bluuebunny/crossref_metadata_2025_split huggingface dataset:
RANKL-induced M1 macrophages are involved in bone formation
Authors: Huang Rong , Wang Xin , Zhou Yinghong , Xiao Yin 
Published: October 2017

AbstractThe activation of M1 macrophages can be achieved by stimulating them with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, M1 can be found under physiological conditions without any pathological stimuli. This study aimed to understand the involvement of RANKL-induced M1 macrophages in bone formation compared with pathologically induced macrophages. Fischer rats were used to investigate macrophage distribution in normal and injured femoral condyles in vivo. Bone marrow-derived macrophages (BMDMs) were activated with LPS+IFN-γ and RANKL to achieve M1 activation in vitro. Gene expression related to inflammation, osteoclastogenesis, angiogenesis, and migration was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS). Tissue macrophages showed distinct expression patterns at different bone regions. RANKL was found in close proximity to inducible nitric oxide synthase-positive (iNOS+) cells in vivo, suggesting an association between RANKL expression and iNOS+ cells, especially in trabecular bone. RANKL-induced macrophages showed a different cytokine secretion profile compared with pathologically induced macrophages. Both osteoclasts and M1 macrophages peaked on day 7 during bone healing. RANKL could trigger M1-like macrophages with properties that were different from those of LPS+IFN-γ-induced macrophages. These RANKL-activated M1 macrophages were actively involved in bone formation.
Spatial constraints govern competition of mutant clones in human epidermis
Authors: Lynch M. D. , Lynch C. N. S. , Craythorne E. , Liakath-Ali K. , Mallipeddi R. , Barker J. N. , Watt F. M. 
Published: October 2017

AbstractDeep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.
Sparse synaptic connectivity is required for decorrelation and pattern separation in feedforward networks
Authors: Cayco-Gajic N. Alex , Clopath Claudia , Silver R. Angus 
Published: October 2017

AbstractPattern separation is a fundamental function of the brain. The divergent feedforward networks thought to underlie this computation are widespread, yet exhibit remarkably similar sparse synaptic connectivity. Marr-Albus theory postulates that such networks separate overlapping activity patterns by mapping them onto larger numbers of sparsely active neurons. But spatial correlations in synaptic input and those introduced by network connectivity are likely to compromise performance. To investigate the structural and functional determinants of pattern separation we built models of the cerebellar input layer with spatially correlated input patterns, and systematically varied their synaptic connectivity. Performance was quantified by the learning speed of a classifier trained on either the input or output patterns. Our results show that sparse synaptic connectivity is essential for separating spatially correlated input patterns over a wide range of network activity, and that expansion and correlations, rather than sparse activity, are the major determinants of pattern separation.
Hierarchical control of enzymatic actuators using DNA-based switchable memories
Authors: Meijer Lenny H. H. , Joesaar Alex , Steur Erik , Engelen Wouter , van Santen Rutger A. , Merkx Maarten , de Greef Tom F. A. 
Published: October 2017

AbstractInspired by signaling networks in living cells, DNA-based programming aims for the engineering of biochemical networks capable of advanced regulatory and computational functions under controlled cell-free conditions. While regulatory circuits in cells control downstream processes through hierarchical layers of signal processing, coupling of enzymatically driven DNA-based networks to downstream processes has rarely been reported. Here, we expand the scope of molecular programming by engineering hierarchical control of enzymatic actuators using feedback-controlled DNA-circuits capable of advanced regulatory dynamics. We developed a translator module that converts signaling molecules from the upstream network to unique DNA strands driving downstream actuators with minimal retroactivity and support these findings with a detailed computational analysis. We show our modular approach by coupling of a previously engineered switchable memories circuit to downstream actuators based on β-lactamase and luciferase. To the best of our knowledge, our work demonstrates one of the most advanced DNA-based circuits regarding complexity and versatility.
Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy
Authors: Reza Musarrat Maisha , Subramaniyam Nathiya , Sim Chu Ming , Ge Xiaojia , Sathiakumar Durgalakshmi , McFarlane Craig , Sharma Mridula , Kambadur Ravi 
Published: October 2017

AbstractExercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice.
Gene isoforms as expression-based biomarkers predictive of drug response in vitro
Authors: Safikhani Zhaleh , Smirnov Petr , Thu Kelsie L. , Silvester Jennifer , El-Hachem Nehme , Quevedo Rene , Lupien Mathieu , Mak Tak W. , Cescon David , Haibe-Kains Benjamin 
Published: October 2017

AbstractNext-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.
A short linear motif in scaffold Nup145C connects Y-complex with pre-assembled outer ring Nup82 complex
Authors: Teimer Roman , Kosinski Jan , von Appen Alexander , Beck Martin , Hurt Ed 
Published: October 2017

AbstractNucleocytoplasmic transport occurs through nuclear pore complexes (NPCs), which are formed from multiple copies of ~30 different nucleoporins (Nups) and inserted into the double nuclear membrane. Many of these Nups are organized into subcomplexes, of which the Y-shaped Nup84 complex is the major constituent of the nuclear and cytoplasmic rings. The Nup82–Nup159–Nsp1 complex is another module that, however, is only assembled into the cytoplasmic ring. By means of crosslinking mass spectrometry, biochemical reconstitution, and molecular modeling, we identified a short linear motif in the unstructured N-terminal region of Chaetomium thermophilum Nup145C, a subunit of the Y-complex, that is sufficient to recruit the Nup82 complex, but only in its assembled state. This finding points to a more general mechanism that short linear motifs in structural Nups can act as sensors to cooperatively connect pre-assembled NPC modules, thereby facilitating the formation and regulation of the higher-order NPC assembly.
Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis
Authors: Baumer Yvonne , McCurdy Sara , Weatherby Tina M. , Mehta Nehal N. , Halbherr Stefan , Halbherr Pascal , Yamazaki Noboru , Boisvert William A. 
Published: October 2017

AbstractEndothelial cells (EC) play a key role in atherosclerosis. Although EC are in constant contact with low density lipoproteins (LDL), how EC process LDL and whether this influences atherogenesis, is unclear. Here we show that EC take up and metabolize LDL, and when overburdened with intracellular cholesterol, generate cholesterol crystals (CC). The CC are deposited on the basolateral side, and compromise endothelial function. When hyperlipidemic mice are given a high fat diet, CC appear in aortic sinus within 1 week. Treatment with cAMP-enhancing agents, forskolin/rolipram (F/R), mitigates effects of CC on endothelial function by not only improving barrier function, but also inhibiting CC formation both in vitro and in vivo. A proof of principle study using F/R incorporated into liposomes, designed to target inflamed endothelium, shows reduced atherosclerosis and CC formation in ApoE
−/−
mice. Our findings highlight an important mechanism by which EC contribute to atherogenesis under hyperlipidemic conditions.
Sensing and responding to allergic response cytokines through a genetically encoded circuit
Authors: Chassin Hélène , Geering Barbara , Schukur Lina , Ausländer David , Lang Brian , Fussenegger Martin 
Published: October 2017

AbstractWhile constantly rising, the prevalence of allergies is globally one of the highest among chronic diseases. Current treatments of allergic diseases include the application of anti-histamines, immunotherapy, steroids, and anti-immunoglobulin E (IgE) antibodies. Here we report mammalian cells engineered with a synthetic signaling cascade able to monitor extracellular pathophysiological levels of interleukin 4 and interleukin 13, two main cytokines orchestrating allergic inflammation. Upon activation of transgenic cells by these cytokines, designed ankyrin repeat protein (DARPin) E2_79, a non-immunogenic protein binding human IgE, is secreted in a precisely controlled and reversible manner. Using human whole blood cell culturing, we demonstrate that the mammalian dual T helper 2 cytokine sensor produces sufficient levels of DARPin E2_79 to dampen histamine release in allergic subjects exposed to allergens. Hence, therapeutic gene networks monitoring disease-associated cytokines coupled with in situ production, secretion and systemic delivery of immunomodulatory biologics may foster advances in the treatment of allergies.
Structure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease
Authors: Roig-Zamboni Véronique , Cobucci-Ponzano Beatrice , Iacono Roberta , Ferrara Maria Carmina , Germany Stanley , Bourne Yves , Parenti Giancarlo , Moracci Marco , Sulzenbacher Gerlind 
Published: October 2017

AbstractPompe disease, a rare lysosomal storage disease caused by deficiency of the lysosomal acid α-glucosidase (GAA), is characterized by glycogen accumulation, triggering severe secondary cellular damage and resulting in progressive motor handicap and premature death. Numerous disease-causing mutations in the gaa gene have been reported, but the structural effects of the pathological variants were unknown. Here we present the high-resolution crystal structures of recombinant human GAA (rhGAA), the standard care of Pompe disease. These structures portray the unbound form of rhGAA and complexes thereof with active site-directed inhibitors, providing insight into substrate recognition and the molecular framework for the rationalization of the deleterious effects of disease-causing mutations. Furthermore, we report the structure of rhGAA in complex with the allosteric pharmacological chaperone N-acetylcysteine, which reveals the stabilizing function of this chaperone at the structural level.
Piezo-generated charge mapping revealed through direct piezoelectric force microscopy
Authors: Gomez A. , Gich M. , Carretero-Genevrier A. , Puig T. , Obradors X. 
Published: October 2017

AbstractWhile piezoelectric and ferroelectric materials play a key role in many everyday applications, there are still a number of open questions related to their physics. To enhance our understanding of piezoelectrics and ferroelectrics, nanoscale characterization is essential. Here, we develop an atomic force microscopy based mode that obtains a direct quantitative analysis of the piezoelectric coefficient d33. We report nanoscale images of piezogenerated charge in a thick single crystal of periodically poled lithium niobate (PPLN), a bismuth ferrite (BiFO3) thin film, and lead zirconate titanate (PZT) by applying a force and recording the current produced by these materials. The quantification of d33 coefficients for PPLN (14 ± 3 pC per N) and BFO (43 ± 6 pC per N) is in agreement with the values reported in the literature. Even stronger evidence of the reliability of the method is provided by an equally accurate measurement of the significantly larger d33 of PZT.
TRPC3 Is Dispensable for β-Alanine Triggered Acute Itch
Authors: Dong Peter , Guo Changxiong , Huang Shengxiang , Ma Minghong , Liu Qin , Luo Wenqin 
Published: October 2017

AbstractThe detection of pruritic (itchy) stimuli is mediated by a variety of receptors and channels expressed by primary sensory neurons. The G protein-coupled receptor (GPCR) MRGPRD is selectively expressed by a subset of mouse non-peptidergic nociceptors and functions as the molecular receptor for the itch-inducing chemical β-alanine. However, the channels responsible for generating electrical signals downstream of MRGPRD remain unclear. Here, we found that a member of the canonical TRP channel family, TRPC3, is highly expressed in MRGPRD+ non-peptidergic nociceptors, raising the possibility of whether TRPC3 functions as a downstream channel in the MRGPRD signaling pathway. We tested TrpC3 null mice for β-alanine induced itch, and found that these mice exhibit normal responses to β-alanine. At the cellular level, calcium influx triggered by β-alanine is also unchanged in cultured DRG neurons from TrpC3 null mice compared to wild type. Together, our results demonstrate that mouse TrpC3 is dispensable for β-alanine-induced acute itch.
Response of basal metabolic rate to complete submergence of riparian species Salix variegata in the Three Gorges reservoir region
Authors: Lei Shutong , Zeng Bo , Xu Shaojun , Zhang Xiaoping 
Published: October 2017

AbstractOne-year old seedlings ofSalix variegata(submergence-tolerant) andCinnamomum camphora(submergence-intolerant) were selected and subjected to complete submergence (2 m) for 1, 5, 10, and 20 days, to elucidate the submergence- tolerance mechanism ofS.variegatain the Three Gorges reservoir region. The basal CO2emission ratios (BCERs) and O2consumption rates (OCRs) of leaf, stem, and root were determined. The basal O2consumption rates (BOCRs) were calculated from the OCRs of different parts and their biomass allocations and used for evaluating the basal metabolic rate (BMR) of species with BCERs. The results showed that: (1) The BCERs of both species responded to flooding similarly, and no significant differences occurred between the submergedS.variegata(SS) and the submergedC.camphora(SC) seedlings, and between the controlS.variegata(CS) and the controlC.camphora(CC) seedlings. (2) The BOCRs of SS were significantly lower than those of SC on days 1 and 20, while no significant differences occurred between CS and CC for every duration. Therefore, the BMRs, evaluated from BOCRs rather than from BCERs, were related to submergence-tolerance of species, and the response of BMR to submergence would contribute to the survival ofS. variegataseedlings under flooding.
Multiscale modelling the effects of CI genetic evolution in mosquito population on the control of dengue fever
Authors: He Sha , Zhang Xianghong , Liang Juhua , Tang Sanyi 
Published: October 2017

AbstractEndosymbiotic Wolbachia bacteria are widely applied for the control of dengue fever by manipulating the reproductive mechanism of mosquitoes, including maternal inheritance and cytoplasmic incompatibility (CI). CI means that the offsprings from the matings between Wolbachia infected males and uninfected females can not be hatched. At present, CI effect is assumed as a constant in most of dynamic systems for the spread of Wolbachia. However, their spread may arouse the evolution of mosquitoes to resist CI. Thus, a multiscale model combining a birth-pulse model with a gene-induced discrete model for the frequencies of alleles is proposed to describe the spread of Wolbachia in mosquito population with resistance allele of CI. The main results indicate that the strategy of population eradication can not be realized, while the strategy of population replacement may be realized with the success of sensitive or resistance allele. If appropriate Wolbachia strains can not be selected, then there is a high probability of the failure of population replacement. Moreover, Wolbachia-induced parameters may arouse the catastrophic shifts among stable states of the model. In addition, the demographic parameters and Wolbachia-induced parameters may affect the level and the speed of population replacement and the density of uninfected mosquitoes.
Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity
Authors: Gongol Brendan , Marin Traci L. , Jeppson John D. , Mayagoitia Karina , Shin Samuel , Sanchez Nicholas , Kirsch Wolff M. , Vinters Harry V. , Wilson Christopher G. , Ghribi Othman , Soriano Salvador 
Published: October 2017

AbstractThe function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to 27-hydroxycholesterol (27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer’s Disease (AD) brains but not in frontotemporal dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.
Cytocompatibility and antibacterial activity of nanostructured H2Ti5O11·H2O outlayered Zn-doped TiO2 coatings on Ti for percutaneous implants
Authors: Zhang Lan , Zhang Juan , Dai Fang , Han Yong 
Published: October 2017

AbstractTo improve skin-integration and antibacterial activity of percutaneous implants, the coatings comprising an outer layer of H2Ti5O11·H2O (HTO) nanoarrays and an inner layer of microporous Zn-doped TiO2were fabricated on Ti by micro-arc oxidation (MAO) followed with hydrothermal treatment (HT). During HT process, a large proportion of Zn2+migrated out from TiO2layer. TiO2reacted with OH−and H2O, resulting in the nucleation of HTO. The nuclei grew to nanoplates, nanorods and nanofibres with HT process prolonged. Simultaneously, the orientation of nanoarrays changed from quasi-vertical to parallel to substrate. Compared to Ti, adhesion and proliferation of fibroblasts were enhanced on as-MAOed TiO2and HTed coatings. The phenotype, differentiation and extracellular collagen secretion were obviously accelerated on vertical nanorods with proper interspace (e.g. 63 nm). HTed coatings showed enhanced antibacterial activity, which should be ascribed to the nano-topography of HTO.
Revealing the gut bacteriome of Dendroctonus bark beetles (Curculionidae: Scolytinae): diversity, core members and co-evolutionary patterns
Authors: Hernández-García Juan Alfredo , Briones-Roblero Carlos Iván , Rivera-Orduña Flor N. , Zúñiga Gerardo 
Published: October 2017

AbstractDendroctonus bark beetles comprise 20 taxonomically recognized species, which are one of the most destructive pine forest pests in North and Central America, and Eurasia. The aims of this study were to characterize the gut bacterial diversity, to determine the core bacteriome and to explore the ecological association between these bacteria and bark beetles. A total of five bacterial phyla were identified in the gut of 13 Dendroctonus species; Proteobacteria was the most abundant, followed by Firmicutes, Fusobacteria, Actinobacteria and Deinococcus-Thermus. The α-diversity was low as demonstrated in previous studies and significant differences in β-diversity were observed. The core bacteriome was composed of Enterobacter, Pantoea, Pseudomonas, Rahnella, Raoultella, and Serratia. The tanglegram between bacteria and bark beetles suggests that members of bacterial community are acquired from the environment, possibly from the host tree. These findings improve the knowledge about the bacterial community composition, and provide the bases to study the metabolic functions of these bacteria, as well as their interaction with these bark beetles.