bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
Authors: Wang Y , Rao W , Zhang C , Zhang C , Liu M-d , Han F , Yao L-b , Han H , Luo P , Su N , Fei Z 
Published: August 2015

AbstractExcessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca2+ influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a−/−) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a+/+). Additionally, Homer1a overexpression in the cortex of Homer1a−/− mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs.
Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer
Authors: Sette G , Salvati V , Mottolese M , Visca P , Gallo E , Fecchi K , Pilozzi E , Duranti E , Policicchio E , Tartaglia M , Milella M , De Maria R , Eramo A 
Published: August 2015

AbstractTyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.
Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification
Authors: te Raa G D , Moerland P D , Leeksma A C , Derks I A , Yigittop H , Laddach N , Loden-van Straaten M , Navrkalova V , Trbusek M , Luijks D M , Zenz T , Skowronska A , Hoogendoorn M , Stankovic T , van Oers M H , Eldering E , Kater A P 
Published: August 2015

AbstractThe ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53versusATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL.
Destructive tsunami-like wave generated by surf beat over a coral reef during Typhoon Haiyan
Authors: Roeber Volker , Bricker Jeremy D. 
Published: August 2015

AbstractStorm surges cause coastal inundation due to setup of the water surface resulting from atmospheric pressure, surface winds and breaking waves. Here we show that during Typhoon Haiyan, the setup generated by breaking waves near the fringing-reef-protected town of Hernani, the Philippines, oscillated with the incidence of large and small wave groups, and steepened into a tsunami-like wave that caused extensive damage and casualties. Though fringing reefs usually protect coastal communities from moderate storms, they can exacerbate flooding during strong events with energetic waves. Typical for reef-type bathymetries, a very short wave-breaking zone over the steep reef face facilitates the freeing of infragravity-period fluctuations (surf beat) with little energy loss. Since coastal flood planning relies on phase-averaged wave modelling, infragravity surges are not being accounted for. This highlights the necessity for a policy change and the adoption of phase-resolving wave models for hazard assessment in regions with fringing reefs.
Design of a platform technology for systemic delivery of siRNA to tumours using rolling circle transcription
Authors: Jang Mihue , Kim Jong Hwan , Nam Hae Yun , Kwon Ick Chan , Ahn Hyung Jun 
Published: August 2015

AbstractFor therapeutic applications of siRNA, there are technical challenges with respect to targeted and systemic delivery. We here report a new siRNA carrier, RNAtr NPs, in a way that multiple tandem copies of RNA hairpins as a result of rolling circle transcription (RCT) can be readily adapted in tumour-targeted and systemic siRNA delivery. RNAtr NPs provide a means of condensing large amounts of multimeric RNA transcripts into the compact nanoparticles, especially without the aid of polycationic agents, and thus reduce the risk of immunogenicity and cytotoxicity by avoiding the use of synthetic polycationic reagents. This strategy allows the design of a platform technology for systemic delivery of siRNA to tumour sites, because RCT reaction, which enzymatically generates RNA polymers in multiple copy numbers at low cost, can lead to directly accessible routes to targeted and systemic delivery. Therefore, RNAtr NPs suggest great potentials as the siRNA therapeutics for cancer treatment.
Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant
Authors: Yuchi Zhiguang , Yuen Siobhan M. Wong King , Lau Kelvin , Underhill Ainsley Q. , Cornea Razvan L. , Fessenden James D. , Van Petegem Filip 
Published: August 2015

AbstractRyanodine receptors (RyRs) form calcium release channels located in the membranes of the sarcoplasmic and endoplasmic reticulum. RyRs play a major role in excitation-contraction coupling and other Ca2+-dependent signalling events, and consist of several globular domains that together form a large assembly. Here we describe the crystal structures of the SPRY1 and tandem-repeat domains at 1.2–1.5 Å resolution, which reveal several structural elements not detected in recent cryo-EM reconstructions of RyRs. The cryo-EM studies disagree on the position of SPRY domains, which had been proposed based on homology modelling. Computational docking of the crystal structures, combined with FRET studies, show that the SPRY1 domain is located next to FK506-binding protein (FKBP). Molecular dynamics flexible fitting and mutagenesis experiments suggest a hydrophobic cluster within SPRY1 that is crucial for FKBP binding. A RyR1 disease mutation, N760D, appears to directly impact FKBP binding through interfering with SPRY1 folding.
MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation
Authors: Pon Julia R. , Wong Jackson , Saberi Saeed , Alder Olivia , Moksa Michelle , Grace Cheng S. -W. , Morin Gregg B. , Hoodless Pamela A. , Hirst Martin , Marra Marco A. 
Published: August 2015

AbstractMyocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial–mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its’ effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis.
Structural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity
Authors: Winkelmann Donald A. , Forgacs Eva , Miller Matthew T. , Stock Ann M. 
Published: August 2015

AbstractOmecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human β-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the β-sheet that provides the communication link between the actin-binding interface and the nucleotide pocket. The OM-binding interactions and allosteric changes form the structural basis for the kinetic and mechanical tuning of cardiac myosin.
Museum samples reveal rapid evolution by wild honey bees exposed to a novel parasite
Authors: Mikheyev Alexander S. , Tin Mandy M. Y. , Arora Jatin , Seeley Thomas D. 
Published: August 2015

AbstractUnderstanding genetic changes caused by novel pathogens and parasites can reveal mechanisms of adaptation and genetic robustness. Using whole-genome sequencing of museum and modern specimens, we describe the genomic changes in a wild population of honey bees in North America following the introduction of the ectoparasitic mite,Varroa destructor. Even though colony density in the study population is the same today as in the past, a major loss of haplotypic diversity occurred, indicative of a drastic mitochondrial bottleneck, caused by massive colony mortality. In contrast, nuclear genetic diversity did not change, though hundreds of genes show signs of selection. The genetic diversity within each bee colony, particularly as a consequence of polyandry by queens, may enable preservation of genetic diversity even during population bottlenecks. These findings suggest that genetically diverse honey bee populations can recover from introduced diseases by evolving rapid tolerance, while maintaining much of the standing genetic variation.
Gram-scale synthesis of coordination polymer nanodots with renal clearance properties for cancer theranostic applications
Authors: Liu Fuyao , He Xiuxia , Chen Hongda , Zhang Junping , Zhang Huimao , Wang Zhenxin 
Published: August 2015

AbstractAn ultrasmall hydrodynamic diameter is a critical factor for the renal clearance of nanoparticles from the body within a reasonable timescale. However, the integration of diagnostic and therapeutic components into a single ultrasmall nanoparticle remains challenging. In this study, pH-activated nanodots (termed Fe-CPNDs) composed of coordination polymers were synthesized via a simple and scalable method based on coordination reactions among Fe3+, gallic acid and poly(vinylpyrrolidone) at ambient conditions. The Fe-CPNDs exhibited ultrasmall (5.3 nm) hydrodynamic diameters and electrically neutral surfaces. The Fe-CPNDs also exhibited pH-activatable magnetic resonance imaging contrast and outstanding photothermal performance. The features of Fe-CPNDs greatly increased the tumour-imaging sensitivity and facilitated renal clearance after injection in animal models in vivo. Magnetic resonance imaging-guided photothermal therapy using Fe-CPNDs completely suppressed tumour growth. These findings demonstrate that Fe-CPNDs constitute a new class of renal clearable nanomedicine for photothermal therapy and molecular imaging.
The burden of ambient temperature on years of life lost in Guangzhou, China
Authors: Yang Jun , Ou Chun-Quan , Guo Yuming , Li Li , Guo Cui , Chen Ping-Yan , Lin Hua-Liang , Liu Qi-Yong 
Published: August 2015

AbstractLimited evidence is available on the association between temperature and years of life lost (YLL). We applied distributed lag non-linear model to assess the nonlinear and delayed effects of temperature on YLL due to cause-/age-/education-specific mortality in Guangzhou, China. We found that hot effects appeared immediately, while cold effects were more delayed and lasted for 14 days. On average, 1 °C decrease from 25th to 1st percentile of temperature was associated with an increase of 31.15 (95%CI: 20.57, 41.74), 12.86 (8.05, 17.68) and 6.64 (3.68, 9.61) YLL along lag 0–14 days for non-accidental, cardiovascular and respiratory diseases, respectively. The corresponding estimate of cumulative hot effects (1 °C increase from 75th to 99th percentile of temperature) was 12.71 (−2.80, 28.23), 4.81 (−2.25, 11.88) and 2.81 (−1.54, 7.16). Effect estimates of cold and hot temperatures-related YLL were higher in people aged up to 75 years and persons with low education level than the elderly and those with high education level, respectively. The mortality risks associated with cold and hot temperatures were greater on the elderly and persons with low education level. This study highlights that YLL provides a complementary method for assessing the death burden of temperature.
Critical anatomic region of nasopalatine canal based on tridimensional analysis: cone beam computed tomography
Authors: Fernández-Alonso Ana , Antonio Suárez-Quintanilla Juan , Muinelo-Lorenzo Juan , Varela-Mallou Jesús , Smyth Chamosa Ernesto , Mercedes Suárez-Cunqueiro María 
Published: August 2015

AbstractThe study aim of this was to define the critical anatomic region of the premaxilla by evaluating dimensions of nasopalatine canal, buccal bone plate (BBP) and palatal bone plate (PBP). 230 CBCTs were selected with both, one or no upper central incisors present (+/+, −/+, −/−) and periodontal condition was evaluated. T-student test, ANOVA, Pearson´s correlation and a multivariant-linear regression model (MLRM) were used. Regarding gender, significant differences at level 1 (lower NC) were found for: buccal-palatal, transversal and sagittal NC diameters and NC length (NCL). Regarding dental status, significant differences were found for: total BBP length (tBL) and PBP width (PW2) at level 2 (NCL midpoint). NCL was correlated with PW2, tBL and PBP length at level 3 (foramina of Stenson level). An MLRM had a high prediction value for NCL (69.3%). Gender is related to NC dimensions. Dental status has an influence on BBP dimensions, but does not influence on NC and PBP. Periodontal condition should be evaluated for precise premaxillae analysis NC diameters at the three anatomical planes are related to each other, while NCL is related to BBP and PBP lengths. A third of premaxilla is taken up by NC, thus, establishing the critical anatomic region.
Tumor necrosis factor (TNF)-receptor 1 and 2 mediate homeostatic synaptic plasticity of denervated mouse dentate granule cells
Authors: Becker Denise , Deller Thomas , Vlachos Andreas 
Published: August 2015

AbstractNeurological diseases are often accompanied by neuronal cell death and subsequent deafferentation of connected brain regions. To study functional changes after denervation we generated entorhino-hippocampal slice cultures, transected the entorhinal pathway and denervated dentate granule cells in vitro. Our previous work revealed that partially denervated neurons respond to the loss of input with a compensatory, i.e., homeostatic, increase in their excitatory synaptic strength. TNFα maintains this denervation-induced homeostatic strengthening of excitatory synapses. Here, we used pharmacological approaches and mouse genetics to assess the role of TNF-receptor 1 and 2 in lesion-induced excitatory synaptic strengthening. Our experiments disclose that both TNF-receptors are involved in the regulation of denervation-induced synaptic plasticity. In line with this result TNF-receptor 1 and 2 mRNA-levels were upregulated after deafferentation in vitro. These findings implicate TNF-receptor signaling cascades in the regulation of homeostatic plasticity of denervated networks and suggest an important role for TNFα-signaling in the course of neurological diseases accompanied by deafferentation.
Latency of auditory evoked potential monitoring the effects of general anesthetics on nerve fibers and synapses
Authors: Huang Bowan , Liang Feixue , Zhong Lei , Lin Minlin , Yang Juan , Yan Linqing , Xiao Jinfan , Xiao Zhongju 
Published: August 2015

AbstractAuditory evoked potential (AEP) is an effective index for the effects of general anesthetics. However, it’s unknown if AEP can differentiate the effects of general anesthetics on nerve fibers and synapses. Presently, we investigated AEP latency and amplitude changes to different acoustic intensities during pentobarbital anesthesia. Latency more regularly changed than amplitude during anesthesia. AEP Latency monotonically decreased with acoustic intensity increase (i.e., latency-intensity curve) and could be fitted to an exponential decay equation, which showed two components, the theoretical minimum latency and stimulus-dependent delay. From the latency-intensity curves, the changes of these two components (∆L and ∆I) were extracted during anesthesia. ∆L and ∆I monitored the effect of pentobarbital on nerve fibers and synapses. Pentobarbital can induce anesthesia and two side effects, hypoxemia and hypothermia. The hypoxemia was not related with ∆L and ∆I. However, ∆L was changed by the hypothermia, whereas ∆I was changed by the hypothermia and anesthesia. Therefore, we conclude that, AEP latency is superior to amplitude for the effects of general anesthetics, ∆L monitors the effect of hypothermia on nerve fibers and ∆I monitors a combined effect of anesthesia and hypothermia on synapses. When eliminating the temperature factor, ∆I monitors the anesthesia effect on synapses.
Highly Efficient Processing of Multi-photon States
Authors: Lin Qing , He Bing 
Published: August 2015

AbstractHow to implement multi-qubit gates is an important problem in quantum information processing. Based on cross phase modulation, we present an approach to realizing a family of multi-qubit gates that deterministically operate on single photons as the qubits. A general n-qubit unitary operation is a typical example of these gates. The approach greatly relax the requirement on the resources, such as the ancilla photons and coherent beams, as well as the number of operations on the qubits. The improvement in this framework may facilitate large scale quantum information processing.
Caustics and Rogue Waves in an Optical Sea
Authors: Mathis Amaury , Froehly Luc , Toenger Shanti , Dias Frédéric , Genty Goëry , Dudley John M. 
Published: August 2015

AbstractThere are many examples in physics of systems showing rogue wave behaviour, the generation of high amplitude events at low probability. Although initially studied in oceanography, rogue waves have now been seen in many other domains, with particular recent interest in optics. Although most studies in optics have focussed on how nonlinearity can drive rogue wave emergence, purely linear effects have also been shown to induce extreme wave amplitudes. In this paper, we report a detailed experimental study of linear rogue waves in an optical system, using a spatial light modulator to impose random phase structure on a coherent optical field. After free space propagation, different random intensity patterns are generated, including partially-developed speckle, a broadband caustic network and an intermediate pattern with characteristics of both speckle and caustic structures. Intensity peaks satisfying statistical criteria for rogue waves are seen especially in the case of the caustic network and are associated with broader spatial spectra. In addition, the electric field statistics of the intermediate pattern shows properties of an “optical sea” with near-Gaussian statistics in elevation amplitude and trough-to-crest statistics that are near-Rayleigh distributed but with an extended tail where a number of rogue wave events are observed.