bluuebunny/crossref_metadata_2025_split huggingface dataset:
Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice
Authors: Jiang Xuan , Hawkins John S. , Lee Jerry , Lizama Carlos O. , Bos Frank L. , Zape Joan P. , Ghatpande Prajakta , Peng Yongbo , Louie Justin , Lagna Giorgio , Zovein Ann C. , Hata Akiko 
Published: July 2017

AbstractHematopoietic stem and progenitor cells arise from the vascular endothelium of the dorsal aorta and subsequently switch niche to the fetal liver through unknown mechanisms. Here we report that vascular endothelium-specific deletion of mouseDrosha(DroshacKO), an enzyme essential for microRNA biogenesis, leads to anemia and death. A similar number of hematopoietic stem and progenitor cells emerge from Drosha-deficient and control vascular endothelium, butDroshacKO-derived hematopoietic stem and progenitor cells accumulate in the dorsal aorta and fail to colonize the fetal liver. Depletion of thelet-7family of microRNAs is a primary cause of this defect, as it leads to activation of leukotriene B4 signaling and induction of the α4β1 integrin cell adhesion complex in hematopoietic stem and progenitor cells. Inhibition of leukotriene B4 or integrin rescues maturation and migration ofDroshacKOhematopoietic stem and progenitor cells to the fetal liver, while it hampers hematopoiesis in wild-type animals. Our study uncovers a previously undefined role of innate leukotriene B4 signaling as a gatekeeper of the hematopoietic niche transition.
Triggerable tough hydrogels for gastric resident dosage forms
Authors: Liu Jinyao , Pang Yan , Zhang Shiyi , Cleveland Cody , Yin Xiaolei , Booth Lucas , Lin Jiaqi , Lucy Lee Young-Ah , Mazdiyasni Hormoz , Saxton Sarah , Kirtane Ameya R. , Erlach Thomas von , Rogner Jaimie , Langer Robert , Traverso Giovanni 
Published: July 2017

AbstractSystems capable of residing for prolonged periods of time in the gastric cavity have transformed our ability to diagnose and treat patients. Gastric resident systems for drug delivery, ideally need to be: ingestible, be able to change shape or swell to ensure prolonged gastric residence, have the mechanical integrity to withstand the forces associated with gastrointestinal motility, be triggerable to address any side effects, and be drug loadable and release drug over a prolonged period of time. Materials that have been primarily utilized for these applications have been largely restricted to thermoplastics and thermosets. Here we describe a novel set of materials, triggerable tough hydrogels, meeting all these requirement, supported by evaluation in a large animal model and ultimately demonstrate the potential of triggerable tough hydrogels to serve as prolonged gastric resident drug depots. Triggerable tough hydrogels may be applied in myriad of applications, including bariatric interventions, drug delivery, and tissue engineering.
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Authors: Cao Jia , Peng Jinghua , An Hongying , He Qiyi , Boronina Tatiana , Guo Shaodong , White Morris F. , Cole Philip A. , He Ling 
Published: July 2017

AbstractDiabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.
Thrombopoiesis is spatially regulated by the bone marrow vasculature
Authors: Stegner David , vanEeuwijk Judith M. M. , Angay Oğuzhan , Gorelashvili Maximilian G. , Semeniak Daniela , Pinnecker Jürgen , Schmithausen Patrick , Meyer Imke , Friedrich Mike , Dütting Sebastian , Brede Christian , Beilhack Andreas , Schulze Harald , Nieswandt Bernhard , Heinze Katrin G. 
Published: July 2017

AbstractIn mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.
Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
Authors: Schenk Arne , Ghallab Ahmed , Hofmann Ute , Hassan Reham , Schwarz Michael , Schuppert Andreas , Schwen Lars Ole , Braeuning Albert , Teutonico Donato , Hengstler Jan G. , Kuepfer Lars 
Published: July 2017

AbstractDiseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.
Genetic and functional characterization of disease associations explains comorbidity
Authors: Rubio-Perez Carlota , Guney Emre , Aguilar Daniel , Piñero Janet , Garcia-Garcia Javier , Iadarola Barbara , Sanz Ferran , Fernandez-Fuentes Narcís , Furlong Laura I. , Oliva Baldo 
Published: July 2017

AbstractUnderstanding relationships between diseases, such as comorbidities, has important socio-economic implications, ranging from clinical study design to health care planning. Most studies characterize disease comorbidity using shared genetic origins, ignoring pathway-based commonalities between diseases. In this study, we define the disease pathways using an interactome-based extension of known disease-genes and introduce several measures of functional overlap. The analysis reveals 206 significant links among 94 diseases, giving rise to a highly clustered disease association network. We observe that around 95% of the links in the disease network, though not identified by genetic overlap, are discovered by functional overlap. This disease network portraits rheumatoid arthritis, asthma, atherosclerosis, pulmonary diseases and Crohn’s disease as hubs and thus pointing to common inflammatory processes underlying disease pathophysiology. We identify several described associations such as the inverse comorbidity relationship between Alzheimer’s disease and neoplasms. Furthermore, we investigate the disruptions in protein interactions by mapping mutations onto the domains involved in the interaction, suggesting hypotheses on the causal link between diseases. Finally, we provide several proof-of-principle examples in which we model the effect of the mutation and the change of the association strength, which could explain the observed comorbidity between diseases caused by the same genetic alterations.
Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α
Authors: Jung Hoe-Yune , Lee Dongyeop , Ryu Hye Guk , Choi Bo-Hwa , Go Younghoon , Lee Namgyu , Lee Dohyun , Son Heehwa G. , Jeon Jongsu , Kim Seong-Hoon , Yoon Jong Hyuk , Park Seon-Min , Lee Seung-Jae V. , Lee In-Kyu , Choi Kwan Yong , Ryu Sung Ho , Nohara Kazunari , Yoo Seung-Hee , Chen Zheng , Kim Kyong-Tai 
Published: July 2017

AbstractRobust mitochondrial respiration provides energy to support physical performance and physiological well-being, whereas mitochondrial malfunction is associated with various pathologies and reduced longevity. In the current study, we tested whether myricetin, a natural flavonol with diverse biological activities, may impact mitochondrial function and longevity. The mice were orally administered myricetin (50 mg/kg/day) for 3 weeks. Myricetin significantly potentiated aerobic capacity in mice, as evidenced by their increased running time and distance. The elevated mitochondrial function was associated with induction of genes for oxidative phosphorylation and mitochondrial biogenesis in metabolically active tissues. Importantly, myricetin treatment led to decreased PGC-1α acetylation through SIRT1 activation. Furthermore, myricetin significantly improved the healthspan and lifespan of wild-type, but notSir-2.1-deficient,C. elegans. These results demonstrate that myricetin enhances mitochondrial activity, possibly by activating PGC-1α and SIRT1, to improve physical endurance, strongly suggesting myricetin as a mitochondria-activating agent.
Enhanced figure of merit in nanostructured (Bi,Sb)2Te3 with optimized composition, prepared by a straightforward arc-melting procedure
Authors: Serrano-Sánchez F. , Gharsallah M. , Nemes N. M. , Biskup N. , Varela M. , Martínez J. L. , Fernández-Díaz M. T. , Alonso J. A. 
Published: July 2017

AbstractSb-doped Bi2Te3 is known since the 1950s as the best thermoelectric material for near-room temperature operation. Improvements in material performance are expected from nanostructuring procedures. We present a straightforward and fast method to synthesize already nanostructured pellets that show an enhanced ZT due to a remarkably low thermal conductivity and unusually high Seebeck coefficient for a nominal composition optimized for arc-melting: Bi0.35Sb1.65Te3. We provide a detailed structural analysis of the Bi2−xSbxTe3 series (0 ≤ x ≤ 2) based on neutron powder diffraction as a function of composition and temperature that reveals the important role played by atomic vibrations. Arc-melting produces layered platelets with less than 50 nm-thick sheets. The low thermal conductivity is attributed to the phonon scattering at the grain boundaries of the nanosheets. This is a fast and cost-effective production method of highly efficient thermoelectric materials.
Three-Dimensional Imaging of Biological Tissue by Cryo X-Ray Ptychography
Authors: Shahmoradian S. H. , Tsai E. H. R. , Diaz A. , Guizar-Sicairos M. , Raabe J. , Spycher L. , Britschgi M. , Ruf A. , Stahlberg H. , Holler M. 
Published: July 2017

AbstractHigh-throughput three-dimensional cryogenic imaging of thick biological specimens is valuable for identifying biologically- or pathologically-relevant features of interest, especially for subsequent correlative studies. Unfortunately, high-resolution imaging techniques at cryogenic conditions often require sample reduction through sequential physical milling or sectioning for sufficient penetration to generate each image of the 3-D stack. This study represents the first demonstration of using ptychographic hard X-ray tomography at cryogenic temperatures for imaging thick biological tissue in a chemically-fixed, frozen-hydrated state without heavy metal staining and organic solvents. Applied to mammalian brain, this label-free cryogenic imaging method allows visualization of myelinated axons and sub-cellular features such as age-related pigmented cellular inclusions at a spatial resolution of ~100 nanometers and thicknesses approaching 100 microns. Because our approach does not require dehydration, staining or reduction of the sample, we introduce the possibility for subsequent analysis of the same tissue using orthogonal approaches that are expected to yield direct complementary insight to the biological features of interest.
The resident pathobiont Staphylococcus xylosus in Nfkbiz-deficient skin accelerates spontaneous skin inflammation
Authors: Kim Yeji , Lee Yong-Soo , Yang Jin-Young , Lee Su-Hyun , Park Yun-Yong , Kweon Mi-Na 
Published: July 2017

AbstractIκBζ, which is encoded by the Nfkbiz gene, is a member of the nuclear IκB family of proteins that act as transcriptional regulators via association with NF-κB. Nfkbiz-deficient (Nfkbiz−/−) mice develop spontaneous dermatitis; however, the underlying mechanism has yet to be elucidated. In our study, we found higher skin pathology scores and more serum IgE antibodies and trans-epidermal water loss in Nfkbiz−/− than in Nfkbiz-sufficient (Nfkbiz+/−) mice. There was also greater expansion of IFN-γ-, IL-17A-, and IL-22-secreting CD4+ T cells and of IL-17A-secreting γδ+ T cells in the skin of Nfkbiz−/− mice than in with Nfkbiz+/− mice. Pyrosequencing analysis showed decreased diversity of resident bacteria and markedly expanded Staphylococcus (S.) xylosus in the skin of Nfkbiz−/− mice. Oral administration of antibiotics including cephalexin and enrofloxacin ameliorated skin inflammation. Topical application of S. xylosus also resulted in the expansion of IL-17A-secreting CD4+ T cells along with high levels of pro-inflammatory cytokines and chemokines in the skin of Nfkbiz−/− mice. The expansion of commensal S. xylosus may be one cause of skin dysbiosis in Nfkbiz−/− mice and suggests that the Nfkbiz gene may play a regulatory role in the microbiota-skin immunity axis.
APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome
Authors: Fallaize Rosalind , Carvalho-Wells Andrew L. , Tierney Audrey C. , Marin Carmen , Kieć-Wilk Beata , Dembińska-Kieć Aldona , Drevon Christian A. , DeFoort Catherine , Lopez-Miranda José , Risérus Ulf , Saris Wim H. , Blaak Ellen E. , Roche Helen M. , Lovegrove Julie A. 
Published: July 2017

AbstractMetabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.
Angiopoietin-like 4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression
Authors: Teo Ziqiang , Chan Jeremy Soon Kiat , Chong Han Chung , Sng Ming Keat , Choo Chee Chong , Phua Glendon Zhi Ming , Teo Daniel Jin Rong , Zhu Pengcheng , Choong Cleo , Wong Marcus Thien Chong , Tan Nguan Soon 
Published: July 2017

AbstractIn adult skin wounds, collagen expression rapidly re-establishes the skin barrier, although the resultant scar is aesthetically and functionally inferior to unwounded tissue. Although TGFβ signaling and fibroblasts are known to be responsible for scar-associated collagen production, there are currently no prophylactic treatments for scar management. Fibroblasts in crosstalk with wound keratinocytes orchestrate collagen expression, although the precise paracrine pathways involved remain poorly understood. Herein, we showed that the matricellular protein, angiopoietin-like 4 (ANGPTL4), accelerated wound closure and reduced collagen expression in diabetic and ANGPTL4-knockout mice. Similar observations were made in wild-type rat wounds. Using human fibroblasts as a preclinical model for mechanistic studies, we systematically elucidated that ANGPTL4 binds to cadherin-11, releasing membrane-bound β-catenin which translocate to the nucleus and transcriptionally upregulate the expression of Inhibitor of DNA-binding/differentiation protein 3 (ID3). ID3 interacts with scleraxis, a basic helix-loop-helix transcription factor, to inhibit scar-associated collagen types 1α2 and 3α1 production by fibroblasts. We also showed ANGPTL4 interaction with cadherin-11 in human scar tissue. Our findings highlight a central role for matricellular proteins such as ANGPTL4 in the attenuation of collagen expression and may have a broader implication for other fibrotic pathologies.
CDKL5 localizes at the centrosome and midbody and is required for faithful cell division
Authors: Barbiero Isabella , Valente Davide , Chandola Chetan , Magi Fiorenza , Bergo Anna , Monteonofrio Laura , Tramarin Marco , Fazzari Maria , Soddu Silvia , Landsberger Nicoletta , Rinaldo Cinzia , Kilstrup-Nielsen Charlotte 
Published: July 2017

AbstractThe cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with rare neurodevelopmental disorders characterized by the early onset of seizures and intellectual disability. The CDKL5 protein is widely expressed in most tissues and cells with both nuclear and cytoplasmic localization. In post-mitotic neurons CDKL5 is mainly involved in dendritic arborization, axon outgrowth, and spine formation while in proliferating cells its function is still largely unknown. Here, we report that CDKL5 localizes at the centrosome and at the midbody in proliferating cells. Acute inactivation of CDKL5 by RNA interference (RNAi) leads to multipolar spindle formation, cytokinesis failure and centrosome accumulation. At the molecular level, we observed that, among the several midbody components we analyzed, midbodies of CDKL5-depleted cells were devoid of HIPK2 and its cytokinesis target, the extrachromosomal histone H2B phosphorylated at S14. Of relevance, expression of the phosphomimetic mutant H2B-S14D, which is capable of overcoming cytokinesis failure in HIPK2-defective cells, was sufficient to rescue spindle multipolarity in CDKL5-depleted cells. Taken together, these results highlight a hitherto unknown role of CDKL5 in regulating faithful cell division by guaranteeing proper HIPK2/H2B functions at the midbody.
Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes
Authors: Borghese Cecilia M. , Herman Melissa , Snell Lawrence D. , Lawrence Keri J. , Lee Hyun-Young , Backos Donald S. , Vanderlinden Lauren A. , Harris R. Adron , Roberto Marisa , Hoffman Paula L. , Tabakoff Boris 
Published: July 2017

AbstractAminoquinoline derivatives were evaluated against a panel of receptors/channels/transporters in radioligand binding experiments. One of these derivatives (DCUK-OEt) displayed micromolar affinity for brain γ-aminobutyric acid type A (GABAA) receptors. DCUK-OEt was shown to be a positive allosteric modulator (PAM) of GABA currents with α1β2γ2, α1β3γ2, α5β3γ2 and α1β3δ GABAA receptors, while having no significant PAM effect on αβ receptors or α1β1γ2, α1β2γ1, α4β3γ2 or α4β3δ receptors. DCUK-OEt modulation of α1β2γ2 GABAA receptors was not blocked by flumazenil. The subunit requirements for DCUK-OEt actions distinguished DCUK-OEt from other currently known modulators of GABA function (e.g., anesthetics, neurosteroids or ethanol). Simulated docking of DCUK-OEt at the GABAA receptor suggested that its binding site may be at the α + β- subunit interface. In slices of the central amygdala, DCUK-OEt acted primarily on extrasynaptic GABAA receptors containing the α1 subunit and generated increases in extrasynaptic “tonic” current with no significant effect on phasic responses to GABA. DCUK-OEt is a novel chemical structure acting as a PAM at particular GABAA receptors. Given that neurons in the central amygdala responding to DCUK-OEt were recently identified as relevant for alcohol dependence, DCUK-OEt should be further evaluated for the treatment of alcoholism.
Antisocial rewarding in structured populations
Authors: dos Santos Miguel , Peña Jorge 
Published: July 2017

AbstractCooperation in collective action dilemmas usually breaks down in the absence of additional incentive mechanisms. This tragedy can be escaped if cooperators have the possibility to invest in reward funds that are shared exclusively among cooperators (prosocial rewarding). Yet, the presence of defectors who do not contribute to the public good but do reward themselves (antisocial rewarding) deters cooperation in the absence of additional countermeasures. A recent simulation study suggests that spatial structure is sufficient to prevent antisocial rewarding from deterring cooperation. Here we reinvestigate this issue assuming mixed strategies and weak selection on a game-theoretic model of social interactions, which we also validate using individual-based simulations. We show that increasing reward funds facilitates the maintenance of prosocial rewarding but prevents its invasion, and that spatial structure can sometimes select against the evolution of prosocial rewarding. Our results suggest that, even in spatially structured populations, additional mechanisms are required to prevent antisocial rewarding from deterring cooperation in public goods dilemmas.