ischemic stroke, treatment with vildagliptin was not associated with increased risks of CV death, non‐fatal myocardial infarction, non‐fatal stroke and hospitalization for HF.
Physical, chemical, textural, and thermal properties of cashew apple fruit
Authors: Singh Singam Suranjoy , Abdullah S. , Pradhan Rama Chandra , Mishra Sabyasachi 
Published: May 2019

AbstractCashew apple fruit (Anacardium occidentale L.) is an under‐valued and under‐utilized by‐product of the nut‐processing units in India. Despite its huge production and nutritive values, utilization of this fruit is very limited because of certain factors like lack of knowledge on its nutritional importance, astringency, perishability, and poor processing technologies. This study determined different physical, thermal, mechanical, and physicochemical properties of the cashew apple fruit and the importance of processing, machine designing, product‐development, and so on were discussed. The result showed that this fruit has a high moisture content of 85.62% (w.b.), which is the main reason for high softness and perishability. The fruit resembled an oblate‐ellipsoid shape (sphericity: 0.85) with an average dimension of length (50.34 mm), width (42.78 mm), and thickness (36.08 mm). The pH, total sugar, phenolic content, protein and ascorbic acid of this yellowish color fruit were 4.367, 10.573%, 365.303 mg/100 g GAE, 1.130% and 218.933 mg/100 g, respectively. The study also found that this fruit has low thermal properties (thermal conductivity: 0.57 W/m °C; specific heat capacity: 3.816 kJ/kg °C and thermal diffusivity: 0.143 × 10−7 m2/s). The results of this study will help in the commercial production of cashew apple products through product development and designing processing machines.Practical ApplicationThe cashew apple fruit can be taken as a functional food because of its richness in vitamins, dietary fibers, minerals, polyphenols, and other phytochemicals. The scarcity of scientific research on the characterization of engineering and physicochemical properties of this fruit is the main reason for its less popularity. The measured physical, mechanical, thermal, and physicochemical properties of this fruit will be useful to researchers, machine designers for industrial processing, food scientists and technologists in planning, designing and fabrication of postharvest handling equipment, grader, sorter, storage structures, packaging as well as product and by‐product development.
Strategic CSR: A Concept Building Meta‐Analysis
Authors: Vishwanathan Pushpika , van Oosterhout Hans (J.) , Heugens Pursey P. M. A. R. , Duran Patricio , van Essen Marc 
Published: May 2019

AbstractThis study develops the concept of Strategic Corporate Social Responsibility (Strategic CSR) by meta‐analyzing the available empirical evidence on the relationship between CSR and corporate financial performance (CFP). Using meta‐analytic structural equation modeling on effect size data from 344 primary studies, our study documents four empirical mechanisms explaining how CSR positively affects CFP: by 1) enhancing firm reputation, 2) increasing stakeholder reciprocation, 3) mitigating firm risk, and 4) strengthening innovation capacity. We propose these four mechanisms to identify four causally relevant attributes that allow us to conceptually distinguish Strategic CSR from CSR more generally. Our findings indicate that the four mechanisms combined explain 20 per cent of the CSR‐CFP relationship, suggesting that considerable room remains for future empirical research. The development of an empirically informed, causal conceptualization of Strategic CSR responds to a long‐heard call for better‐specified concepts in empirical CSR research.
Role of the Citrus sinensis RNA deadenylase CsCAF1 in citrus canker resistance
Authors: Shimo Hugo Massayoshi , Terassi Carolina , Lima Silva Caio Cesar , Zanella Jackeline de Lima , Mercaldi Gustavo Fernando , Rocco Silvana Aparecida , Benedetti Celso Eduardo 
Published: May 2019

SummaryPoly(A) tail shortening is a critical step in messenger RNA (mRNA) decay and control of gene expression. The carbon catabolite repressor 4 (CCR4)‐associated factor 1 (CAF1) component of the CCR4‐NOT deadenylase complex plays an essential role in mRNA deadenylation in most eukaryotes. However, while CAF1 has been extensively investigated in yeast and animals, its role in plants remains largely unknown. Here, we show that the Citrus sinensis CAF1 (CsCAF1) is a magnesium‐dependent deadenylase implicated in resistance against the citrus canker bacteria Xanthomonas citri. CsCAF1 interacted with proteins of the CCR4‐NOT complex, including CsVIP2, a NOT2 homologue, translin‐associated factor X (CsTRAX) and the poly(A)‐binding proteins CsPABPN and CsPABPC. CsCAF1 also interacted with PthA4, the main X. citri effector required for citrus canker elicitation. We also present evidence suggesting that PthA4 inhibits CsCAF1 deadenylase activity in vitro and stabilizes the mRNA encoded by the citrus canker susceptibility gene CsLOB1, which is transcriptionally activated by PthA4 during canker formation. Moreover, we show that an inhibitor of CsCAF1 deadenylase activity significantly enhanced canker development, despite causing a reduction in PthA4‐dependent CsLOB1 transcription. These results thus link CsCAF1 with canker development and PthA4‐dependent transcription in citrus plants.
Transboundary extraction of groundwater in the presence of hydraulic fracturing
Authors: Poudel Biswo N. , Paudel Krishna P. 
Published: May 2019

AbstractWe studied transboundary groundwater management problems in the presence of hydraulic fracturing. We found that the presence of risk suggests there should be caution when considering hydraulic fracturing. Our results from the cooperative solution show a decrease in hydraulic fracturing and increase in the steady state survival rate of groundwater. We also provide a Pigouvian type tax that could be imposed on natural gas developers.