bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction
Authors: Robin A Y , Krishna Kumar K , Westphal D , Wardak A Z , Thompson G V , Dewson G , Colman P M , Czabotar P E 
Published: July 2015

AbstractThe BH3-only protein Bim is a potent direct activator of the proapoptotic effector protein Bax, but the structural basis for its activity has remained poorly defined. Here we describe the crystal structure of the BimBH3 peptide bound to BaxΔC26 and structure-based mutagenesis studies. Similar to BidBH3, the BimBH3 peptide binds into the cognate surface groove of Bax using the conserved hydrophobic BH3 residues h1–h4. However, the structure and mutagenesis data show that Bim is less reliant compared with Bid on its ‘h0’ residues for activating Bax and that a single amino-acid difference between Bim and Bid encodes a fivefold difference in Bax-binding potency. Similar to the structures of BidBH3 and BaxBH3 bound to BaxΔC21, the structure of the BimBH3 complex with BaxΔC displays a cavity surrounded by Bax α1, α2, α5 and α8. Our results are consistent with a model in which binding of an activator BH3 domain to the Bax groove initiates separation of its core (α2–α5) and latch (α6–α8) domains, enabling its subsequent dimerisation and the permeabilisation of the mitochondrial outer membrane.
Loss of apoptosis-inducing factor critically affects MIA40 function
Authors: Meyer K , Buettner S , Ghezzi D , Zeviani M , Bano D , Nicotera P 
Published: July 2015

AbstractMitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in the AIFM1 gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities and progressive mitochondrial encephalomyopathies. In humans, rodents and invertebrates, AIF deficiency results in loss of respiratory complexes and, therefore, impaired OXPHOS. The molecular mechanisms underlying AIF-induced mitochondrial dysfunction remain elusive. Here we show that AIF physically interacts with the oxidoreductase CHCHD4/MIA40. In patient-derived fibroblasts as well as in tissues and glia cells from Harlequin (Hq) mutant mice, AIF deficiency correlates with decreased MIA40 protein levels, without affecting mRNA transcription. Importantly, MIA40 overexpression counteracts loss of respiratory subunits in Hq cells. Together, our findings suggest that MIA40 reduction contributes to the effects of AIF deficiency on OXPHOS, as it may impact on the correct assembly and maintenance of the respiratory subunits. This may be relevant for the development of new therapeutic approaches for AIF-related mitochondrial disorders.
miR-612 negatively regulates colorectal cancer growth and metastasis by targeting AKT2
Authors: Sheng L , He P , Yang X , Zhou M , Feng Q 
Published: July 2015

AbstractColorectal cancer (CRC) is one of the most common cancers worldwide, with a particularly high incidence in developed countries. Distant metastasis and recurrence are the main causes of CRC-related deaths. MicroRNAs (miRNAs) in the serum make them potential biomarkers for cancers, as reported in serum or tumor tissues from CRC patients. In this study, we found that miR-612 expression was significantly lower in CRC tissues or cells compared with peritumor tissues or normal cells, and lower in metastatic CRC specimens compared with non-metastatic specimens, whereas AKT2 exhibited opposite trend. Gain-of-function and loss-of-function assays showed that miR-612 inhibited CRC cell proliferation and migration in vitro by Cell Counting Kit-8 and transwell assays. Further analysis revealed that miR-612 directly suppressed AKT2, which in turn inhibited the downstream epithelial–mesenchymal transition-related signaling pathway. These results were additionally validated in vivo by tumorigenesis and liver metastasis experiments. The results of this study suggested a critical role of miR-612 in the development of CRC.
Genome-wide burden of deleterious coding variants increased in schizophrenia
Authors: Loohuis Loes M. Olde , Vorstman Jacob A. S. , Ori Anil P. , Staats Kim A. , Wang Tina , Richards Alexander L. , Leonenko Ganna , Walters James T. , DeYoung Joseph ,   GROUP consortium, Kahn René S. , Linszen Don , Os Jim van , Wiersma Durk , Bruggeman Richard , Cahn Wiepke , Haan Lieuwe de , Krabbendam Lydia , Myin-Germeys Inez , Cantor Rita M. , Ophoff Roel A. 
Published: July 2015

AbstractSchizophrenia is a common complex disorder with polygenic inheritance. Here we show that by using an approach that compares the individual loads of rare variants in 1,042 schizophrenia cases and 961 controls, schizophrenia cases carry an increased burden of deleterious mutations. At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥0.01% in the population. In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study. In addition, the genes implicated by the increased burden of rare coding variants highlight the involvement of neurodevelopment in the aetiology of schizophrenia.
Telomeric G-quadruplexes are a substrate and site of localization for human telomerase
Authors: Moye Aaron L. , Porter Karina C. , Cohen Scott B. , Phan Tram , Zyner Katherine G. , Sasaki Natsuki , Lovrecz George O. , Beck Jennifer L. , Bryan Tracy M. 
Published: July 2015

AbstractIt has been hypothesized that G-quadruplexes can sequester the 3′ end of the telomere and prevent it from being extended by telomerase. Here we purify and characterize stable, conformationally homogenous human telomeric G-quadruplexes, and demonstrate that human telomerase is able to extend parallel, intermolecular conformations in vitro. These G-quadruplexes align correctly with the RNA template of telomerase, demonstrating that at least partial G-quadruplex resolution is required. A highly purified preparation of human telomerase retains this extension ability, establishing that the core telomerase enzyme complex is sufficient for partial G-quadruplex resolution and extension. The parallel-specific G-quadruplex ligand N-methyl mesoporphyrin IX (NMM) causes an increase in telomeric G-quadruplexes, and we show that telomerase colocalizes with a subset of telomeric G-quadruplexes in vivo. The ability of telomerase to partially unwind, extend and localize to these structures implies that parallel telomeric G-quadruplexes may play an important biological role.
TD-60 links RalA GTPase function to the CPC in mitosis
Authors: Papini Diana , Langemeyer Lars , Abad Maria A. , Kerr Alastair , Samejima Itaru , Eyers Patrick A. , Jeyaprakash A. Arockia , Higgins Jonathan M. G. , Barr Francis A. , Earnshaw William C. 
Published: July 2015

AbstractTD-60 (also known as RCC2) is a highly conserved protein that structurally resembles the Ran guanine exchange factor (GEF) RCC1, but has not previously been shown to have GEF activity. TD-60 has a typical chromosomal passenger complex (CPC) distribution in mitotic cells, but associates with integrin complexes and is involved in cell motility during interphase. Here we show that TD-60 exhibits GEF activity, in vitro and in cells, for the small GTPase RalA. TD-60 or RalA depletion causes spindle abnormalities in prometaphase associated with abnormal centromeric accumulation of CPC components. TD-60 and RalA apparently work together to contribute to the regulation of kinetochore–microtubule interactions in early mitosis. Importantly, several mitotic phenotypes caused by TD-60 depletion are reverted by the expression of a GTP-locked mutant, RalA (Q72L). The demonstration that a small GTPase participates in the regulation of the CPC reveals a level of mitotic regulation not suspected in previous studies.
Two routes to senescence revealed by real-time analysis of telomerase-negative single lineages
Authors: Xu Zhou , Fallet Emilie , Paoletti Camille , Fehrmann Steffen , Charvin Gilles , Teixeira Maria Teresa 
Published: July 2015

AbstractIn eukaryotes, telomeres cap chromosome ends to maintain genomic stability. Failure to maintain telomeres leads to their progressive erosion and eventually triggers replicative senescence, a pathway that protects against unrestricted cell proliferation. However, the mechanisms underlying the variability and dynamics of this pathway are still elusive. Here we use a microfluidics-based live-cell imaging assay to investigate replicative senescence in individual Saccharomyces cerevisiae cell lineages following telomerase inactivation. We characterize two mechanistically distinct routes to senescence. Most lineages undergo an abrupt and irreversible switch from a replicative to an arrested state, consistent with telomeres reaching a critically short length. In contrast, other lineages experience frequent and stochastic reversible arrests, consistent with the repair of accidental telomere damage by Pol32, a subunit of polymerase δ required for break-induced replication and for post-senescence survival. Thus, at the single-cell level, replicative senescence comprises both deterministic cell fates and chaotic cell division dynamics.
The range and nature of non-motor symptoms in drug-naive Parkinson’s disease patients: a state-of-the-art systematic review
Authors: Zis Panagiotis , Erro Roberto , Walton Courtney C , Sauerbier Anna , Chaudhuri Kallol Ray 
Published: July 2015

AbstractNon-motor symptoms (NMS) are a key component of Parkinson’s disease (PD). A range of NMS, most notably impaired sense of smell, sleep dysfunction, and dysautonomia are present from the ‘pre-motor’ phase to the final palliative stage. Theories as to the pathogenesis of PD such as those proposed by Braak and others also support the occurrence of NMS in PD years before motor symptoms start. However, research addressing the range and nature of NMS in PD has been confounded by the fact that many NMS arise as part of drug-related side effects. Thus, drug-naive PD (DNPD) patients provide an ideal population to study the differences in the presentation of NMS. The aim of this paper is therefore to systematically review all the available studies of NMS in DNPD patients. We believe this is the first review of its kind. The current review confirms the increasing research being conducted into NMS in DNPD patients as well as the necessity for further investigation into less-studied NMS, such as pain. Moreover, the data confirms non-motor heterogeneity among PD patients, and, therefore, further research into the concept of non-motor subtyping is encouraged. The review suggests that the clinical assessment of NMS should be integral to any assessment of PD in clinical and research settings.
Suggestions for health information technology trials for respiratory disorders in low- and middle-income country settings: what can we learn from trials in high-income country settings?
Authors: Chavannes Niels H , Du Puy Robert S , Bai Chunxue 
Published: July 2015

AbstractHealth Information Technology (HIT) is sometimes seen as a silver bullet for human resource, medical and economic challenges facing health systems. The evidence supporting widespread use of HIT is, however, still patchy and inconsistent. In this Perspective piece, we seek to interpret and draw key lessons from a selection of illustrative trials in developed countries with robust health-care settings in respiratory medicine that failed to demonstrate effectiveness, and offer suggestions to maximise the chances of success in subsequent HIT deployments. Particularly low- and middle-income countries, with relatively weak health infrastructures and limited health care, propose considerable room for improvement. Early experiences of studying HIT thus far in high-income country settings suggest that this process should preferably begin with trials of low-cost, well-established technologies in patient groups with a moderate burden of disease while carefully evaluating patient safety.
Agriculture intensifies soil moisture decline in Northern China
Authors: Liu Yaling , Pan Zhihua , Zhuang Qianlai , Miralles Diego G. , Teuling Adriaan J. , Zhang Tonglin , An Pingli , Dong Zhiqiang , Zhang Jingting , He Di , Wang Liwei , Pan Xuebiao , Bai Wei , Niyogi Dev 
Published: July 2015

AbstractNorthern China is one of the most densely populated regions in the world. Agricultural activities have intensified since the 1980s to provide food security to the country. However, this intensification has likely contributed to an increasing scarcity in water resources, which may in turn be endangering food security. Based onin-situmeasurements of soil moisture collected in agricultural plots during 1983–2012, we find that topsoil (0–50 cm) volumetric water content during the growing season has declined significantly (p < 0.01), with a trend of −0.011 to −0.015 m3m−3per decade. Observed discharge declines for the three large river basins are consistent with the effects of agricultural intensification, although other factors (e.g. dam constructions) likely have contributed to these trends. Practices like fertilizer application have favoured biomass growth and increased transpiration rates, thus reducing available soil water. In addition, the rapid proliferation of water-expensive crops (e.g., maize) and the expansion of the area dedicated to food production have also contributed to soil drying. Adoption of alternative agricultural practices that can meet the immediate food demand without compromising future water resources seem critical for the sustainability of the food production system.
China’s rising hydropower demand challenges water sector
Authors: Liu Junguo , Zhao Dandan , Gerbens-Leenes P. W. , Guan Dabo 
Published: July 2015

AbstractDemand for hydropower is increasing, yet the water footprints (WFs) of reservoirs and hydropower and their contributions to water scarcity, are poorly understood. Here, we calculate reservoir WFs (freshwater that evaporates from reservoirs) and hydropower WFs (the WF of hydroelectricity) in China based on data from 875 representative reservoirs (209 with power plants). In 2010, the reservoir WF totaled 27.9 × 109 m3 (Gm3), or 22% of China’s total water consumption. Ignoring the reservoir WF seriously underestimates human water appropriation. The reservoir WF associated with industrial, domestic and agricultural WFs caused water scarcity in 6 of the 10 major Chinese river basins from 2 to 12 months annually. The hydropower WF was 6.6 Gm3 yr−1 or 3.6 m3 of water to produce a GJ (109 J) of electricity. Hydropower is a water intensive energy carrier. As a response to global climate change, the Chinese government has promoted a further increase in hydropower energy by 70% by 2020 compared to 2012. This energy policy imposes pressure on available freshwater resources and increases water scarcity. The water-energy nexus requires strategic and coordinated implementations of hydropower development among geographical regions, as well as trade-off analysis between rising energy demand and water use sustainability.
Wedge hybrid plasmonic THz waveguide with long propagation length and ultra-small deep-subwavelength mode area
Authors: Gui Chengcheng , Wang Jian 
Published: July 2015

AbstractWe present a novel design of wedge hybrid plasmonic terahertz (THz) waveguide consisting of a silicon (Si) nanowire cylinder above a triangular gold wedge with surrounded high-density polyethylene as cladding. It features long propagation length and ultra-small deep-subwavelength mode confinement. The mode properties of wedge hybrid plasmonic THz waveguide are comprehensively characterized in terms of propagation length (L), normalized mode area (Aeff /A0), figure of merit (FoM) and chromatic dispersion (D). The designed wedge hybrid plasmonic THz waveguide enables an ultra-small deep-subwavelength mode area which is more than one-order of magnitude smaller compared to previous rectangular one. When choosing the diameter of Si nanowire cylinder, a smaller diameter (e.g. 10 μm) is preferred to achieve longer L and higher FoM, while a larger diameter (e.g. 60 μm) is favorable to obtain smaller Aeff /A0 and higher FoM. We further study the impacts of possible practical fabrication errors on the mode properties. The simulated results of propagation length and normalized mode area show that the proposed wedge hybrid plasmonic THz waveguide is tolerant to practical fabrication errors in geometry parameters such as misalignment in the horizontal direction, variation of wedge tip angle and variation of wedge tip curvature radius.
CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells
Authors: Han Jianfeng , Chu Jianhong , Keung Chan Wing , Zhang Jianying , Wang Youwei , Cohen Justus B. , Victor Aaron , Meisen Walter H. , Kim Sung-hak , Grandi Paola , Wang Qi-En , He Xiaoming , Nakano Ichiro , Chiocca E. Antonio , Glorioso III Joseph C. , Kaur Balveen , Caligiuri Michael A. , Yu Jianhua 
Published: July 2015

AbstractGlioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.
Galangin attenuates airway remodelling by inhibiting TGF-β1-mediated ROS generation and MAPK/Akt phosphorylation in asthma
Authors: Liu Ya-Nan , Zha Wang-Jian , Ma Yuan , Chen Fei-Fei , Zhu Wen , Ge Ai , Zeng Xiao-Ning , Huang Mao 
Published: July 2015

AbstractGalangin, a natural flavonol, has attracted much attention for its potential anti-inflammatory properties. However, its role in the regulation of airway remodelling in asthma has not been explored. The present study aimed to elucidate the effects of galangin on chronic inflammation and airway remodelling and to investigate the underlying mechanisms both in vivo and in vitro. Ovalbumin (OVA)-sensitised mice were administered with galangin 30 min before challenge. Our results showed that severe inflammatory responses and airway remodelling occurred in OVA-induced mice. Treatment with galangin markedly attenuated the leakage of inflammatory cells into bronchoalveolar lavage fluid (BALF) and decreased the level of OVA-specific IgE in serum. Galangin significantly inhibited goblet cell hyperplasia, collagen deposition and α-SMA expression. Lowered level of TGF-β1 and suppressed expression of VEGF and MMP-9 were observed in BALF or lung tissue, implying that galangin has an optimal anti-remodelling effect in vivo. Consistently, the TGF-β1-induced proliferation of airway smooth muscle cells was reduced by galangin in vitro, which might be due to the alleviation of ROS levels and inhibition of MAPK pathway. Taken together, the present findings highlight a novel role for galangin as a promising anti-remodelling agent in asthma, which likely involves the TGF-β1-ROS-MAPK pathway.
Regulation of mTOR Signaling by Semaphorin 3F-Neuropilin 2 Interactions In Vitro and In Vivo
Authors: Nakayama Hironao , Bruneau Sarah , Kochupurakkal Nora , Coma Silvia , Briscoe David M. , Klagsbrun Michael 
Published: July 2015

AbstractSemaphorin 3F (SEMA3F) provides neuronal guidance cues via its ability to bind neuropilin 2 (NRP2) and Plexin A family molecules. Recent studies indicate that SEMA3F has biological effects in other cell types, however its mechanism(s) of function is poorly understood. Here, we analyze SEMA3F-NRP2 signaling responses in human endothelial, T cell and tumor cells using phosphokinase arrays, immunoprecipitation and Western blot analyses. Consistently, SEMA3F inhibits PI-3K and Akt activity and responses are associated with the disruption of mTOR/rictor assembly and mTOR-dependent activation of the RhoA GTPase. We also find that the expression of vascular endothelial growth factor, as well as mTOR-inducible cellular activation responses and cytoskeleton stability are inhibited by SEMA3F-NRP2 interactions in vitro. In vivo, local and systemic overproduction of SEMA3F reduces tumor growth in NRP2-expressing xenografts. Taken together, SEMA3F regulates mTOR signaling in diverse human cell types, suggesting that it has broad therapeutic implications.
Building an organic computing device with multiple interconnected brains
Authors: Pais-Vieira Miguel , Chiuffa Gabriela , Lebedev Mikhail , Yadav Amol , Nicolelis Miguel A. L. 
Published: July 2015

AbstractRecently, we proposed that Brainets, i.e. networks formed by multiple animal brains, cooperating and exchanging information in real time through direct brain-to-brain interfaces, could provide the core of a new type of computing device: an organic computer. Here, we describe the first experimental demonstration of such a Brainet, built by interconnecting four adult rat brains. Brainets worked by concurrently recording the extracellular electrical activity generated by populations of cortical neurons distributed across multiple rats chronically implanted with multi-electrode arrays. Cortical neuronal activity was recorded and analyzed in real time and then delivered to the somatosensory cortices of other animals that participated in the Brainet using intracortical microstimulation (ICMS). Using this approach, different Brainet architectures solved a number of useful computational problems, such as discrete classification, image processing, storage and retrieval of tactile information and even weather forecasting. Brainets consistently performed at the same or higher levels than single rats in these tasks. Based on these findings, we propose that Brainets could be used to investigate animal social behaviors as well as a test bed for exploring the properties and potential applications of organic computers.