bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anti-apoptotic Bcl-2 family protein A1/Bfl-1 regulates neutrophil survival and homeostasis and is controlled via PI3K and JAK/STAT signaling
Authors: Vier J , Groth M , Sochalska M , Kirschnek S 
Published: February 2016

AbstractNeutrophil granulocytes are innate effector cells of the first line of defense against pyogenic bacteria. Neutrophil lifespan is short, is prolonged by pro-inflammatory stimuli, controls functionality of the cells and can determine tissue damage. Experimental analysis of primary neutrophils is difficult because of their short lifespan and lack of possibilities of genetic manipulation. The Hoxb8 system of neutrophil differentiation from immortalized progenitor cells offers the advantage of unlimited production of neutrophils in vitro as well as easy genetic modification. We here use this system to analyze the role of the poorly characterized anti-apoptotic B-cell lymphoma protein 2 (Bcl-2) family member A1/Bfl-1 (Bcl-2-related protein A1) for survival and homeostasis of neutrophils and of neutrophil progenitors. Low constitutive mRNA and protein expression of A1 was detected, while A1 was transiently upregulated early during differentiation. Pro-inflammatory stimuli caused strong, mainly transcriptional, A1 upregulation, in contrast to posttranscriptional regulation of Mcl-1 (induced myeloid leukemia cell differentiation protein). Inhibitor studies showed that phosphoinositide-3 kinase (PI3K)/Akt and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) is required for A1 expression and survival of progenitors and mature neutrophils. ShRNA-mediated constitutive A1 knockdown (KD) impaired maintenance of progenitors. ShRNA experiments further showed that A1 was required early during neutrophil differentiation as well as in mature neutrophils upon pro-inflammatory stimulation. Our data further indicate differential regulation of the two anti-apoptotic proteins A1 and Mcl-1. Relevant findings were confirmed in primary human neutrophils. Our data indicate that A1, in addition to the well-established Mcl-1, substantially contributes to neutrophil survival and homeostasis. A1 may thus be a promising target for anti-inflammatory therapy.
Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death
Authors: Venkatadri R , Muni T , Iyer A K V , Yakisich J S , Azad N 
Published: February 2016

AbstractBreast cancer is the most frequently diagnosed cancer in women, and one of the leading causes of cancer-related deaths worldwide. Recent evidences indicate that dietary agents such as resveratrol may inhibit cancer progression through modulation of microRNAs (miRNAs). We demonstrate that resveratrol regulates apoptotic and cell cycle machinery in breast cancer cells by modulating key tumor-suppressive miRNAs including miR-125b-5p, miR-200c-3p, miR-409-3p, miR-122-5p and miR-542-3p. Resveratrol-mediated miRNA modulation regulates key anti-apoptotic and cell cycle proteins including Bcl-2, X-linked inhibitor of apoptosis protein and CDKs, which are critical for its activity. Modulating miRNAs with mimics or inhibitors further validated a key role for miR-542-3p in MCF-7 and miR-122-5p in MDA-MB-231 breast cancer cell death in response to resveratrol. In conclusion, this study reveals novel miRNAs modulated by resveratrol that have a key role in breast cancer cell death.
Accurate prediction of cellular co-translational folding indicates proteins can switch from post- to co-translational folding
Authors: Nissley Daniel A. , Sharma Ajeet K. , Ahmed Nabeel , Friedrich Ulrike A. , Kramer Günter , Bukau Bernd , O’Brien Edward P. 
Published: February 2016

AbstractThe rates at which domains fold and codons are translated are important factors in determining whether a nascent protein will co-translationally fold and function or misfold and malfunction. Here we develop a chemical kinetic model that calculates a protein domain’s co-translational folding curve during synthesis using only the domain’s bulk folding and unfolding rates and codon translation rates. We show that this model accurately predicts the course of co-translational folding measured in vivo for four different protein molecules. We then make predictions for a number of different proteins in yeast and find that synonymous codon substitutions, which change translation-elongation rates, can switch some protein domains from folding post-translationally to folding co-translationally—a result consistent with previous experimental studies. Our approach explains essential features of co-translational folding curves and predicts how varying the translation rate at different codon positions along a transcript’s coding sequence affects this self-assembly process.
In-line three-dimensional holography of nanocrystalline objects at atomic resolution
Authors: Chen F.-R. , Van Dyck D. , Kisielowski C. 
Published: February 2016

AbstractResolution and sensitivity of the latest generation aberration-corrected transmission electron microscopes allow the vast majority of single atoms to be imaged with sub-Ångstrom resolution and their locations determined in an image plane with a precision that exceeds the 1.9-pm wavelength of 300 kV electrons. Such unprecedented performance allows expansion of electron microscopic investigations with atomic resolution into the third dimension. Here we report a general tomographic method to recover the three-dimensional shape of a crystalline particle from high-resolution images of a single projection without the need for sample rotation. The method is compatible with low dose rate electron microscopy, which improves on signal quality, while minimizing electron beam-induced structure modifications even for small particles or surfaces. We apply it to germanium, gold and magnesium oxide particles, and achieve a depth resolution of 1–2 Å, which is smaller than inter-atomic distances.
Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis
Authors: Gomez-Ospina Natalia , Potter Carol J. , Xiao Rui , Manickam Kandamurugu , Kim Mi-Sun , Kim Kang Ho , Shneider Benjamin L. , Picarsic Jennifer L. , Jacobson Theodora A. , Zhang Jing , He Weimin , Liu Pengfei , Knisely A. S. , Finegold Milton J. , Muzny Donna M. , Boerwinkle Eric , Lupski James R. , Plon Sharon E. , Gibbs Richard A. , Eng Christine M. , Yang Yaping , Washington Gabriel C. , Porteus Matthew H. , Berquist William E. , Kambham Neeraja , Singh Ravinder J. , Xia Fan , Enns Gregory M. , Moore David D. 
Published: February 2016

AbstractNeonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
Myosin light-chain phosphatase regulates basal actomyosin oscillations during morphogenesis
Authors: Valencia-Expósito Andrea , Grosheva Inna , Míguez David G. , González-Reyes Acaimo , Martín-Bermudo María D. 
Published: February 2016

AbstractContractile actomyosin networks generate forces that drive tissue morphogenesis. Actomyosin contractility is controlled primarily by reversible phosphorylation of the myosin-II regulatory light chain through the action of myosin kinases and phosphatases. While the role of myosin light-chain kinase in regulating contractility during morphogenesis has been largely characterized, there is surprisingly little information on myosin light-chain phosphatase (MLCP) function in this context. Here, we use live imaging of Drosophila follicle cells combined with mathematical modelling to demonstrate that the MLCP subunit flapwing (flw) is a key regulator of basal myosin oscillations and cell contractions underlying egg chamber elongation. Flw expression decreases specifically on the basal side of follicle cells at the onset of contraction and flw controls the initiation and periodicity of basal actomyosin oscillations. Contrary to previous reports, basal F-actin pulsates similarly to myosin. Finally, we propose a quantitative model in which periodic basal actomyosin oscillations arise in a cell-autonomous fashion from intrinsic properties of motor assemblies.
Voltage collapse in complex power grids
Authors: Simpson-Porco John W. , Dörfler Florian , Bullo Francesco 
Published: February 2016

AbstractA large-scale power grid’s ability to transfer energy from producers to consumers is constrained by both the network structure and the nonlinear physics of power flow. Violations of these constraints have been observed to result in voltage collapse blackouts, where nodal voltages slowly decline before precipitously falling. However, methods to test for voltage collapse are dominantly simulation-based, offering little theoretical insight into how grid structure influences stability margins. For a simplified power flow model, here we derive a closed-form condition under which a power network is safe from voltage collapse. The condition combines the complex structure of the network with the reactive power demands of loads to produce a node-by-node measure of grid stress, a prediction of the largest nodal voltage deviation, and an estimate of the distance to collapse. We extensively test our predictions on large-scale systems, highlighting how our condition can be leveraged to increase grid stability margins.
Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease
Authors: Perez-Lloret Santiago , Barrantes Francisco J 
Published: February 2016

AbstractIn view of its ability to explain the most frequent motor symptoms of Parkinson’s Disease (PD), degeneration of dopaminergic neurons has been considered one of the disease’s main pathophysiological features. Several studies have shown that neurodegeneration also affects noradrenergic, serotoninergic, cholinergic and other monoaminergic neuronal populations. In this work, the characteristics of cholinergic deficits in PD and their clinical correlates are reviewed. Important neurophysiological processes at the root of several motor and cognitive functions remit to cholinergic neurotransmission at the synaptic, pathway, and circuital levels. The bulk of evidence highlights the link between cholinergic alterations and PD motor symptoms, gait dysfunction, levodopa-induced dyskinesias, cognitive deterioration, psychosis, sleep abnormalities, autonomic dysfunction, and altered olfactory function. The pathophysiology of these symptoms is related to alteration of the cholinergic tone in the striatum and/or to degeneration of cholinergic nuclei, most importantly the nucleus basalis magnocellularis and the pedunculopontine nucleus. Several results suggest the clinical usefulness of antimuscarinic drugs for treating PD motor symptoms and of inhibitors of the enzyme acetylcholinesterase for the treatment of dementia. Data also suggest that these inhibitors and pedunculopontine nucleus deep-brain stimulation might also be effective in preventing falls. Finally, several drugs acting on nicotinic receptors have proved efficacious for treating levodopa-induced dyskinesias and cognitive impairment and as neuroprotective agents in PD animal models. Results in human patients are still lacking.
A Modular Assembly Platform for Rapid Generation of DNA Constructs
Authors: Akama-Garren Elliot H. , Joshi Nikhil S. , Tammela Tuomas , Chang Gregory P. , Wagner Bethany L. , Lee Da-Yae , Rideout III William M. , Papagiannakopoulos Thales , Xue Wen , Jacks Tyler 
Published: February 2016

AbstractTraditional cloning methods have limitations on the number of DNA fragments that can be simultaneously manipulated, which dramatically slows the pace of molecular assembly. Here we describe GMAP, a Gibson assembly-based modular assembly platform consisting of a collection of promoters and genes, which allows for one-step production of DNA constructs. GMAP facilitates rapid assembly of expression and viral constructs using modular genetic components, as well as increasingly complicated genetic tools using contextually relevant genomic elements. Our data demonstrate the applicability of GMAP toward the validation of synthetic promoters, identification of potent RNAi constructs, establishment of inducible lentiviral systems, tumor initiation in genetically engineered mouse models and gene-targeting for the generation of knock-in mice. GMAP represents a recombinant DNA technology designed for widespread circulation and easy adaptation for other uses, such as synthetic biology, genetic screens and CRISPR-Cas9.
Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress
Authors: Zhang Peng , Zhou Lujun , Pei Chunli , Lin Xinhua , Yuan Zengqiang 
Published: February 2016

AbstractSecreted Wnts play diverse roles in a non-cell-autonomous fashion. However, the cell-autonomous effect of unsecreted Wnts remains unknown. Endoplasmic reticulum (ER) stress is observed in specialized secretory cells and participates in pathophysiological processes. The correlation between Wnt secretion and ER stress remains poorly understood. Here, we demonstrated that Drosophila miR-307a initiates ER stress specifically in wingless (wg)-expressing cells through targeting wntless (wls/evi). This phenotype could be mimicked by retromer loss-of-function or porcupine (porc) depletion and rescued by wg knockdown, arguing that unsecreted Wg triggers ER stress. Consistently, we found that disrupting the secretion of human Wnt5a also induced ER stress in mammalian cells. Furthermore, we showed that a C-terminal KKVY-motif of Wg is required for its retrograde Golgi-to-ER transport, thus inducing ER stress. Next, we investigated if COPI, the regulator of retrograde transport, is responsible for unsecreted Wg to induce ER stress. To our surprise, we found that COPI acts as a novel regulator of Wg secretion. Taken together, this study reveals a previously unknown Golgi-to-ER retrograde route of Wg and elucidates a correlation between Wnt secretion and ER stress during development.
An approach to quantifying 3D responses of cells to extreme strain
Authors: Li Yuhui , Huang Guoyou , Li Moxiao , Wang Lin , Elson Elliot L. , Jian Lu Tian , Genin Guy M. , Xu Feng 
Published: February 2016

AbstractThe tissues of hollow organs can routinely stretch up to 2.5 times their length. Although significant pathology can arise if relatively large stretches are sustained, the responses of cells are not known at these levels of sustained strain. A key challenge is presenting cells with a realistic and well-defined three-dimensional (3D) culture environment that can sustain such strains. Here, we describe an in vitro system called microscale, magnetically-actuated synthetic tissues (micro-MASTs) to quantify these responses for cells within a 3D hydrogel matrix. Cellular strain-threshold and saturation behaviors were observed in hydrogel matrix, including strain-dependent proliferation, spreading, polarization and differentiation and matrix adhesion retained at strains sufficient for apoptosis. More broadly, the system shows promise for defining and controlling the effects of mechanical environment upon a broad range of cells.
How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies
Authors: Shen Liang , Liu Cui-Cui , An Chun-Yan , Ji Hong-Fang 
Published: February 2016

AbstractCurcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.–)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.–-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.
Continuous-wave phase-matched molecular optical modulator
Authors: Zaitsu Shin-ichi , Izaki Hirotomo , Tsuchiya Takao , Imasaka Totaro 
Published: February 2016

AbstractIn optical modulation, the highest available modulation rate is basically limited to the GHz frequency range at best. This is because optical modulation is often performed using electro-optic or acousto-optic effects that require application of an external signal to solid-state nonlinear optical materials. Here we describe optical modulation of continuous-wave radiation at frequencies exceeding 10 THz based on ultrafast variation of molecule polarizability arising from coherent molecular motion. The optical modulation efficiency is extensively enhanced by fulfilling phase-matching conditions with the help of dispersion control of the optical cavity, generating sidebands with a highest ratio of 7.3 × 10−3. These results will pave the way for development of versatile optical modulation-based techniques in a wide range of research fields in optical sciences, such as mode-locked lasers operating in the THz range.
Laser induced mortality of Anopheles stephensi mosquitoes
Authors: Keller Matthew D. , Leahy David J. , Norton Bryan J. , Johanson ric , Mullen Emma R. , Marvit Maclen , Makagon Arty 
Published: February 2016

AbstractSmall, flying insects continue to pose great risks to both human health and agricultural production throughout the world, so there remains a compelling need to develop new vector and pest control approaches. Here, we examined the use of short (<25 ms) laser pulses to kill or disable anesthetized femaleAnopheles stephensimosquitoes, which were chosen as a representative species. The mortality of mosquitoes exposed to laser pulses of various wavelength, power, pulse duration, and spot size combinations was assessed 24 hours after exposure. For otherwise comparable conditions, green and far-infrared wavelengths were found to be more effective than near- and mid-infrared wavelengths. Pulses with larger laser spot sizes required lower lethal energy densities, or fluence, but more pulse energy than for smaller spot sizes with greater fluence. Pulse duration had to be reduced by several orders of magnitude to significantly lower the lethal pulse energy or fluence required. These results identified the most promising candidates for the lethal laser component in a system being designed to identify, track, and shoot down flying insects in the wild.
Sulphur Kβ emission spectra reveal protonation states of aqueous sulfuric acid
Authors: Niskanen Johannes , Sahle Christoph J. , Ruotsalainen Kari O. , Müller Harald , Kavčič Matjaž , Žitnik Matjaž , Bučar Klemen , Petric Marko , Hakala Mikko , Huotari Simo 
Published: February 2016

AbstractIn this paper we report an X-ray emission study of bulk aqueous sulfuric acid. Throughout the range of molarities from 1 M to 18 M the sulfur Kβ emission spectra from H2SO4 (aq) depend on the molar fractions and related deprotonation of H2SO4. We compare the experimental results with results from emission spectrum calculations based on atomic structures of single molecules and structures from ab initio molecular dynamics simulations. We show that the S Kβ emission spectrum is a sensitive probe of the protonation state of the acid molecules. Using non-negative matrix factorization we are able to extract the fractions of different protonation states in the spectra and the results are in good agreement with the simulation for the higher part of the concentration range.
Comparative genomics of mitochondria in chlorarachniophyte algae: endosymbiotic gene transfer and organellar genome dynamics
Authors: Tanifuji Goro , Archibald John M. , Hashimoto Tetsuo 
Published: February 2016

AbstractChlorarachniophyte algae possess four DNA-containing compartments per cell, the nucleus, mitochondrion, plastid and nucleomorph, the latter being a relic nucleus derived from a secondary endosymbiont. While the evolutionary dynamics of plastid and nucleomorph genomes have been investigated, a comparative investigation of mitochondrial genomes (mtDNAs) has not been carried out. We have sequenced the complete mtDNA of Lotharella oceanica and compared it to that of another chlorarachniophyte, Bigelowiella natans. The linear mtDNA of L. oceanica is 36.7 kbp in size and contains 35 protein genes, three rRNAs and 24 tRNAs. The codons GUG and UUG appear to be capable of acting as initiation codons in the chlorarachniophyte mtDNAs, in addition to AUG. Rpl16, rps4 and atp8 genes are missing in L.oceanica mtDNA, despite being present in B. natans mtDNA. We searched for and found, mitochondrial rpl16 and rps4 genes with spliceosomal introns in the L. oceanica nuclear genome, indicating that mitochondrion-to-host-nucleus gene transfer occurred after the divergence of these two genera. Despite being of similar size and coding capacity, the level of synteny between L. oceanica and B. natans mtDNA is low, suggesting frequent rearrangements. Overall, our results suggest that chlorarachniophyte mtDNAs are more evolutionarily dynamic than their plastid counterparts.
Acute knockdown of the insulin receptor or its substrates Irs1 and 2 in 3T3-L1 adipocytes suppresses adiponectin production
Authors: Groeneveld Matthijs P. , Brierley Gemma V. , Rocha Nuno M. , Siddle Kenneth , Semple Robert K. 
Published: February 2016

AbstractLoss of function of the insulin receptor (INSR) in humans produces severe insulin resistance. Unlike “common” insulin resistance, this is associated with elevated plasma levels of the insulin-sensitising, adipose-derived protein adiponectin. The underlying mechanism for this paradox is unclear and it is at odds with the acute stimulation of adiponectin secretion reported on insulin treatment of cultured adipocytes. Given recent evidence for ligand-independent actions of the INSR, we used a lentiviral system to knock down Insr or its substrates Irs1 and Irs2 conditionally in 3T3-L1 murine preadipocytes/adipocytes to assess whether acute loss of their expression has different consequences to withdrawal of insulin. Efficient knockdown of either Insr or Irs1/2 was achieved by conditional shRNA expression, severely attenuating insulin-stimulated AKT phosphorylation and glucose uptake. Dual knockdown of Irs1 and Irs2 but not Insr in preadipocytes impaired differentiation to adipocytes. Acute knockdown of Insr or both Irs1 and Irs2 in adipocytes increased Adipoq mRNA expression but reduced adiponectin secretion, assessed by immunoassay. Knockdown sustained for 14 days also reduced immunoassay-detected adiponectin secretion and moreover induced delipidation of the cells. These findings argue against a distinct effect of Insr deficiency to promote adiponectin secretion as the explanation for paradoxical insulin receptoropathy-related hyperadiponectinaemia.