bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice
Authors: Charpentier Julie , Waget Aurélie , Klopp Pascale , Magnan Christophe , Cruciani-Guglielmacci Céline , Lee Shin Jae , Burcelin Rémy , Grasset Estelle 
Published: August 2018

Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct β-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice.NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia.
Amount of daily exercise is an essential stimulation to alter the epigenome of skeletal muscle in rats
Authors: Ohsawa Ikumi , Konno Ryotaro , Masuzawa Ryo , Kawano Fuminori 
Published: August 2018

Long-term running training causes epigenetic changes in the skeletal muscles. Here we tested the effects of the total amount or duration of running training on the distribution of histones in the rat plantaris muscle. Post-weaned young rats were assigned to 3 different training groups: Run-1, 30 min/day running exercise for 8 wk using an animal treadmill at 24 m/min; Run-2, 15 min/day for 8 wk; and Run-3, 60 min/day for 4 wk. Citrate synthase activity was not significantly changed by running training, although the slight increase was observed in Run-3. Genes that were previously defined as showing the typical responses to running training were targeted to measure the distribution of histones using chromatin immunoprecipitation. The distribution of acetylated histone 3 was elevated in Run-2 and Run-3, but not in Run-1. Incorporation of H3.3 into the nucleosome was stimulated in Run-1, whereas H3.3 distribution was unchanged in Run-2 or downregulated in Run-3. Significant downregulation of H3.3 expression was also detected in Run-3. We further checked the responses of the target genes during acute running. Target genes were transcriptionally activated and histone acetylation was stimulated at the loci in response to acute running. These results suggested that the exchange of the histone component to H3.3 was stimulated by running training, inhibiting the accumulation of acetylated histones in Run-1. Additionally, it was further suggested that the enhanced daily amount of running caused changes in the H3.3 expression, affecting the rate of the histone exchange in Run-3. NEW & NOTEWORTHY Chromatin remodeling in the skeletal muscle is a potent mechanism preventing disuse atrophy in later life that can be acquired via long-term exercise training. Here we demonstrated in rats that daily exercise amount is a key factor in the development of epigenetic changes in the skeletal muscle. To acquire a health benefit, our research suggests the importance of considering the time endurance for daily exercise bouts.
Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain
Authors: McGaraughty Steve , Chu Katharine L. , Xu Jun 
Published: August 2018

This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data were collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared with naive animals (1.9 Hz) but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low-intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high-intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high-intensity stimulation did not change relative to control in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Nav1.7, Nav1.8, P2X7, P2X3, H3), other targets affected neither evoked nor spontaneous firing of WDR neurons (e.g., H4, TRPM8, KCNQ2/3), and some only modulated evoked (e.g, ASIC1a, Cav3.2) whereas others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites, although the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics. NEW & NOTEWORTHY Data from multiple individual experiments were combined to show firing properties of wide dynamic range and nociceptive specific spinal dorsal horn neurons across varied pathological pain models. This high-powered analysis describes the sensitization following different forms of injury. Effects of diverse pharmacology on these neurons is also summarized from published and unpublished data all recorded under the same conditions to facilitate comparison. This comprehensive overview describes the function and utility of these neurons.
Glutamate-Weighted Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Detects Glutaminase Inhibition in a Mouse Model of Triple-Negative Breast Cancer
Authors: Zhou Rong , Bagga Puneet , Nath Kavindra , Hariharan Hari , Mankoff David A. , Reddy Ravinder 
Published: August 2018

Abstract
Glutamate is an important metabolite of glutaminolysis, a metabolic pathway used by many aggressive cancers, including triple-negative breast cancer (TNBC). With the exception of the brain, in vivo detection of glutamate in tissues using 1H magnetic resonance spectroscopy (MRS) is challenging. Compared with MRS, glutamate-weighted chemical exchange saturation transfer MR imaging (GluCEST MRI) offers a more sensitive detection mechanism that is free of glutamine interference. Here, we developed a robust, highly repeatable GluCEST MRI protocol in mice bearing human TNBC xenografts and treated with a potent glutaminase inhibitor, CB-839. In paired studies, treatment with CB-839 for 2 days reduced the GluCEST asymmetry value compared with baseline (P &lt; 0.05, n = 10). The absolute change of the GluCEST asymmetry value was −2.5 percent points after CB-839 treatment versus +0.3 after vehicle (P &lt; 0.01). Correspondingly, treatment with CB-839 reduced tumor glutamate concentrations by 1.5 mmol/L, consistent with prior calibration between changes of the GluCEST value versus tissue glutamate concentration; CB-839, however, did not change tumor intracellular pH. These results demonstrate in a mouse model of breast cancer the utility of GluCEST MRI to detect the early response to glutaminase inhibition.
Significance: A sensitive method enables noninvasive detection of tumor response to inhibitors of glutamine metabolism. Cancer Res; 78(19); 5521–6. ©2018 AACR.
Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells
Authors: Bélanger François , Fortier Emile , Dubé Maxime , Lemay Jean-François , Buisson Rémi , Masson Jean-Yves , Elsherbiny Abdelhamid , Costantino Santiago , Carmona Euridice , Mes-Masson Anne-Marie , Wurtele Hugo , Drobetsky Elliot 
Published: August 2018

Abstract
Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNA crosslinks that block replicative DNA polymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPA-dependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here, we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, RF instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines.
Significance: The influence of replication protein A exhaustion on cisplatin sensitivity harbors important implications toward improving therapy of various cancers that initially respond to platinum-based agents but later relapse due to intrinsic or acquired drug resistance. Cancer Res; 78(19); 5561–73. ©2018 AACR.
Reassessing the Association between Circulating Vitamin D and IGFBP-3: Observational and Mendelian Randomization Estimates from Independent Sources
Authors: Tan Vanessa Y. , Biernacka Kalina M. , Dudding Tom , Bonilla Carolina , Gilbert Rebecca , Kaplan Robert C. , Qibin Qi , Teumer Alexander , Martin Richard M. , Perks Claire M. , Timpson Nicholas J. , Holly Jeff M.P. 
Published: August 2018

AbstractBackground:Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting.Methods:Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). Observational and MR analyses were conducted to assess the relationship between inactive vitamin D [25(OH)D] and IGFBP-3 using data from the ProtecT study (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995).Results:The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02–1.28]. The OR for advanced prostate cancer per SD unit increase in IGFBP-3 was 1.22 (95% CI, 1.07–1.40). Observationally, a SD increase in 25(OH)D was associated with a 0.1SD (95% CI, 0.05–0.14) increase in IGFBP-3. MR analyses found little evidence for a causal relationship between circulating 25(OH)D and IGFBP-3 in the circulation.Conclusions:This study provided confirmatory evidence that IGFBP-3 is a risk factor for prostate cancer risk and progression. Observationally, there was evidence that 25(OH)D is associated with IGFBP-3, but MR analyses suggested that these findings were unlikely to be causal. Findings may be limited by the nature of instrumentation of 25(OH)D and IGFBP-3 and the utility of circulating measures. 25(OH)D appears unlikely to be causally related to IGFBP-3 in the circulation, however, our findings do not preclude causal associations at the tissue level.Impact:IGFBP-3 is a prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.
The Fossilized Meaning of Chreia as Anecdote
Authors: Searby Denis Michael 
Published: August 2018

Abstract
The Hellenistic and early Imperial evidence of χρεία (chreia) in the sense of anecdote is summarized with the aim of completeness. The special rhetorical sense of this common Greek word is discussed, and a new explanation of the semantic derivation is offered: it is suggested that the sense of anecdote derives from the earlier sense of dealings rather than utility. The proposal that Metrocles or the Cynics invented the micro-genre of chreiai is strongly criticized. It is to the Socratics more generally we should look for its origins, if the genre must be supposed to have originated among philosophers, which is not certain.
The One and the Many
Authors: Woznicki Christopher 
Published: August 2018

AbstractWhat metaphysical account of human nature best makes sense of T.F. Torrance’s doctrine of atonement? Here I argue that the account that best makes sense of Torrance’s doctrine of atonement is one in which Christ instantiates an abstract universal human nature and the rest of humanity participates in an abstract universal human nature. In defending this thesis, I examine Torrance’s doctrine of atonement and his use of the anhypostasia–enhypostasia distinction. I conclude by defending the significance of the an-enhypostasia distinction for abstract universal theories of Christ’s human nature.
Rapid-Scan Radar Observations of an Oklahoma Tornadic Hailstorm Producing Giant Hail
Authors: Witt Arthur , Burgess Donald W. , Seimon Anton , Allen John T. , Snyder Jeffrey C. , Bluestein Howard B. 
Published: August 2018

AbstractRapid-scan radar observations of a supercell that produced near-record size hail in Oklahoma are examined. Data from the National Weather Radar Testbed Phased Array Radar (PAR) in Norman, Oklahoma, are used to study the overall character and evolution of the storm. Data from the nearby polarimetric KOUN WSR-88D and rapid-scanning X-band polarimetric (RaXPol) mobile radar are used to study the evolution of low- to midaltitude dual-polarization parameters above two locations where giant hailstones up to 16 cm in diameter were observed. The PAR observation of the supercell’s maximum storm-top divergent outflow is similar to the strongest previously documented value. The storm’s mesocyclone rotational velocity at midaltitudes reached a maximum that is more than double the median value for similar observations from other storms producing giant hail. For the two storm-relative areas where giant hail was observed, noteworthy findings include 1) the giant hail occurred outside the main precipitation core, in areas with low-altitude reflectivities of 40–50 dBZ; 2) the giant hail was associated with dual-polarization signatures consistent with past observations of large hail at 10-cm wavelength, namely, low ZDR, low ρHV, and low KDP; 3) the giant hail fell along both the northeast and southwest edges of the primary updraft at ranges of 6–10 km from the updraft center; and 4) with the exception of one isolated report, the giant hail fell to the northeast and northwest of the large tornado and the parent mesocyclone.
Examining the Goals of the Regional Climate Outlook Forums: What Role for User Engagement?
Authors: Daly Meaghan , Dessai Suraje 
Published: August 2018

Abstract
Over the last 20 years, Regional Climate Outlook Forums (RCOFs) have brought together scientific experts and stakeholders to produce regional-scale climate information products for society. This article examines the goals and practices of RCOFs, with a focus on user engagement, in order to draw out practical lessons for future implementation of RCOFs. Analysis of literature and documents (n = 72), interviews with key informants (n = 25), and participant observation were used in this research. Results show that approaches to user engagement in the RCOFs vary significantly from region to region and have been shaped by differences in the priority placed on user engagement relative to the other goals of the RCOFs, the role of RCOFs in the broader climate services delivery chain, the landscapes of potential users and institutions, and views about what the role of users can and should be. Findings indicate that approaches to user engagement necessarily reflect the regional context. This research suggests that more reflexivity about the current framing of RCOF goals is needed, including how users can and should be involved within RCOFs and how the benefits and value of RCOFs are conceptualized, assessed, and communicated in the future.
Agents never become stewards: explaining the lack of innovation in public–private partnerships
Authors: Parrado Salvador , Reynaers Anne-Marie 
Published: August 2018

Design–Build–Finance–Maintain–Operate contracts, as a specific public–private partnership, supposedly provide opportunities for innovation due to the long-term perspective, the use of output specifications and the collaborative environment. The literature suggests that the dynamics between procurers and consortia influence the actual contribution of these conditions to innovative practices. We therefore assess in three cases in the Netherlands and Spain how and to what extent the relationship between procurers and consortia affect these three conditions and therewith the possibilities for realising innovation and for capturing economic and social value. Findings show that the potential of Design–Build–Finance–Maintain–Operate contracts for innovation is hampered because procurers and consortia behave like principals and agents who distrust each other and who let short-term self-interested goals prevail over long-term pro-organisational goals. The cases have shown that the limited realisation of innovation and less-than-expected value generation seem to be due to the absence of a clear scheme that allows for capturing value. Points for practitioners • Potential innovation in Design–Build–Finance–Maintain–Operate contracts is restricted to the building of the infrastructure and the early operational phases of the contract because renegotiation clauses are normally too rigid. •   An adequate system to work out financial risks that create economic value for the contractor are needed to produce social value through innovation. • The contract needs to work out a ‘binding’ collaboration scheme among the consortium members to reap the benefits of innovation.
A cluster randomised controlled trial of a sugar-sweetened beverage intervention in secondary schools: Pilot study protocol
Authors: Ooi Jia Ying , Sutherland Rachel , Nathan Nicole , Yoong Sze Lin , Janssen Lisa , Wrigley Jessica , Wolfenden Luke 
Published: August 2018

Background: Due to the rising prevalence of overweight and obesity in children and adolescents, reducing childhood overweight and obesity rates is a public-health priority. A significant source of excess sugar and energy in children’s diets comes from sugar-sweetened beverages (SSB), with adolescents having the highest intake of all age groups. However, existing interventions targeting SSB intake in adolescents have multiple limitations. Schools have proven to be an appropriate setting for improving student health. Aim: To assess the effectiveness of a school-based SSB intervention in reducing daily SSB consumption and daily percentage energy from SSBs of secondary-school students. Methods: A pilot study ( switchURsip) was designed based on the Health Promoting Schools framework components. A convenience sample of schools in New South Wales, Australia will be used to recruit six schools (three intervention; three control). The study incorporates strategies that focus on factors associated with SSB intake in adolescents. These strategies include: lesson plans on SSB; communication with students and parents; school challenge to build peer support; and school nutrition environment modifications. Support strategies to facilitate implementation are executive leadership and school committees, auditing and feedback, providing resources, staff professional learning and communication and marketing. Conclusion: The high intake of SSB in adolescents has been consistently linked to having overweight and obesity, hence, interventions in this area should be prioritised. This pilot study intends to address identified evidence gaps by piloting the first intervention in Australia of its kind to reduce SSB intake in adolescents.
The Resulting Variation in Nutrient Intake With the Inclusion of Walnuts in the Diets of Adults at Risk for Type 2 Diabetes: A Randomized, Controlled, Crossover Trial
Authors: Njike Valentine Y. , Costales Victoria C. , Petraro Paul , Annam Rachel , Yarandi Niloufarsadat , Katz David L. 
Published: August 2018

Purpose: We previously demonstrated that including walnuts in the diets of adults at risk for type 2 diabetes mellitus (T2DM) led to improved overall diet quality. This report examines the specific changes in their nutrient intake. Design: This was a randomized, controlled, modified Latin square parallel design trial with 2 treatment arms. Participants were randomized to walnut intake with, or without, dietary advice to regulate caloric intake. Within each treatment arm, they were further randomized to one of 2 sequence permutations (walnut-included/walnut-excluded or walnut-excluded/walnut-included diet), with a 3-month washout between treatment phases. Setting: Community hospital in Lower Naugatuck Valley in Connecticut. Participants: Cohort of 112 participants (31 men and 81 women) at risk for T2DM. Intervention: Participants included 56 g (366 kcal) of walnuts in their daily diets for 6 months. Measures: Nutrient intake was assessed using web-based Automated Self-Administered 24-Hour Dietary Assessment. Analysis: Data were analyzed using generalized linear models. Results: Walnut inclusion led to increased intake of total fat, calcium, magnesium, thiamin, total saturated fatty acids, and monounsaturated and polyunsaturated fatty acids (379.0 ± 90.3 g vs −136.5 ± 92.7 g, P < .01; 230.7 ± 114.2 mg vs −95.2 ± 117.4 mg, P = .05; 111.0 ± 33.9 mg vs −32.3 ± 34.9 mg, P < .01; 0.28 ± 0.2 mg vs −0.47 ± 0.2 mg, P = .02; 8.6 ± 3.4 g vs −1.1 ± 3.5 g, P =.05; 6.3 ± 3.9 g vs −6.3 ± 4.0 g, P = .03; and 25.4 ± 4.0 vs −6.6 ± 4.2 g, P < .01, respectively). Vitamin C intake decreased (−65.3 ± 55.3 mg vs 98.9 ± 56.8 mg, P = .04). Protein intake increased from baseline with the inclusion of walnuts (20.0 ± 8.8 g, P < .05). Walnut inclusion led to an increase in total calories consumed when caloric intake is not regulated. Conclusion: Including walnuts in the diets of these adults led to increased dietary intake of some nutrients associated with lower risk of developing T2DM and other cardiometabolic risk factors.