bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
Authors: Wang Caixia , Dai Huaiqian , Xiong Zhi , Song Qiancheng , Zou Zhipeng , Li Mangmang , Nie Jing , Bai Xiaochun , Chen Zhenguo 
Published: April 2018

AbstractDEP domain containing mTOR-interacting protein (DEPTOR) was originally identified as an in vivo dual inhibitor of mechanistic target of rapamycin (mTOR). It was recently reported to be involved in renal physiology and pathology in vitro; however, its detailed roles and mechanisms in vivo are completely unknown. We observed that DEPTOR expression in the kidney was markedly increased on day 3 after cisplatin treatment, at which time cell apoptosis peaked, implicating DEPTOR in cisplatin-induced acute kidney injury (AKI). We then used the Cre–LoxP system to generate mutant mice in which the DEPTOR gene was specifically deleted in the proximal tubule cells. DEPTOR deficiency did not alter the renal histology or functions in the saline-treated group, indicating that DEPTOR is not essential for kidney function under physiological conditions. Interestingly, DEPTOR deletion extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, suggesting that the absence of DEPTOR ameliorates cisplatin-induced AKI. Mechanistically, DEPTOR modulated p38 MAPK signaling and TNFα production in vivo and in vitro, rather than mTOR signaling, thus moderating the inflammatory response and cell apoptosis induced by cisplatin. Collectively, our findings demonstrate the roles and mechanisms of DEPTOR in the regulation of the renal physiology and pathology, and demonstrate that the loss of DEPTOR in the proximal tubules protects against cisplatin-induced AKI.
Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma
Authors: Ye Huilin , Zhou Quanbo , Zheng Shangyou , Li Guolin , Lin Qing , Wei Lusheng , Fu Zhiqiang , Zhang Bin , Liu Yimin , Li Zhihua , Chen Rufu 
Published: April 2018

AbstractTumor-associated macrophages (TAMs) are frequently found near pancreatic cancer cells, but it is uncertain whether they are involved in pancreatic cancer progression and the Warburg effect. Here, we show that CCL18 secreted by TAMs facilitates malignant progression and induced a glycolytic phenotype in pancreatic cancer, partially owing to paracrine induction of VCAM-1 in pancreatic cancer cells. Reciprocally, VCAM-1-induced lactate production from pancreatic cancer cells with enhanced aerobic glycolysis activates macrophages to a TAM-like phenotype, forming a positive feedback loop. VCAM-1 was found to be highly expressed in human pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines, and is associated with disease progression and predicts clinical outcome in PDAC patients. Flow cytometry analysis further demonstrated that VCAM-1 downregulation induced an accumulation of PDAC cells in G0/G1 phase, accompanied by a significant decrease in S phase. Downregulation of VCAM-1 significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cellsin vitro, whereas the ectopic expression of VCAM-1 had the opposite effect. VCAM-1 on pancreatic cancer cells might tethers THP-1 monocytes to cancer cells via counter–receptor interaction, providing a survival advantage to pancreatic cancer cells that infiltrate leukocyte-rich microenvironments. Furthermore, downregulation of VCAM-1 could repress tumor growth in mouse xenograft models. In particular, our results highlighted the contribution of VCAM-1 to the maintenance of the Warburg effect in PDAC cells. Finally, we investigated the clinical correlations of CCL18 and VCAM-1 in human PDAC specimens. In summary, these findings indicate that the CCL18/PITPNM3/NF-kB/VCAM-1 regulatory network might provide a potential new therapeutic strategy for PDAC.
A serum microRNA signature predicts trastuzumab benefit in HER2-positive metastatic breast cancer patients
Authors: Li Huiping , Liu Jiang , Chen Jianing , Wang Huiyun , Yang Linbin , Chen Fei , Fan Siting , Wang Jing , Shao Bin , Yin Dong , Zeng Musheng , Li Mengfeng , Li Jun , Su Fengxi , Liu Qiang , Yao Herui , Su Shicheng , Song Erwei 
Published: April 2018

AbstractTrastuzumab is a standard treatment for HER2-positive (HER2+) breast cancer, but some patients are refractory to the therapy. MicroRNAs (miRNAs) have been used to predict therapeutic effects for various cancers, but whether miRNAs can serve as biomarkers for HER2+ metastatic breast cancer (MBC) patients remains unclear. Using miRNA microarray, we identify 13 differentially expressed miRNAs in the serum of HER2+ MBC patients with distinct response to trastuzumab, and four miRNAs are selected to construct a signature to predict survival using LASSO model. Further, our data show that miR-940 is mainly released from the tumor cells and miR-451a, miR-16-5p and miR-17-3p are mainly from the immune cells. All these four miRNAs directly target signaling molecules that play crucial roles in regulating trastuzumab resistance. In summary, we develop a serum-based miRNA signature that potentially predicts the therapeutic benefit of trastuzumab for HER2+ MBC patients and warrants future validation in prospective clinical trials.
Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons
Authors: Dhandapani Rahul , Arokiaraj Cynthia Mary , Taberner Francisco J. , Pacifico Paola , Raja Sruthi , Nocchi Linda , Portulano Carla , Franciosa Federica , Maffei Mariano , Hussain Ahmad Fawzi , de Castro Reis Fernanda , Reymond Luc , Perlas Emerald , Garcovich Simone , Barth Stefan , Johnsson Kai , Lechner Stefan G. , Heppenstall Paul A. 
Published: April 2018

AbstractMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury in mice. Mice in which TrkB-Cre-expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB-positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.
Repeated evolution of self-compatibility for reproductive assurance
Authors: Nieuwenhuis Bart P. S. , Tusso Sergio , Bjerling Pernilla , Stångberg Josefine , Wolf Jochen B. W. , Immler Simone 
Published: April 2018

AbstractSexual reproduction in eukaryotes requires the fusion of two compatible gametes of opposite sexes or mating types. To meet the challenge of finding a mating partner with compatible gametes, evolutionary mechanisms such as hermaphroditism and self-fertilization have repeatedly evolved. Here, by combining the insights from comparative genomics, computer simulations and experimental evolution in fission yeast, we shed light on the conditions promoting separate mating types or self-compatibility by mating-type switching. Analogous to multiple independent transitions between switchers and non-switchers in natural populations mediated by structural genomic changes, novel switching genotypes readily evolved under selection in the experimental populations. Detailed fitness measurements accompanied by computer simulations show the benefits and costs of switching during sexual and asexual reproduction, governing the occurrence of both strategies in nature. Our findings illuminate the trade-off between the benefits of reproductive assurance and its fitness costs under benign conditions facilitating the evolution of self-compatibility.
Barium bioaccumulation by bacterial biofilms and implications for Ba cycling and use of Ba proxies
Authors: Martinez-Ruiz Francisca , Jroundi Fadwa , Paytan Adina , Guerra-Tschuschke Isabel , Abad María del Mar , González-Muñoz María Teresa 
Published: April 2018

AbstractBa proxies have been broadly used to reconstruct past oceanic export production. However, the precise mechanisms underlying barite precipitation in undersaturated seawater are not known. The link between bacterial production and particulate Ba in the ocean suggests that bacteria may play a role. Here we show that under experimental conditions marine bacterial biofilms, particularly extracellular polymeric substances (EPS), are capable of bioaccumulating Ba, providing adequate conditions for barite precipitation. An amorphous P-rich phase is formed at the initial stages of Ba bioaccumulation, which evolves into barite crystals. This supports that in high productivity regions where large amounts of organic matter are subjected to bacterial degradation, the abundant EPS would serve to bind the necessary Ba and form nucleation sites leading to barite precipitation. This also provides new insights into barite precipitation and opens an exciting field to explore the role of EPS in mineral precipitation in the ocean.
Causes and implications of the unforeseen 2016 extreme yield loss in the breadbasket of France
Authors: Ben-Ari Tamara , Boé Julien , Ciais Philippe , Lecerf Remi , Van der Velde Marijn , Makowski David 
Published: April 2018

AbstractIn 2016, France, one of the leading wheat-producing and wheat-exporting regions in the world suffered its most extreme yield loss in over half a century. Yet, yield forecasting systems failed to anticipate this event. We show that this unprecedented event is a new type of compound extreme with a conjunction of abnormally warm temperatures in late autumn and abnormally wet conditions in the following spring. A binomial logistic regression accounting for fall and spring conditions is able to capture key yield loss events since 1959. Based on climate projections, we show that the conditions that led to the 2016 wheat yield loss are projected to become more frequent in the future. The increased likelihood of such compound extreme events poses a challenge: farming systems and yield forecasting systems, which often support them, must adapt.
Long ncRNA A-ROD activates its target gene DKK1 at its release from chromatin
Authors: Ntini Evgenia , Louloupi Annita , Liz Julia , Muino Jose M. , Marsico Annalisa , Ørom Ulf Andersson Vang 
Published: April 2018

Abstract
Long ncRNAs are often enriched in the nucleus and at chromatin, but whether their dissociation from chromatin is important for their role in transcription regulation is unclear. Here, we group long ncRNAs using epigenetic marks, expression and strength of chromosomal interactions; we find that long ncRNAs transcribed from loci engaged in strong long-range chromosomal interactions are less abundant at chromatin, suggesting the release from chromatin as a crucial functional aspect of long ncRNAs in transcription regulation of their target genes. To gain mechanistic insight into this, we functionally validate the long ncRNA A-ROD, which enhances DKK1 transcription via its nascent spliced released form. Our data provide evidence that the regulatory interaction requires dissociation of A-ROD from chromatin, with target specificity ensured within the pre-established chromosomal proximity. We propose that the post-transcriptional release of a subset of long ncRNAs from the chromatin-associated template plays an important role in their function as transcription regulators.
Immunosilencing peptides by stereochemical inversion and sequence reversal: retro-D-peptides
Authors: Arranz-Gibert Pol , Ciudad Sonia , Seco Jesús , García Jesús , Giralt Ernest , Teixidó Meritxell 
Published: April 2018

AbstractPeptides are experiencing a new era in medical research, finding applications ranging from therapeutics to vaccines. In spite of the promising properties of peptide pharmaceuticals, their development continues to be hindered by three weaknesses intrinsic to their structure, namely protease sensitivity, clearance through the kidneys, and immune system activation. Here we report on two retro-D-peptides (H2N-hrpyiah-CONH2 and H2N-pwvpswmpprht-CONH2), which are protease-resistant and retain the original BBB shuttle activity of the parent peptide but are much less immunogenic than the parent peptide. Hence, we envisage that retro-D-peptides, which display a similar topological arrangement as their parent peptides, will expand drug design and help to overcome factors that lead to the failure of peptide pharmaceuticals in pre- and clinical trials. Furthermore, we reveal requirements to avoid or elicit specific humoral responses to therapeutic peptides, which might have a strong impact in both vaccine design and peptide therapeutic agents.
Real-time visual interactions across the boundary of awareness
Authors: Meital-Kfir Noya , Sagi Dov 
Published: April 2018

AbstractRecently, using Motion Induced-Blindness (MIB), we have shown that two visual stimuli, one consciously experienced and one not, interact as a function of feature and object similarity, pointing to preserved visual representations of objects, and their constitutive features, in the absence of perceptual awareness. Here we investigated whether these representations preserve the memory of the previously perceived stimulus by testing interactions with the unperceived stimulus modified while it is invisible. Observers performed the MIB task, wherein an object ‘Target’ (a plaid object) was morphed into one of its features (an oriented Gabor patch) once its disappearance was reported. Reappearances of the morphed target were induced by a visible ‘Cue’ (object or feature), with reappearance frequency used to quantify the interaction between the visible cue and the invisible target. Reappearance rates were highest when the morphed target and the cue shared the same orientations, with the plaid-cue showing reappearance rates equal to that of the orthogonal-cue. Our findings indicate that target-cue interactions do not depend on memory-stored representations, but rather, on the current state of the consciously unavailable target. We suggest that visual objects can be constructed and deconstructed in the absence of conscious perception, but only objects are consciously available.
Pulmonary Effects of Adjusting Tidal Volume to Actual or Ideal Body Weight in Ventilated Obese Mice
Authors: Guivarch Elise , Voiriot Guillaume , Rouzé Anahita , Kerbrat Stéphane , Tran Van Nhieu Jeanne , Montravers Philippe , Maitre Bernard , Mekontso Dessap Armand , Desmard Mathieu , Boczkowski Jorge 
Published: April 2018

AbstractObese patients could be more susceptible to mechanical ventilation (MV)-induced lung injury than non-obese patients due to weight-dependent changes in lung properties. The aim of this study was therefore to evaluate the pulmonary effects of 2 hours low VT MV in a diet-induced obese mice model, with VT calculated on either the actual body weight (VTaw) or the ideal body weight (VTiw) . First, we hypothesized that a MV with VTaw would be associated with altered lung mechanics and an increased lung inflammation. Second, we hypothesised that a MV with a VTiw would preserve lung mechanics and limit lung inflammation. We analyzed lung mechanics and inflammation using bronchoalveolar lavage (BAL) cell counts, flow cytometry tissue analysis and histology. Lung mechanics and inflammation were comparable in control and obese mice receiving VTiw. By contrast, obese mice receiving VTaw had significantly more alterations in lung mechanics, BAL cellularity and lung influx of monocytes as compared to control mice. Their monocyte expression of Gr1 and CD62L was also increased. Alveolar neutrophil infiltration was significantly increased in all obese mice as compared to controls. In conclusion, our findings suggest that protective MV with a VTaw is deleterious, with a marked alteration in lung mechanics and associated lung inflammation as compared to lean mice. With VTiw, lung mechanics and inflammation were close to that of control mice, except for an increased alveolar infiltrate of polymorphonuclear neutrophils. This inflammation might be attenuated by a blunted recruitment of inflammatory cells associated with obesity.
Strengthening of Al-Fe3Al composites by the generation of harmonic structures
Authors: Shahid R. N. , Scudino S. 
Published: April 2018

AbstractStrengthening of alloys can be efficiently attained by the creation of harmonic structures: bimodal microstructures generated by controlled milling of the particulate precursors, which consist of coarse-grained cores embedded in a continuous fine-grained matrix. Here, we extend the concept of harmonic structures to metal matrix composites and analyze the effectiveness of such bimodal microstructures for strengthening composites consisting of a pure Al matrix reinforced with Fe3Al particles. Preferential microstructural refinement limited to the surface of the particles, where the Fe3Al phase is progressively fragmented, occurs during ball milling of the Al-Fe3Al composite powder mixtures. The refined surface becomes the continuous fine-grained matrix that encloses macro-regions with coarser reinforcing particles in the harmonic composites synthesized during subsequent powder consolidation. The generation of the bimodal microstructure has a significant influence on the strength of the harmonic composites, which exceeds that of the conventional material by a factor of 2 while retaining considerable plastic deformation. Finally, modeling of the mechanical properties indicates that the strength of the harmonic composites can be accurately described by taking into account both the volume fraction of reinforcement and the characteristic microstructural features describing the harmonic structure.
Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia
Authors: Heitmeier Monique R. , Payne Maria A. , Weinheimer Carla , Kovacs Attila , Hresko Richard C. , Jay Patrick Y. , Hruz Paul W. 
Published: April 2018

AbstractGLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart.
Production and delivery of Helicobacter pylori NapA in Lactococcus lactis and its protective efficacy and immune modulatory activity
Authors: Peng Xiaoyan , Zhang Rongguang , Duan Guangcai , Wang Chen , Sun Nan , Zhang Linghan , Chen Shuaiyin , Fan Qingtang , Xi Yuanlin 
Published: April 2018

AbstractHelicobacter pylori neutrophil-activating protein A subunit (NapA) has been identified as a virulence factor, a protective antigen and a potent immunomodulator. NapA shows unique application potentials for anti-H. pylori vaccines and treatment strategies of certain allergic diseases and carcinomas. However, appropriate production and utilization modes of NapA still remain uncertain to date. This work has established a novel efficient production and utilization mode of NapA by using L. lactis as an expression host and delivery vector, and demonstrated immune protective efficacy and immune modulatory activity of the engineered L. lactis by oral vaccination of mice. It was observed for the first time that H. pylori NapA promotes both polarized Th17 and Th1 responses, which may greatly affect the clinical application of NapA. This report offers a promising anti-H. pylori oral vaccine candidate and a potent mucosal immune modulatory agent. Meanwhile, it uncovers a way to produce and deliver the oral vaccine and immunomodulator by fermentation of food like milk, which might have striking effects on control of H. pylori infection, gastrointestinal cancers, and Th2 bias allergic diseases, including many food allergies.
Large-scale brain network associated with creative insight: combined voxel-based morphometry and resting-state functional connectivity analyses
Authors: Ogawa Takeshi , Aihara Takatsugu , Shimokawa Takeaki , Yamashita Okito 
Published: April 2018

AbstractCreative insight occurs with an “Aha!” experience when solving a difficult problem. Here, we investigated large-scale networks associated with insight problem solving. We recruited 232 healthy participants aged 21–69 years old. Participants completed a magnetic resonance imaging study (MRI; structural imaging and a 10 min resting-state functional MRI) and an insight test battery (ITB) consisting of written questionnaires (matchstick arithmetic task, remote associates test, and insight problem solving task). To identify the resting-state functional connectivity (RSFC) associated with individual creative insight, we conducted an exploratory voxel-based morphometry (VBM)-constrained RSFC analysis. We identified positive correlations between ITB score and grey matter volume (GMV) in the right insula and middle cingulate cortex/precuneus, and a negative correlation between ITB score and GMV in the left cerebellum crus 1 and right supplementary motor area. We applied seed-based RSFC analysis to whole brain voxels using the seeds obtained from the VBM and identified insight-positive/negative connections, i.e. a positive/negative correlation between the ITB score and individual RSFCs between two brain regions. Insight-specific connections included motor-related regions whereas creative-common connections included a default mode network. Our results indicate that creative insight requires a coupling of multiple networks, such as the default mode, semantic and cerebral-cerebellum networks.