bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies
Authors: Dominguez Charli , Tsang Kwong-Yok , Palena Claudia 
Published: September 2016

AbstractThe epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib has been approved for years as a first-line therapy for patients harboring EGFR-sensitizing mutations. With the promising implementation of immunotherapeutic strategies for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize immune approaches in the context of conventional or targeted therapies. Tumor cells are known to evade immune attack by multiple strategies, including undergoing phenotypic plasticity via a process designated as the epithelial–mesenchymal transition (EMT). As signaling through EGFR is a major inducer of EMT in epithelial cells, we have investigated the effect of EGFR inhibition with erlotinib on tumor phenotype and susceptibility to immune attack. Our data shows that short-term exposure of tumor cells to low-dose erlotinib modulates tumor plasticity and immune-mediated cytotoxicity in lung cancer cells harboring a sensitizing EGFR mutation, leading to a remarkable enhancement of tumor lysis mediated by innate NK cells and antigen-specific T cells. This effect positively correlated with the ability of short-term EGFR blockade to modulate tumor phenotype towards a more epithelial one, as well as to increase susceptibility to caspase-mediated apoptosis. The effect, however, was lost when erlotinib was utilized for long periods of timein vitroorin vivo, which resulted in gain of mesenchymal features and decreased (rather than increased) tumor lysis in response to immune effector mechanisms. Our data provides rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.
Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure
Authors: Wen Zongmei , Lei Zhen , Yao Lu , Jiang Ping , Gu Tao , Ren Feng , Liu Yan , Gou Chunyan , Li Xiuhui , Wen Tao 
Published: September 2016

AbstractAcute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients’ sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.
Kinase-independent function of RIP1, critical for mature T-cell survival and proliferation
Authors: Dowling John P , Cai Yubo , Bertin John , Gough Peter J , Zhang Jianke 
Published: September 2016

AbstractThe death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses. However, the function of RIP1 in the adult lymphoid system has not been well understood, primarily owing to perinatal lethality in mice lacking the entire RIP1 protein in germ cells. This current study investigated the requirement for RIP1 in the T lineage using viable RIP1 mutant mice containing a conditional and kinase-dead RIP1 allele. Disabling the kinase activity of RIP1 had no obvious impact on the T-cell compartment. However, T-cell-specific deletion of RIP1 led to a severe T-lymphopenic condition, owing to a dramatically reduced mature T-cell pool in the periphery. Interestingly, the immature T-cell compartment in the thymus appeared intact. Further analysis showed that mature RIP1−/− T cells were severely defective in antigen receptor-induced proliferative responses. Moreover, the RIP1−/− T cells displayed greatly increased death and contained elevated caspase activities, an indication of apoptosis. In total, these results revealed a novel, kinase-independent function of RIP1, which is essential for not only promoting TCR-induced proliferative responses but also in blocking apoptosis in mature T cells.
Local quantum thermal susceptibility
Authors: De Pasquale Antonella , Rossini Davide , Fazio Rosario , Giovannetti Vittorio 
Published: September 2016

AbstractThermodynamics relies on the possibility to describe systems composed of a large number of constituents in terms of few macroscopic variables. Its foundations are rooted into the paradigm of statistical mechanics, where thermal properties originate from averaging procedures which smoothen out local details. While undoubtedly successful, elegant and formally correct, this approach carries over an operational problem, namely determining the precision at which such variables are inferred, when technical/practical limitations restrict our capabilities to local probing. Here we introduce the local quantum thermal susceptibility, a quantifier for the best achievable accuracy for temperature estimation via local measurements. Our method relies on basic concepts of quantum estimation theory, providing an operative strategy to address the local thermal response of arbitrary quantum systems at equilibrium. At low temperatures, it highlights the local distinguishability of the ground state from the excited sub-manifolds, thus providing a method to locate quantum phase transitions.
Experimental evidence of pollination in marine flowers by invertebrate fauna
Authors: van Tussenbroek Brigitta I. , Villamil Nora , Márquez-Guzmán Judith , Wong Ricardo , Monroy-Velázquez L. Verónica , Solis-Weiss Vivianne 
Published: September 2016

AbstractPollen transport by water-flow (hydrophily) is a typical, and almost exclusive, adaptation of plants to life in the marine environment. It is thought that, unlike terrestrial environments, animals are not involved in pollination in the sea. The male flowers of the tropical marine angiosperm Thalassia testudinum open-up and release pollen in mucilage at night when invertebrate fauna is active. Here we present experimental evidence that, in the absence of water-flow, these invertebrates visit the flowers, carry and transfer mucilage mass with embedded pollen from the male flowers to the stigmas of the female flowers. Pollen tubes are formed on the stigmas, indicating that pollination is successful. Thus, T. testudinum has mixed abiotic–biotic pollination. We propose a zoobenthophilous pollination syndrome (pollen transfer in the benthic zone by invertebrate animals) which shares many characteristics with hydrophily, but flowers are expected to open-up during the night.
Appropriate use of inhaled corticosteroids in COPD: the candidates for safe withdrawal
Authors: Yawn Barbara P , Suissa Samy , Rossi Andrea 
Published: September 2016

AbstractInternational guidance on chronic obstructive pulmonary disease (COPD) management recommends the use of inhaled corticosteroids (ICS) in those patients at increased likelihood of exacerbation. In spite of this guidance, ICS are prescribed in a large number of patients who are unlikely to benefit. Given the evidence of the risks associated with ICS and the limited indications for their use, there is interest in understanding the effects of withdrawing ICS when prescribed inappropriately. In this review, we discuss the findings of large ICS withdrawal trials, with primary focus on the more recent trials using active comparators. Data from these trials indicate that ICS may be withdrawn without adverse impact on exacerbation risk and patient-reported outcomes in patients with moderate COPD and no history of frequent exacerbations. Considering the safety concerns associated with ICS use, these medications should be withdrawn in patients for whom they are not recommended, while maintaining adequate bronchodilator therapy.
Food allergen detection by mass spectrometry: the role of systems biology
Authors: Croote Derek , Quake Stephen R 
Published: September 2016

AbstractFood allergy prevalence is rising worldwide, motivating the development of assays that can sensitively and reliably detect trace amounts of allergens in manufactured food. Mass spectrometry (MS) is a promising alternative to commonly employed antibody-based assays owing to its ability to quantify multiple proteins in complex matrices with high sensitivity. In this review, we discuss a targeted MS workflow for the quantitation of allergenic protein in food products that employs selected reaction monitoring (SRM). We highlight the aspects of SRM method development unique to allergen quantitation and identify opportunities for simplifying the process. One promising avenue identified through a comprehensive survey of published MS literature is the use of proteotypic peptides, which are peptides whose presence appears robust to variations in food matrix, sample preparation protocol, and MS instrumentation. We conclude that proteotypic peptides exist for a subset of allergenic milk, egg, and peanut proteins. For less studied allergens such as soy, wheat, fish, shellfish, and tree nuts, we offer guidance and tools for peptide selection and specificity verification as part of an interactive web database, the Allergen Peptide Browser (http://www.AllergenPeptideBrowser.org). With ongoing improvements in MS instrumentation, analysis software, and strategies for targeted quantitation, we expect an increasing role of MS as an analytical tool for ensuring regulatory compliance.
Blocking Notch signal in myeloid cells alleviates hepatic ischemia reperfusion injury by repressing the activation of NF-κB through CYLD
Authors: Yu Heng-Chao , Bai Lu , Yang Zhao-Xu , Qin Hong-Yan , Tao Kai-Shan , Han Hua , Dou Ke-Feng 
Published: September 2016

AbstractIschemia-reperfusion (I/R) is a major reason of hepatocyte injury during liver surgery and transplantation. Myeloid cells including macrophages and neutrophils play important roles in sustained tissue inflammation and damage, but the mechanisms regulating myeloid cells activity have been elusive. In this study, we investigate the role of Notch signaling in myeloid cells during hepatic I/R injury by using a mouse model of myeloid specific conditional knockout of RBP-J. Myeloid-specific RBP-J deletion alleviated hepatic I/R injury. RBP-J deletion in myeloid cells decreased hepatocytes apoptosis after hepatic I/R injury. Furthermore, myeloid-specific RBP-J deletion led to attenuated inflammation response in liver after I/R injury. Consistently, Notch blockade reduced the production of inflammatory cytokines by macrophages in vitro. We also found that blocking Notch signaling reduced NF-κB activation and increased cylindromatosis (CYLD) expression and knockdown of CYLD rescued reduction of inflammatory cytokines induced by Notch blockade in macrophages during I/R injury in vitro. On the other hand, activation of Notch signaling in macrophages led to increased inflammatory cytokine production and NF-κB activation and decreased CYLD expression in vitro. These data suggest that activation of Notch signaling in myeloid cells aggravates I/R injury, by enhancing the inflammation response by NF-κB through down regulation of CYLD.
Transcriptome landscape of perennial wild Cicer microphyllum uncovers functionally relevant molecular tags regulating agronomic traits in chickpea
Authors: Srivastava Rishi , Bajaj Deepak , Malik Ayushi , Singh Mohar , Parida Swarup K. 
Published: September 2016

AbstractThe RNA-sequencing followed by de-novo transcriptome assembly identified 11621 genes differentially xpressed in roots vs. shoots of a wild perennial Cicer microphyllum. Comparative analysis of transcriptomes between microphyllum and cultivated desi cv. ICC4958 detected 12772 including 3242 root- and 1639 shoot-specific microphyllum genes with 85% expression validation success rate. Transcriptional reprogramming of microphyllum root-specific genes implicates their possible role in regulating differential natural adaptive characteristics between wild and cultivated chickpea. The transcript-derived 5698 including 282 in-silico polymorphic SSR and 127038 SNP markers annotated at a genome-wide scale exhibited high amplification and polymorphic potential among cultivated (desi and kabuli) and wild accessions suggesting their utility in chickpea genomics-assisted breeding applications. The functional significance of markers was assessed based on their localization in non-synonymous coding and regulatory regions of microphyllum root-specific genes differentially expressed predominantly in ICC 4958 roots under drought stress. A high-density 490 genic SSR- and SNP markers-anchored genetic linkage map identified six major QTLs regulating drought tolerance-related traits, yield per plant and harvest-index in chickpea. The integration of high-resolution QTL mapping with comparative transcriptome profiling delineated five microphyllum root-specific genes with non-synonymous and regulatory SNPs governing drought-responsive yield traits. Multiple potential key regulators and functionally relevant molecular tags delineated can drive translational research and drought tolerance-mediated chickpea genetic enhancement.
Metabolic profile and safety of piperlongumine
Authors: de Lima Moreira Fernanda , Habenschus Maísa D. , Barth Thiago , Marques Lucas M. M. , Pilon Alan Cesar , da Silva Bolzani Vanderlan , Vessecchi Ricardo , Lopes Norberto P. , de Oliveira Anderson R. M. 
Published: September 2016

AbstractPiperlongumine (PPL), a natural plant product, has been extensively studied in cancer treatment going up on clinical trials. Since the first report related to its use on cancer research (in 2011) around 80 papers have been published in less than 10 years, but a gap still remaining. There are no metabolism studies of PPL in human organism. For the lack of a better view, here, the CYP450 in vitro oxidation of PPL was described for the first time. In addition, the enzymatic kinetic data, the predicted in vivo parameters, the produced metabolites, the phenotyping study and possible piperlongumine-drug interactions in vivo is presented.
Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy
Authors: Sakellariou Giorgos K. , Pearson Timothy , Lightfoot Adam P. , Nye Gareth A. , Wells Nicola , Giakoumaki Ifigeneia I. , Vasilaki Aphrodite , Griffiths Richard D. , Jackson Malcolm J. , McArdle Anne 
Published: September 2016

AbstractAge-related loss of skeletal muscle mass and function is a major contributor to morbidity and has a profound effect on the quality of life of older people. The potential role of age-dependent mitochondrial dysfunction and cumulative oxidative stress as the underlying cause of muscle aging remains a controversial topic. Here we show that the pharmacological attenuation of age-related mitochondrial redox changes in muscle with SS31 is associated with some improvements in oxidative damage and mitophagy in muscles of old mice. However, this treatment failed to rescue the age-related muscle fiber atrophy associated with muscle atrophy and weakness. Collectively, these data imply that the muscle mitochondrial redox environment is not a key regulator of muscle fiber atrophy during sarcopenia but may play a key role in the decline of mitochondrial organelle integrity that occurs with muscle aging.
Landscape-scale spatial heterogeneity in phytodetrital cover and megafauna biomass in the abyss links to modest topographic variation
Authors: Morris Kirsty J. , Bett Brian J. , Durden Jennifer M. , Benoist Noelie M. A. , Huvenne Veerle A. I. , Jones Daniel O. B. , Robert Katleen , Ichino Matteo C. , Wolff George A. , Ruhl Henry A. 
Published: September 2016

AbstractSinking particulate organic matter (POM, phytodetritus) is the principal limiting resource for deep-sea life. However, little is known about spatial variation in POM supply to the abyssal seafloor, which is frequently assumed to be homogenous. In reality, the abyss has a highly complex landscape with millions of hills and mountains. Here, we show a significant increase in seabed POM % cover (by ~1.05 times), and a large significant increase in megafauna biomass (by ~2.5 times), on abyssal hill terrain in comparison to the surrounding plain. These differences are substantially greater than predicted by current models linking water depth to POM supply or benthic biomass. Our observed variations in POM % cover (phytodetritus), megafauna biomass, sediment total organic carbon and total nitrogen, sedimentology, and benthic boundary layer turbidity, all appear to be consistent with topographically enhanced current speeds driving these enhancements. The effects are detectable with bathymetric elevations of only 10 s of metres above the surrounding plain. These results imply considerable unquantified heterogeneity in global ecology.
Regulation of aPKC activity by Nup358 dependent SUMO modification
Authors: Yadav Santosh Kumar , Magre Indrasen , Singh Aditi , Khuperkar Deepak , Joseph Jomon 
Published: September 2016

AbstractAtypical PKC (aPKC) family members are involved in regulation of diverse cellular processes, including cell polarization. aPKCs are known to be activated by phosphorylation of specific threonine residues in the activation loop and turn motif. They can also be stimulated by interaction with Cdc42~GTP-Par6 complex. Here we report that PKCζ, a member of the aPKC family, is activated by SUMOylation. We show that aPKC is endogenously modified by SUMO1 and the nucleoporin Nup358 acts as its SUMO E3 ligase. Results from in vitro SUMOylation and kinase assays showed that the modification enhances the kinase activity of PKCζ by ~10-fold. By monitoring the phosphorylation of Lethal giant larvae (Lgl), a downstream target of aPKC, we confirmed these findings in vivo. Consistent with the function of Nup358 as a SUMO E3 ligase for aPKC, depletion of Nup358 attenuated the extent of SUMOylation and the activity of aPKC. Moreover, overexpression of the C-terminal fragment of Nup358 that possesses the E3 ligase activity enhanced SUMOylation of endogenous aPKC and its kinase activity. Collectively, our studies reveal a role for Nup358-dependent SUMOylation in the regulation of aPKC activity and provide a framework for understanding the role of Nup358 in cell polarity.
Photonic Crystal Microchip Laser
Authors: Gailevicius Darius , Koliadenko Volodymyr , Purlys Vytautas , Peckus Martynas , Taranenko Victor , Staliunas Kestutis 
Published: September 2016

AbstractThe microchip lasers, being very compact and efficient sources of coherent light, suffer from one serious drawback: low spatial quality of the beam strongly reducing the brightness of emitted radiation. Attempts to improve the beam quality, such as pump-beam guiding, external feedback, either strongly reduce the emission power, or drastically increase the size and complexity of the lasers. Here it is proposed that specially designed photonic crystal in the cavity of a microchip laser, can significantly improve the beam quality. Experiments show that a microchip laser, due to spatial filtering functionality of intracavity photonic crystal, improves the beam quality factor M2 reducing it by a factor of 2 and increase the brightness of radiation by a factor of 3. This comprises a new kind of laser, the “photonic crystal microchip laser”, a very compact and efficient light source emitting high spatial quality high brightness radiation.
Molecular bases of K+ secretory cells in the inner ear: shared and distinct features between birds and mammals
Authors: Wilms Viviane , Köppl Christine , Söffgen Chris , Hartmann Anna-Maria , Nothwang Hans Gerd 
Published: September 2016

AbstractIn the cochlea, mammals maintain a uniquely high endolymphatic potential (EP), which is not observed in other vertebrate groups. However, a high [K+] is always present in the inner ear endolymph. Here, we show that Kir4.1, which is required in the mammalian stria vascularis to generate the highly positive EP, is absent in the functionally equivalent avian tegmentum vasculosum. In contrast, the molecular repertoire required for K+ secretion, specifically NKCC1, KCNQ1, KCNE1, BSND and CLC-K, is shared between the tegmentum vasculosum, the vestibular dark cells and the marginal cells of the stria vascularis. We further show that in barn owls, the tegmentum vasculosum is enlarged and a higher EP (~+34 mV) maintained, compared to other birds. Our data suggest that both the tegmentum vasculosum and the stratified stria vascularis evolved from an ancestral vestibular epithelium that already featured the major cell types of the auditory epithelia. Genetic recruitment of Kir4.1 specifically to strial melanocytes was then a crucial step in mammalian evolution enabling an increase in the cochlear EP. An increased EP may be related to high-frequency hearing, as this is a hallmark of barn owls among birds and mammals among amniotes.
TRPM7-like channels are functionally expressed in oocytes and modulate post-fertilization embryo development in mouse
Authors: Carvacho Ingrid , Ardestani Goli , Lee Hoi Chang , McGarvey Kaitlyn , Fissore Rafael A. , Lykke-Hartmann Karin 
Published: September 2016

AbstractThe Transient Receptor Potential (TRP) channels are a family of cationic ion channels widely distributed in mammalian tissues. In general, the global genetic disruption of individual TRP channels result in phenotypes associated with impairment of a particular tissue and/or organ function. An exception is the genetic ablation of the TRP channel TRPM7, which results in early embryonic lethality. Nevertheless, the function of TRPM7 in oocytes, eggs and pre-implantation embryos remains unknown. Here, we described an outward rectifying non-selective current mediated by a TRP ion channel in immature oocytes (germinal vesicle stage), matured oocytes (metaphase II eggs) and 2-cell stage embryos. The current is activated by specific agonists and inhibited by distinct blockers consistent with the functional expression of TRPM7 channels. We demonstrated that the TRPM7-like channels are homo-tetramers and their activation mediates calcium influx in oocytes and eggs, which is fundamental to support fertilization and egg activation. Lastly, we showed that pharmacological inhibition of the channel function delays pre-implantation embryo development and reduces progression to the blastocyst stage. Our data demonstrate functional expression of TRPM7-like channels in mouse oocytes, eggs and embryos that may play an essential role in the initiation of embryo development.