bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothalamus proteomics from mouse models with obesity and anorexia reveals therapeutic targets of appetite regulation
Authors: Manousopoulou A , Koutmani Y , Karaliota S , Woelk C H , Manolakos E S , Karalis K , Garbis S D 
Published: April 2016

AbstractObjective:This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation.Methods:Four to six-week-old male C56BL/6J mice were fed a normal (control 1 group;n=7) or a HFD (HFD group;n=10) for 8 weeks. The control 2 (n=7) and lipopolysaccharide (LPS) groups (n=10) were fed a normal diet for 8 weeks before receiving an injection of saline and LPS, respectively. Hypothalamic regions were analysed using a quantitative proteomics method based on a combination of techniques including iTRAQ stable isotope labeling, orthogonal two-dimensional liquid chromatography hyphenated with nanospray ionization and high-resolution mass spectrometry. Key proteins were validated with quantitative PCR.Results:Quantitative proteomics of the hypothalamous regions profiled a total of 9249 protein groups (q<0.05). Of these, 7718 protein groups were profiled with a minimum of two unique peptides for each. Hierachical clustering of the differentiated proteome revealed distinct proteomic signatures for the hypothalamus under the HFD and LPS nutritional conditions. Literature research with in silico bioinformatics interpretation of the differentiated proteome identified key biological relevant proteins and implicated pathways. Furthermore, the study identified potential pharmacologic targets. In the LPS groups, the anorexigen pro-opiomelanocortin was downregulated. In mice with obesity, nuclear factor-κB, glycine receptor subunit alpha-4 (GlyR) and neuropeptide Y levels were elevated, whereas serotonin receptor 1B levels decreased.Conclusions:High-precision quantitative proteomics revealed that under acute systemic inflammation in the hypothalamus as a response to LPS, homeostatic mechanisms mediating loss of appetite take effect. Conversely, under chronic inflammation in the hypothalamus as a response to HFD, mechanisms mediating a sustained ‘perpetual cycle’ of appetite enhancement were observed. The GlyR protein may constitute a novel treatment target for the reduction of central orexigenic signals in obesity.
Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice
Authors: Weisberg S , Leibel R , Tortoriello D V 
Published: April 2016

Abstract
Background:
Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background).

Results:
In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity.

Conclusions:
These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance.
Attenuation of cold stress-induced exacerbation of cardiac and adipose tissue pathology and metabolic disorders in a rat model of metabolic syndrome by the glucocorticoid receptor antagonist RU486
Authors: Nagasawa K , Matsuura N , Takeshita Y , Ito S , Sano Y , Yamada Y , Uchinaka A , Murohara T , Nagata K 
Published: April 2016

Abstract
Objectives:
Chronic stress affects the central nervous system as well as endocrine, metabolic and immune systems. However, the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We recently characterized DahlS.Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We have now investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology as well as on metabolic parameters in this model.

Methods:
DS/obese rats were exposed to cold stress (immersion in ice-cold water to a depth of 1–2 cm for 2 h per day) with or without subcutaneous injection of the GR antagonist RU486 (2 mg kg−1day−1) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr+/Lepr+) littermates served as a control.

Results:
Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction in DS/obese rats in a manner sensitive to RU486 treatment. Cold stress with or without RU486 did not affect body weight or fat mass. In contrast, cold stress further increased cardiac oxidative stress as well as macrophage infiltration and proinflammatory gene expression in LV and visceral fat tissue, with all of these effects being attenuated by RU486. Cold stress also further increased GR and 11β-hydroxysteroid dehydrogenase type 1 mRNA and protein abundance in LV and visceral adipose tissue, and these effects were again inhibited by RU486. In addition, RU486 ameliorated the stress-induced aggravation of dyslipidemia, glucose intolerance and insulin resistance in DS/obese rats.

Conclusions:
Our results implicate GR signaling in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as of abnormal glucose and lipid metabolism in a rat model of MetS.
A novel lineage restricted, pericyte-like cell line isolated from human embryonic stem cells
Authors: Greenwood-Goodwin Midori , Yang Jiwei , Hassanipour Mohammad , Larocca David 
Published: April 2016

AbstractPericytes (PCs) are endothelium-associated cells that play an important role in normal vascular function and maintenance. We developed a method comparable to GMP quality protocols for deriving self-renewing perivascular progenitors from the human embryonic stem cell (hESC), line ESI-017. We identified a highly scalable, perivascular progenitor cell line that we termed PC-A, which expressed surface markers common to mesenchymal stromal cells. PC-A cells were not osteogenic or adipogenic under standard differentiation conditions and showed minimal angiogenic support function in vitro. PC-A cells were capable of further differentiation to perivascular progenitors with limited differentiation capacity, having osteogenic potential (PC-O) or angiogenic support function (PC-M), while lacking adipogenic potential. Importantly, PC-M cells expressed surface markers associated with pericytes. Moreover, PC-M cells had pericyte-like functionality being capable of co-localizing with human umbilical vein endothelial cells (HUVECs) and enhancing tube stability up to 6 days in vitro. We have thus identified a self-renewing perivascular progenitor cell line that lacks osteogenic, adipogenic and angiogenic potential but is capable of differentiation toward progenitor cell lines with either osteogenic potential or pericyte-like angiogenic function. The hESC-derived perivascular progenitors described here have potential applications in vascular research, drug development and cell therapy.
PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits
Authors: Broadhead Matthew J. , Horrocks Mathew H. , Zhu Fei , Muresan Leila , Benavides-Piccione Ruth , DeFelipe Javier , Fricker David , Kopanitsa Maksym V. , Duncan Rory R. , Klenerman David , Komiyama Noboru H. , Lee Steven F. , Grant Seth G. N. 
Published: April 2016

AbstractThe molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.
Exercise capacity and cardiac hemodynamic response in female ApoE/LDLR−/− mice: a paradox of preserved V’O2max and exercise capacity despite coronary atherosclerosis
Authors: Wojewoda M. , Tyrankiewicz U. , Gwozdz P. , Skorka T. , Jablonska M. , Orzylowska A. , Jasinski K. , Jasztal A. , Przyborowski K. , Kostogrys R. B. , Zoladz J. A. , Chlopicki S. 
Published: April 2016

AbstractWe assessed exercise performance, coronary blood flow and cardiac reserve of female ApoE/LDLR−/− mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise capacity was assessed as whole body maximal oxygen consumption (V’O2max), maximum running velocity (vmax) and maximum distance (DISTmax) during treadmill exercise. Cardiac systolic and diastolic function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress) were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was assessed in isolated perfused hearts. In female ApoE/LDLR−/− mice V’O2max, vmax and DISTmax were not impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac reserve were also preserved in female ApoE/LDLR−/− mice as evidenced by preserved fractional area change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endothelium-dependent responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh) were preserved, while endothelium-independent responses induced by NO-donors were augmented in female ApoE/LDLR−/− mice. Basal COX-2-dependent production of 6-keto-PGF1α was increased. Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving PGI2- and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in V’O2max and exercise capacity.
A comprehensive simulation framework for imaging single particles and biomolecules at the European X-ray Free-Electron Laser
Authors: Yoon Chun Hong , Yurkov Mikhail V. , Schneidmiller Evgeny A. , Samoylova Liubov , Buzmakov Alexey , Jurek Zoltan , Ziaja Beata , Santra Robin , Loh N. Duane , Tschentscher Thomas , Mancuso Adrian P. 
Published: April 2016

AbstractThe advent of newer, brighter, and more coherent X-ray sources, such as X-ray Free-Electron Lasers (XFELs), represents a tremendous growth in the potential to apply coherent X-rays to determine the structure of materials from the micron-scale down to the Angstrom-scale. There is a significant need for a multi-physics simulation framework to perform source-to-detector simulations for a single particle imaging experiment, including (i) the multidimensional simulation of the X-ray source; (ii) simulation of the wave-optics propagation of the coherent XFEL beams; (iii) atomistic modelling of photon-material interactions; (iv) simulation of the time-dependent diffraction process, including incoherent scattering; (v) assembling noisy and incomplete diffraction intensities into a three-dimensional data set using the Expansion-Maximisation-Compression (EMC) algorithm and (vi) phase retrieval to obtain structural information. We demonstrate the framework by simulating a single-particle experiment for a nitrogenase iron protein using parameters of the SPB/SFX instrument of the European XFEL. This exercise demonstrably yields interpretable consequences for structure determination that are crucial yet currently unavailable for experiment design.
Electronic and chemical structure of the H2O/GaN(0001) interface under ambient conditions
Authors: Zhang Xueqiang , Ptasinska Sylwia 
Published: April 2016

AbstractWe employed ambient pressure X-ray photoelectron spectroscopy to investigate the electronic and chemical properties of the H2O/GaN(0001) interface under elevated pressures and/or temperatures. A pristine GaN(0001) surface exhibited upward band bending, which was partially flattened when exposed to H2O at room temperature. However, the GaN surface work function was slightly reduced due to the adsorption of molecular H2O and its dissociation products. At elevated temperatures, a negative charge generated on the surface by a vigorous H2O/GaN interfacial chemistry induced an increase in both the surface work function and upward band bending. We tracked the dissociative adsorption of H2O onto the GaN(0001) surface by recording the core-level photoemission spectra and obtained the electronic and chemical properties at the H2O/GaN interface under operando conditions. Our results suggest a strong correlation between the electronic and chemical properties of the material surface and we expect that their evolutions lead to significantly different properties at the electrolyte/electrode interface in a photoelectrochemical solar cell.
Large gap electron-hole superfluidity and shape resonances in coupled graphene nanoribbons
Authors: Zarenia M. , Perali A. , Peeters F. M. , Neilson D. 
Published: April 2016

AbstractWe predict enhanced electron-hole superfluidity in two coupled electron-hole armchair-edge terminated graphene nanoribbons separated by a thin insulating barrier. In contrast to graphene monolayers, the multiple subbands of the nanoribbons are parabolic at low energy with a gap between the conduction and valence bands and with lifted valley degeneracy. These properties make screening of the electron-hole interaction much weaker than for coupled electron-hole monolayers, thus boosting the pairing strength and enhancing the superfluid properties. The pairing strength is further boosted by the quasi one-dimensional quantum confinement of the carriers, as well as by the large density of states near the bottom of each subband. The latter magnifies superfluid shape resonances caused by the quantum confinement. Several superfluid partial condensates are present for finite-width nanoribbons with multiple subbands. We find that superfluidity is predominately in the strongly-coupled BEC and BCS-BEC crossover regimes, with large superfluid gaps up to 100 meV and beyond. When the gaps exceed the subband spacing, there is significant mixing of the subbands, a rounding of the shape resonances and a resulting reduction in the one-dimensional nature of the system.
Generation of transgenic cynomolgus monkeys that express green fluorescent protein throughout the whole body
Authors: Seita Yasunari , Tsukiyama Tomoyuki , Iwatani Chizuru , Tsuchiya Hideaki , Matsushita Jun , Azami Takuya , Okahara Junko , Nakamura Shinichiro , Hayashi Yoshitaka , Hitoshi Seiji , Itoh Yasushi , Imamura Takeshi , Nishimura Masaki , Tooyama Ikuo , Miyoshi Hiroyuki , Saitou Mitinori , Ogasawara Kazumasa , Sasaki Erika , Ema Masatsugu 
Published: April 2016

AbstractNonhuman primates are valuable for human disease modelling, because rodents poorly recapitulate some human diseases such as Parkinson’s disease and Alzheimer’s disease amongst others. Here, we report for the first time, the generation of green fluorescent protein (GFP) transgenic cynomolgus monkeys by lentivirus infection. Our data show that the use of a human cytomegalovirus immediate-early enhancer and chicken beta actin promoter (CAG) directed the ubiquitous expression of the transgene in cynomolgus monkeys. We also found that injection into mature oocytes before fertilization achieved homogenous expression of GFP in each tissue, including the amnion and fibroblasts, whereas injection into fertilized oocytes generated a transgenic cynomolgus monkey with mosaic GFP expression. Thus, the injection timing was important to create transgenic cynomolgus monkeys that expressed GFP homogenously in each of the various tissues. The strategy established in this work will be useful for the generation of transgenic cynomolgus monkeys for transplantation studies as well as biomedical research.
Bare and boron-doped cubic silicon carbide nanowires for electrochemical detection of nitrite sensitively
Authors: Yang Tao , Zhang Liqin , Hou Xinmei , Chen Junhong , Chou Kuo-Chih 
Published: April 2016

AbstractFabrication of eletrochemical sensors based on wide bandgap compound semiconductors has attracted increasing interest in recent years. Here we report for the first time electrochemical nitrite sensors based on cubic silicon carbide (SiC) nanowires (NWs) with smooth surface and boron-doped cubic SiC NWs with fin-like structure. Multiple techniques including scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and electron energy loss spectroscopy (EELS) were used to characterize SiC and boron-doped SiC NWs. As for the electrochemical behavior of both SiC NWs electrode, the cyclic voltammetric results show that both SiC electrodes exhibit wide potential window and excellent electrocatalytic activity toward nitrite oxidation. Differential pulse voltammetry (DPV) determination reveals that there exists a good linear relationship between the oxidation peak current and the concentration in the range of 50–15000 μmoL L−1 (cubic SiC NWs) and 5–8000 μmoL L−1 (B-doped cubic SiC NWs) with the detection limitation of 5 and 0.5 μmoL L−1 respectively. Compared with previously reported results, both as-prepared nitrite sensors exhibit wider linear response range with comparable high sensitivity, high stability and reproducibility.
Production of Potent Fully Human Polyclonal Antibodies against Ebola Zaire Virus in Transchromosomal Cattle
Authors: Dye John M. , Wu Hua , Hooper Jay W. , Khurana Surender , Kuehne Ana I. , Coyle Elizabeth M. , Ortiz Ramon A. , Fuentes Sandra , Herbert Andrew S. , Golding Hana , Bakken Russell A. , Brannan Jennifer M. , Kwilas Steve A. , Sullivan Eddie J. , Luke Thomas C. , Smith Gale , Glenn Gregory , Li Wenfang , Ye Ling , Yang Chinglai , Compans Richard W. , Tripp Ralph A. , Jiao Jin-an 
Published: April 2016

AbstractPolyclonal antibodies, derived from humans or hyperimmunized animals, have been used prophylactically or therapeutically as countermeasures for a variety of infectious diseases. SAB Biotherapeutics has successfully developed a transchromosomic (Tc) bovine platform technology that can produce fully human immunoglobulins rapidly, and in substantial quantities, against a variety of disease targets. In this study, two Tc bovines expressing high levels of fully human IgG were hyperimmunized with a recombinant glycoprotein (GP) vaccine consisting of the 2014 Ebola virus (EBOV) Makona isolate. Serum collected from these hyperimmunized Tc bovines contained high titers of human IgG against EBOV GP as determined by GP specific ELISA, surface plasmon resonance (SPR), and virus neutralization assays. Fully human polyclonal antibodies against EBOV were purified and evaluated in a mouse challenge model using mouse adapted Ebola virus (maEBOV). Intraperitoneal administration of the purified anti-EBOV IgG (100 mg/kg) to BALB/c mice one day after lethal challenge with maEBOV resulted in 90% protection; whereas 100% of the control animals succumbed. The results show that hyperimmunization of Tc bovines with EBOV GP can elicit protective and potent neutralizing fully human IgG antibodies rapidly and in commercially viable quantities.
Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure
Authors: Suzuki Jun , Corfas Gabriel , Liberman M. Charles 
Published: April 2016

AbstractIn acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and post-synaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery, as seen in the suprathreshold amplitude of auditory brainstem response Wave 1. Cochlear delivery of neurotrophins in humans is likely achievable as an office procedure via transtympanic injection, making our results highly significant in a translational context.
Strategies of Mesenchymal Invasion of Patient-derived Brain Tumors: Microenvironmental Adaptation
Authors: Cha Junghwa , Kang Seok-Gu , Kim Pilnam 
Published: April 2016

AbstractThe high mortality in glioblastoma multiforme (GBM) patients is primarily caused by extensive infiltration into adjacent tissue and subsequent rapid recurrence. There are no clear therapeutic strategies that target the infiltrative subpopulation of GBM mass. Using mesenchymal mode of invasion, the GBM is known to widely infiltrate by interacting with various unique components within brain microenvironment such as hyaluronic acid (HA)-rich matrix and white matter tracts. However, it is unclear how these GBM microenvironments influence the strategies of mesenchymal invasion. We hypothesize that GBM has different strategies to facilitate such invasion through adaptation to their local microenvironment. Using our in vitro biomimetic microenvironment platform for three-dimensional GBM tumorspheres (TSs), we found that the strategies of GBM invasion were predominantly regulated by the HA-rich ECM microenvironment, showing marked phenotypic changes in the presence of HA, which were mainly mediated by HA synthase (HAS). Interestingly, after inhibition of the HAS gene, GBM switched their invasion strategies to a focal adhesion (FA)-mediated invasion. These results demonstrate that the microenvironmental adaptation allowed a flexible invasion strategy for GBM. Using our model, we suggest a new inhibitory pathway for targeting infiltrative GBM and propose an importance of multi-target therapy for GBM, which underwent microenvironmental adaptation.