bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy
Authors: Shiloh Ruth , Gilad Yuval , Ber Yaara , Eisenstein Miriam , Aweida Dina , Bialik Shani , Cohen Shenhav , Kimchi Adi 
Published: April 2018

AbstractAutophagy is an intracellular degradation process essential for adaptation to metabolic stress. DAPK2 is a calmodulin-regulated protein kinase, which has been implicated in autophagy regulation, though the mechanism is unclear. Here, we show that the central metabolic sensor, AMPK, phosphorylates DAPK2 at a critical site in the protein structure, between the catalytic and the calmodulin-binding domains. This phosphorylation activates DAPK2 by functionally mimicking calmodulin binding and mitigating an inhibitory autophosphorylation, providing a novel, alternative mechanism for DAPK2 activation during metabolic stress. In addition, we show that DAPK2 phosphorylates the core autophagic machinery protein, Beclin-1, leading to dissociation of its inhibitor, Bcl-XL. Importantly, phosphorylation of DAPK2 by AMPK enhances DAPK2’s ability to phosphorylate Beclin-1, and depletion of DAPK2 reduces autophagy in response to AMPK activation. Our study reveals a unique calmodulin-independent mechanism for DAPK2 activation, critical to its function as a novel downstream effector of AMPK in autophagy.
Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models
Authors: St Clair Joshua R. , Ramirez David , Passman Samantha , Benninger Richard K. P. 
Published: April 2018

AbstractIn type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and β-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and β-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast-enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre-symptomatic T1D and therapeutic reversal.
Impact of alkali on the passivation of silicate glass
Authors: Collin Marie , Fournier Maxime , Charpentier Thibault , Moskura Mélanie , Gin Stéphane 
Published: April 2018

AbstractAmorphous silica-rich surface layers, also called gels, can passivate silicate glass and minerals depending on environmental conditions. However, several uncertainties remain on the mechanisms controlling the formation of these layers. In this paper, the influence of exogenous ions supplied by solutions is studied, both on the formation and on the properties of the gel formed on international simple glass (ISG). ISG was altered at 90 °C, pH90 °C 7, in silica-saturated solutions containing various alkaline cations separately (Li+, Na+, K+, and Cs+). The alteration kinetics observed with Li and Na in the solution is similar to that observed with no ions, while K and Cs in the solution tend to decrease glass alteration. Furthermore, for K or Cs ions, the kinetics decreases as the ionic strength of the solution increases. The passivation layer formed in these solutions shows a selectivity toward cations following the series K > Cs > Na >> Li. These alkalis replace Ca from pristine glass in the altered structures, leading to differences in [AlO4]− units charge compensation. Importantly, exchange between Ca and alkali also affects the total quantity of water inside each gel and this effect is well correlated with the observed drop in glass alteration.
Direct observation of multiple conformational states in Cytochrome P450 oxidoreductase and their modulation by membrane environment and ionic strength
Authors: Bavishi Krutika , Li Darui , Eiersholt Stine , Hooley Emma N. , Petersen Troels C. , Møller Birger Lindberg , Hatzakis Nikos S. , Laursen Tomas 
Published: April 2018

AbstractCytochrome P450 oxidoreductase (POR) is the primary electron donor in eukaryotic cytochrome P450 (CYP) containing systems. A wealth of ensemble biophysical studies of Cytochrome P450 oxidoreductase (POR) has reported a binary model of the conformational equilibrium directing its catalytic efficiency and biomolecular recognition. In this study, full length POR from the crop plant Sorghum bicolor was site-specifically labeled with Cy3 (donor) and Cy5 (acceptor) fluorophores and reconstituted in nanodiscs. Our single molecule fluorescence resonance energy transfer (smFRET) burst analyses of POR allowed the direct observation and quantification of at least three dominant conformational sub-populations, their distribution and occupancies. Moreover, the state occupancies were remodeled significantly by ionic strength and the nature of reconstitution environment, i.e. phospholipid bilayers (nanodiscs) composed of different lipid head group charges vs. detergent micelles. The existence of conformational heterogeneity in POR may mediate selective activation of multiple downstream electron acceptors and association in complexes in the ER membrane.
Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients
Authors: Douillard Aymeric , Picot Marie-Christine , Delcourt Cécile , Defoort-Dhellemmes Sabine , Marzouka Nour Al-Dain , Lacroux Annie , Zanlonghi Xavier , Drumare Isabelle , Jozefowicz Elsa , Bocquet Béatrice , Baudoin Corinne , Perez-Roustit Sarah , Arsène Sophie , Gissot Valérie , Devin François , Arndt Carl , Wolff Benjamin , Mauget-Faÿsse Martine , Quaranta Maddalena , Mura Thibault , Deplanque Dominique , Oubraham Hassiba , Cohen Salomon Yves , Gastaud Pierre , Zambrowski Olivia , Creuzot-Garcher Catherine , Saïd Saddek Mohand , Sahel José-Alain , Souied Eric , Milazzo Solange , Garavito Rocio Blanco , Kalatzis Vasiliki , Puech Bernard , Hamel Christian , Audo Isabelle , Meunier Isabelle 
Published: April 2018

AbstractEMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.106) was lower in Provence-Côte d’Azur with a Mediterranean diet (1.9/1.106), and higher in regions with intensive farming or industrialized activities (5 to 20/1.106). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.
Optically Tunable Gratings Based on Coherent Population Oscillation
Authors: Zhang Xiao-Jun , Wang Hai-Hua , Wang Lei , Wu Jin-Hui 
Published: April 2018

AbstractWe theoretically study the optically tunable gratings based on a L-type atomic medium using coherent population oscillations from the angle of reflection and transmission of the probe field. Adopting a standing-wave driving field, the refractive index of the medium as well as the absorption are periodically modified. Consequently, the Bragg scattering causes the effective reflection. We show that different intensities of the control field lead to three types of reflection profile which actually correspond to different absorption/amplification features of the medium. We present a detailed analyses about the influence of amplification on the reflection profile as well. The coherent population oscillation is robust to the dephasing effect, and such induced gratings could have promising applications in nonlinear optics and all-optical information processing.
Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue
Authors: Abu Hamdeh Sami , Shevchenko Ganna , Mi Jia , Musunuri Sravani , Bergquist Jonas , Marklund Niklas 
Published: April 2018

AbstractThe early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.
Inferring a nonlinear biochemical network model from a heterogeneous single-cell time course data
Authors: Shindo Yuki , Kondo Yohei , Sako Yasushi 
Published: April 2018

AbstractMathematical modeling and analysis of biochemical reaction networks are key routines in computational systems biology and biophysics; however, it remains difficult to choose the most valid model. Here, we propose a computational framework for data-driven and systematic inference of a nonlinear biochemical network model. The framework is based on the expectation-maximization algorithm combined with particle smoother and sparse regularization techniques. In this method, a “redundant” model consisting of an excessive number of nodes and regulatory paths is iteratively updated by eliminating unnecessary paths, resulting in an inference of the most likely model. Using artificial single-cell time-course data showing heterogeneous oscillatory behaviors, we demonstrated that this algorithm successfully inferred the true network without any prior knowledge of network topology or parameter values. Furthermore, we showed that both the regulatory paths among nodes and the optimal number of nodes in the network could be systematically determined. The method presented in this study provides a general framework for inferring a nonlinear biochemical network model from heterogeneous single-cell time-course data.
Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
Authors: Ibarrola Jaime , Sadaba Rafael , Martinez-Martinez Ernesto , Garcia-Peña Amaia , Arrieta Vanessa , Alvarez Virginia , Fernández-Celis Amaya , Gainza Alicia , Cachofeiro Victoria , Santamaria Enrique , Fernandez-Irigoyen Joaquin , Jaisser Frederic , Lopez-Andres Natalia 
Published: April 2018

AbstractAldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulation could be a deleterious mechanism which induces mitochondrial dysfunction and oxidative stress in cardiac cells. Aldo down-regulated AKAP-12 via its mineralocorticoid receptor, increased oxidative stress and induced mitochondrial dysfunction characterized by decreased mitochondrial-DNA and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions in human cardiac fibroblasts. CRISPR/Cas9-mediated knock-down of AKAP-12 produced similar deleterious effects in human cardiac fibroblasts. CRISPR/Cas9-mediated activation of AKAP-12 blunted Aldo effects on mitochondrial dysfunction and oxidative stress in human cardiac fibroblasts. In Aldo-salt-treated rats, cardiac AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased and paralleled increased oxidative stress. In myocardial biopsies from patients with aortic stenosis (AS, n = 26), AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased as compared to Controls (n = 13). Circulating Aldo levels inversely correlated with cardiac AKAP-12. PGC-1α positively associated with AKAP-12 and with mitochondrial-DNA. Aldo decreased AKAP-12 expression, impairing mitochondrial biogenesis and increasing cardiac oxidative stress. AKAP-12 down-regulation triggered by Aldo may represent an important event in the development of mitochondrial dysfunction and cardiac oxidative stress.
Up-regulation of microRNA-203 in influenza A virus infection inhibits viral replication by targeting DR1
Authors: Zhang Sen , Li Jing , Li Junfeng , Yang Yinhui , Kang Xiaoping , Li Yuchang , Wu Xiaoyan , Zhu Qingyu , Zhou Yusen , Hu Yi 
Published: April 2018

AbstractMicroRNAs (miRNAs) are small noncoding RNA molecules that play important roles in various biological processes. Much evidence shows that miRNAs are closely associated with numerous virus infections; however, involvement of cellular miRNAs in influenza A virus (IAV) infection is unclear. Here, we found that expression of miR-203 was up-regulated markedly via two different mechanisms during IAV infection. First, we examined the effects of type I interferon induced by IAV on direct activation of miR-203 expression. Next, we showed that DNA demethylation within the miR-203 promoter region in A549 cells induced its up-regulation, and that expression of DNA methyltransferase 1 was down-regulated following H5N1 virus infection. Ectopic expression of miR-203 in turn inhibited H5N1 virus replication by targeting down-regulator of transcription 1 (DR1), which was identified as a novel target of miR-203. Silencing DR1 in miR-203 knockout cells using a specific siRNA inhibited replication of the H5N1 virus, an effect similar to that of miR-203. In summary, the data show that host cell expression of miR-203 is up-regulated upon IAV infection, which increases antiviral responses by suppressing a novel target gene, DR1. Thus, we have identified a novel mechanism underlying the relationship between miR-203 and IAV infection.
Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
Authors: Kim Kook Hwan , Kim Seong Hun , Han Dai Hoon , Jo Young Suk , Lee Yong-ho , Lee Myung-Shik 
Published: April 2018

AbstractGrowth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.
Variations of Prevalence and Incidence of Atrial Fibrillation and Oral Anticoagulation Rate According to Different Analysis Approaches
Authors: Yang Pil-Sung , Ryu Soorack , Kim Daehoon , Jang Eunsun , Yu Hee Tae , Kim Tae-Hoon , Hwang Jinseub , Joung Boyoung , Lip Gregory Y. H. 
Published: April 2018

AbstractThe reported incidence and prevalence of atrial fibrillation (AF) has been inconsistent across published studies. Using the National Health Insurance Service database of Korea, the prevalence and incidence of AF, and oral anticoagulation (OAC) use of AF patients were explored according to three different approaches; ‘formal approach’, considering individual AF diagnosis and mortality; ‘limited diagnosis approach’, using upper 5 main diagnosis; and ‘medical use approach’, using the number of medical use AF population by year without considering individual AF history and mortality. The AF prevalence progressively increased by 2.46-fold from 0.50% in 2004 to 1.54% in 2015 when using a ‘formal approach’ (p for trend <0.001). The overall prevalence was 1.09% and 0.97% when using a ‘formal approach’ and ‘limited diagnosis approaches’, respectively. Overall prevalence decreased to 0.52% with a ‘medical use approach’. The trend of annual AF incidence was stable when using a ‘formal approach’, but increased by 15% when using a ‘medical use approach’. OAC rate in 2015 was 2.1 times higher when using a ‘medical use approach’ compared to using a ‘formal approach’ (40.3% vs. 19.1%, p < 0.001). Given the wide variability in prevalence and incidence figures with different analysis approaches, careful attention to the analysis methodology is needed.
Effect of the sodium–glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db/db mice of different ages
Authors: Takahashi Kiyohiko , Nakamura Akinobu , Miyoshi Hideaki , Nomoto Hiroshi , Kitao Naoyuki , Omori Kazuno , Yamamoto Kohei , Cho Kyu Yong , Terauchi Yasuo , Atsumi Tatsuya 
Published: April 2018

AbstractTo examine the effects of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes.
Neural and behavioural correlates of repeated social defeat
Authors: Butler Julie M. , Whitlow Sarah M. , Roberts David A. , Maruska Karen P. 
Published: April 2018

AbstractDominance hierarchies are common across the animal kingdom and have important consequences for reproduction and survival. Animals of lower social status cope with repeated social defeat using proactive and reactive behaviours. However, there remains a paucity of information on how an individual’s coping behaviours changes over time or what neural mechanisms are involved. We used a resident-intruder paradigm in the African cichlid fish Astatotilapia burtoni to investigate the neural correlates of these two opposing behaviour groups. Fish initially used both proactive and reactive behaviours, but had a dramatic increase in use of proactive behaviours during the third interaction, and this was followed by cessation of proactive behaviours and exclusive use of reactive coping. By quantifying neural activation in socially-relevant brain regions, we identify a subset of brain nuclei, including those homologous to the mammalian amygdala, showing higher activation in fish displaying proactive but not reactive behaviours. Fish displaying reactive behaviours had greater neural activation in the superior raphe, suggesting a possible conserved function during social defeat across vertebrates. These data provide the first evidence on the involvement of specific brain regions underlying proactive and reactive coping in fishes, indicating that these nuclei have conserved functions during social defeat across taxa.
Progression of Post-Traumatic Osteoarthritis in rat meniscectomy models: Comprehensive monitoring using MRI
Authors: Ali Tonima S. , Prasadam Indira , Xiao Yin , Momot Konstantin I. 
Published: April 2018

AbstractKnee injury often triggers post-traumatic osteoarthritis (PTOA) that affects articular cartilage (AC), subchondral bone, meniscus and the synovial membrane. The available treatments for PTOA are largely ineffective due to late diagnosis past the “treatment window”. This study aimed to develop a detailed understanding of the time line of the progression of PTOA in murine models through longitudinal observation of the femorotibial joint from the onset of the disease to the advanced stage. Quantitative magnetic resonance microimaging (µMRI) and histology were used to evaluate PTOA-associated changes in the knee joints of rats subjected to knee meniscectomy. Systematic longitudinal changes in the articular cartilage thickness, cartilage T2 and the T2 of epiphysis within medial condyles of the tibia were all found to be associated with the development of PTOA in the animals. The following pathogenesis cascade was found to precede advanced PTOA: meniscal injury → AC swelling → subchondral bone remodelling → proteoglycan depletion → free water influx → cartilage erosion. Importantly, the imaging protocol used was entirely MRI-based. This protocol is potentially suitable for whole-knee longitudinal, non-invasive assessment of the development of OA. The results of this work will inform the improvement of the imaging methods for early diagnosis of PTOA.