bluuebunny/crossref_metadata_2025 huggingface dataset:
The roles of prostaglandin F2 in regulating the expression of matrix metalloproteinase-12 via an insulin growth factor-2-dependent mechanism in sheared chondrocytes
Authors: Guan Pei-Pei , Ding Wei-Yan , Wang Pu
Published: October 2018

Osteoarthritis (OA) was recently identified as being regulated by the induction of cyclooxygenase-2 (COX-2) in response to high fluid shear stress. Although the metabolic products of COX-2, including prostaglandin (PG)E2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), and PGF2α, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2α in OA are largely overlooked. Thus, we showed that high fluid shear stress induced the mRNA expression of MMP-12 via cyclic (c)AMP- and PGF2α-dependent signaling pathways. Specifically, we found that high fluid shear stress (20 dyn/cm2) significantly increased the expression of MMP-12 at 6 h ( > fivefold), which then slightly decreased until 48 h ( > threefold). In addition, shear stress enhanced the rapid synthesis of PGE2 and PGF2α, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2α receptor (FPR)-, cAMP- and insulin growth factor-2 (IGF-2)-dependent phosphatidylinositide 3-kinase (PI3-K)/protein kinase B (AKT), c-Jun N-terminal kinase (JNK)/c-Jun, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-activating pathways. Prolonged shear stress induced the synthesis of 15d-PGJ2, which is responsible for suppressing the high levels of MMP-12 at 48 h. These in vitro observations were further validated by in vivo experiments to evaluate the mechanisms of MMP-12 upregulation during the onset of OA by high fluid shear stress. By delineating this signaling pathway, our data provide a targeted therapeutic basis for combating OA.
Influence of Dietary Restriction on Irritable Bowel Syndrome
Authors: Kamal Afrin , Pimentel Mark
Published: October 2018

Up to two-thirds of patients with IBS attribute their gastrointestinal symptoms to food. The therapeutic focus of IBS has been to alleviate gastrointestinal symptoms, approached by pharmaceutical and non-pharmaceutical treatments. Although the most traditional approach has involved the use of medications such as bulking agents, anticholinergics, antispasmodics, and antidiarrheals, unfortunately these are only modestly effective and patients are left with a small menu of successful pharmacologic agents. These treatments, however, are not always enough to alleviate symptoms. Alternative approaches have therefore been tried, including dietary manipulation. This article aims to review dietary restrictions as a non-pharmaceutical management approach for IBS, covering literature on various dietary triggers and the impact of dietary manipulation on gastrointestinal symptoms.
Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens
Authors: Liu Jinxu , Gandhi Pauravi J. , Pavuluri Ratnamala , Shelkar Gajanan P. , Dravid Shashank M.
Published: October 2018

Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel. Instead it serves a synaptogenic function by interacting with presynaptic Neurexin protein. Recent neuroanatomical studies have demonstrated enriched expression of GluD1 in the NAc but its role in reward behavior, MSN function, and drug-induced plasticity remains unknown. Using a combination of constitutive and conditional GluD1 KO models, we evaluated the effect of GluD1 ablation on cocaine-conditioned place preference (CPP) and cocaine-induced structural and functional plasticity. GluD1 KO mice showed higher cocaine CPP. Selective ablation of GluD1 from striatal neurons but not cortico-limbic excitatory neurons reproduced higher CPP. Higher cocaine preference in GluD1 KO correlated with an increase in spine density, greater maturation of dendritic spines, and basally upregulated spine-regulating active cofilin. GluD1 loss did not affect basal excitatory neurotransmission or plasticity but masked the generation of cocaine-induced silent synapses. Finally, loss of GluD1 increased the GluN2B subunit contribution to NMDA receptor currents in MSNs and a partial agonist of GluN2B-containing NMDA receptors normalized the higher active cofilin and cocaine preference in GluD1 KO mice. Together, these findings demonstrate a critical role of GluD1 in controlling susceptibility to cocaine preference and cocaine-induced plasticity by modulating NMDA receptor subunit contribution.
MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway
Authors: Bao Jie , Yu Yan , Chen Jianan , He Yuting , Chen Xiaolong , Ren Zhigang , Xue Chen , Liu Liwen , Hu Qiuyue , Li Juan , Cui Guangying , Sun Ranran
Published: October 2018

Emerging evidence has shown that microRNA-126 (miR-126) is aberrantly downregulated and plays a vital role in carcinogenesis in various cancers, including HCC. However, the underlying biological mechanisms of miR-126 in HCC are still largely unknown. In present study, we found that miR-126 was downregulated both in HCC tissues and cell lines. Low expression level of miR-126 was associated with poor overall survival (OS), late TNM stage and the presence of recurrence. Overexpression of miR-126 significantly decreased cell proliferation, metastasis and promoted apoptosis in vitro. Additional, high miR-126 expression reduced the tumor growth in vivo. Further we discovered that PLK (polo-like kinases)-4, a critical regulator in cell cycle, was a target of miR-126. PLK-4 overexpression could rescue the inhibitory effects of miR-126 on cell proliferation and invasion. Moreover, PLK-4 mRNA and protein levels were significantly upregulated in HCC tissues and positively associated with malignancies and poor OS. Knockdown PLK-4 significantly inhibited cell proliferation, invasion and promoted cell apoptosis in vitro whereas decreased tumor growth in vivo. More importantly, bioinformatics analysis combined with validation experiments in vitro and in vivo showed that activation of the ATR/CHEK1 pathway was involved in the oncogenic functions of PLK4 in HCC. We also validated that PLK4 could directly interact with ATR through CoIP assay. Taken together, we demonstrate that miRNA-126/PLK-4 axis is critical for tumorigenesis and progression of HCC, and the newly identified PLK-4/ATR/CHEK1 pathway may be a potential therapeutic target for HCC treatment.
CIRBP is a novel oncogene in human bladder cancer inducing expression of HIF-1α
Authors: Lu Mengxin , Ge Qiangqiang , Wang Gang , Luo Yongwen , Wang Xiaolong , Jiang Wei , Liu Xuefeng , Wu Chin-Lee , Xiao Yu , Wang Xinghuan
Published: October 2018

Cold-inducible RNA binding protein (CIRBP) has been reported to be associated with distinct tumorigenesis. In this study, we investigated the role of CIRBP in human bladder cancer (BCa), indicating that CIRBP is overexpressed in BCa tissues and cell lines to promote proliferation and migration. Moreover, CIRBP could induce expression of HIF-1α via binding to the 3′-UTR of its mRNA to increase the mRNA stability in BCa cells. Furthermore, we demonstrated that PTGIS is a HIF-1α targeted gene, a major regulator in hypoxic cancer progression by activating transcription of various oncogenes. Our results also suggested that overexpression of HIF-1α may suppress the expression of PTGIS in BCa cells, by binding to HRE sequence at the promoter region of PTGIS. In addition, we found a strongly downregulation of PTGIS in BCa tissue and transcriptionally inhibited by HIF-1α in BCa cells, which could be triggered by its DNA methylation. Further result suggested that knockdown of CIRBP could promote the expression of PTGIS, meanwhile knockdown of PTGIS could partially rescue CIRBP-deficiency induced inhibition of migration and proliferation in BCa cells. Taken together, our study indicated that CIRBP could be a novel oncogene in human bladder cancer inducing transcription of HIF-1α, which could inhibit expression of methylated PTGIS.
A discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy
Authors: Yu Guocan , Yu Shan , Saha Manik Lal , Zhou Jiong , Cook Timothy R. , Yung Bryant C. , Chen Jin , Mao Zhengwei , Zhang Fuwu , Zhou Zijian , Liu Yijing , Shao Li , Wang Sheng , Gao Changyou , Huang Feihe , Stang Peter J. , Chen Xiaoyuan
Published: October 2018

Photodynamic therapy is an effective alternative to traditional treatments due to its minimally invasive nature, negligible systemic toxicity, fewer side effects, and avoidance of drug resistance. However, it is still challenging to design photosensitizers with high singlet oxygen (1O2) quantum yields (QY) due to severe aggregation of the hydrophobic photosensitizers. Herein, we developed a discrete organoplatinum(II) metallacage using therapeutic cis-(PEt3)2Pt(OTf)2 as the building block to improve the 1O2 QY, thus achieving synergistic anticancer efficacy. The metallacage-loaded nanoparticles (MNPs) with tri-modality imaging capability allow precise diagnosis of tumor and real-time monitoring the delivery, biodistribution, and excretion of the MNPs. MNPs exhibited excellent anti-metastatic effect and superior anti-tumor performance against U87MG, drug resistant A2780CIS, and orthotopic tumor models, ablating the tumors without recurrence after a single treatment. Gene chip analyses confirmed the contribution of different therapeutic modalities to the tumor abrogation. This supramolecular platform holds potential in precise cancer theranostics.
Emergence of superconductivity in the cuprates via a universal percolation process
Authors: Pelc Damjan , Vučković Marija , Grbić Mihael S. , Požek Miroslav , Yu Guichuan , Sasagawa Takao , Greven Martin , Barišić Neven
Published: October 2018

A pivotal step toward understanding unconventional superconductors would be to decipher how superconductivity emerges from the unusual normal state. In the cuprates, traces of superconducting pairing appear above the macroscopic transition temperature Tc, yet extensive investigation has led to disparate conclusions. The main difficulty has been to separate superconducting contributions from complex normal-state behaviour. Here we avoid this problem by measuring nonlinear conductivity, an observable that is zero in the normal state. We uncover for several representative cuprates that the nonlinear conductivity vanishes exponentially above Tc, both with temperature and magnetic field, and exhibits temperature-scaling characterized by a universal scale Ξ0. Attempts to model the response with standard Ginzburg-Landau theory are systematically unsuccessful. Instead, our findings are captured by a simple percolation model that also explains other properties of the cuprates. We thus resolve a long-standing conundrum by showing that the superconducting precursor in the cuprates is strongly affected by intrinsic inhomogeneity.
DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
Authors: Xiao Xiao , Liang Jiankai , Huang Chunlong , Li Kai , Xing Fan , Zhu Wenbo , Lin Ziqing , Xu Wencang , Wu Guangen , Zhang Jifu , Lin Xi , Tan Yaqian , Cai Jing , Hu Jun , Chen Xueqin , Huang Youwei , Qin Zixi , Qiu Pengxin , Su Xingwen , Chen Lijun , Lin Yuan , Zhang Haipeng , Yan Guangmei
Published: October 2018

Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers.
mRNAs and lncRNAs intrinsically form secondary structures with short end-to-end distances
Authors: Lai Wan-Jung C. , Kayedkhordeh Mohammad , Cornell Erica V. , Farah Elie , Bellaousov Stanislav , Rietmeijer Robert , Salsi Enea , Mathews David H. , Ermolenko Dmitri N.
Published: October 2018

The 5′ and 3′ termini of RNA play important roles in many cellular processes. Using Förster resonance energy transfer (FRET), we show that mRNAs and lncRNAs have an intrinsic propensity to fold in the absence of proteins into structures in which the 5′ end and 3′ end are ≤7 nm apart irrespective of mRNA length. Computational estimates suggest that the inherent proximity of the ends is a universal property of most mRNA and lncRNA sequences. Only guanosine-depleted RNA sequences with low sequence complexity are unstructured and exhibit end-to-end distances expected for the random coil conformation of RNA. While the biological implications remain to be explored, short end-to-end distances could facilitate the binding of protein factors that regulate translation initiation by bridging mRNA 5′ and 3′ ends. Furthermore, our studies provide the basis for measuring, computing and manipulating end-to-end distances and secondary structure in RNA in research and biotechnology.
Narrow bounds for the quantum capacity of thermal attenuators
Authors: Rosati Matteo , Mari Andrea , Giovannetti Vittorio
Published: October 2018

Thermal attenuator channels model the decoherence of quantum systems interacting with a thermal bath, e.g., a two-level system subject to thermal noise and an electromagnetic signal traveling through a fiber or in free-space. Hence determining the quantum capacity of these channels is an outstanding open problem for quantum computation and communication. Here we derive several upper bounds on the quantum capacity of qubit and bosonic thermal attenuators. We introduce an extended version of such channels which is degradable and hence has a single-letter quantum capacity, bounding that of the original thermal attenuators. Another bound for bosonic attenuators is given by the bottleneck inequality applied to a particular channel decomposition. With respect to previously known bounds we report better results in a broad range of attenuation and noise: we can now approximate the quantum capacity up to a negligible uncertainty for most practical applications, e.g., for low thermal noise.
A RNA producing DNA hydrogel as a platform for a high performance RNA interference system
Authors: Song Jaejung , Lee Minhyuk , Kim Taeyoung , Na Jeongkyeong , Jung Yebin , Jung Gyoo Yeol , Kim Sungjee , Park Nokyoung
Published: October 2018

RNA interference (RNAi) is a mechanism in which small interfering RNA (siRNA) silences a target gene. Herein, we describe a DNA hydrogel capable of producing siRNA and interfering with protein expression. This RNAi-exhibiting gel (termed I-gel for interfering gel) consists of a plasmid carrying the gene transcribing siRNA against the target mRNA as part of the gel scaffold. The RNAi efficiency of the I-gel has been confirmed by green fluorescent protein (GFP) expression assay and RNA production quantification. The plasmid stability in the I-gel results in an 8-times higher transcription efficiency than that of the free plasmid. We further applied the I-gel to live cells and confirmed its effect in interfering with the GFP expression. The I-gel shows higher RNAi effect than plasmids in free form or complexed with Lipofectamine. This nanoscale hydrogel, which is able to produce RNA in a cell, provides a platform technology for efficient RNAi system.
Quantum effects on dislocation motion from ring-polymer molecular dynamics
Authors: Freitas Rodrigo , Asta Mark , Bulatov Vasily V.
Published: October 2018

Quantum motion of atoms known as zero-point vibration was recently proposed to explain a long-standing discrepancy between theoretically computed and experimentally measured low-temperature plastic strength of iron and possibly other metals with high atomic masses. This finding challenges the traditional notion that quantum motion of atoms is relatively unimportant in solids comprised of heavy atoms. Here we report quantum dynamic simulations of quantum effects on dislocation motion within the exact formalism of Ring-Polymer Molecular Dynamics (RPMD). To extend the reach of quantum atomistic simulations to length and time scales relevant for extended defects in materials, we implemented RPMD in the open-source code LAMMPS thus making the RPMD method widely available to the community. We use our RPMD/LAMMPS approach for direct calculations of dislocation mobility and its effects on the yield strength of α-iron. Our simulation results establish that quantum effects are noticeable at temperatures below 50 K but account for only a modest (≈13% at T = 0 K) overall reduction in the Peierls barrier, at variance with the factor of two reduction predicted earlier based on the more approximate framework of harmonic transition state theory. Our results confirm that zero-point vibrations provide ample additional agitation for atomic motion that increases with decreasing temperature, however its enhancing effect on dislocation mobility is largely offset by an increase in the effective atom size, an effect known as quantum dispersion that has not been accounted for in the previous calculations.
Efficient quantum simulation of photosynthetic light harvesting
Authors: Wang Bi-Xue , Tao Ming-Jie , Ai Qing , Xin Tao , Lambert Neill , Ruan Dong , Cheng Yuan-Chung , Nori Franco , Deng Fu-Guo , Long Gui-Lu
Published: October 2018

Near-unity energy transfer efficiency has been widely observed in natural photosynthetic complexes. This phenomenon has attracted broad interest from different fields, such as physics, biology, chemistry, and material science, as it may offer valuable insights into efficient solar-energy harvesting. Recently, quantum coherent effects have been discovered in photosynthetic light harvesting, and their potential role on energy transfer has seen the heated debate. Here, we perform an experimental quantum simulation of photosynthetic energy transfer using nuclear magnetic resonance (NMR). We show that an N-chromophore photosynthetic complex, with arbitrary structure and bath spectral density, can be effectively simulated by a system with log2N qubits. The computational cost of simulating such a system with a theoretical tool, like the hierarchical equation of motion, which is exponential in N, can be potentially reduced to requiring a just polynomial number of qubits N using NMR quantum simulation. The benefits of performing such quantum simulation in NMR are even greater when the spectral density is complex, as in natural photosynthetic complexes. These findings may shed light on quantum coherence in energy transfer and help to provide design principles for efficient artificial light harvesting.
Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague
Authors: Levy Yinon , Vagima Yaron , Tidhar Avital , Aftalion Moshe , Gur David , Nili Uri , Chitlaru Theodore , Zauberman Ayelet , Mamroud Emanuelle
Published: October 2018

The generation of adaptive immunity by vaccination is usually a prolonged process that requires multiple dosing over several months. Hence, vaccines are administered for disease prevention a relatively long time prior to possible infection as opposed to post-exposure prophylaxis, which typically requires rapid intervention such as antibiotic therapy. The emergence of pathogens resistant to common antibiotic treatments has prompted the search for alternative therapeutic strategies. We previously demonstrated that vaccination of mice with the F1 capsular antigen ofYersinia pestiselicits specific and effective yet, unexpectedly, rapid anti-plague immunity. Here, we show by applying genetic and immunological approaches that the F1 antigen is targeted by peritoneal innate-like B1b cells that generate a prompt T-independent (TI) anti-F1 humoral response. The rapid F1-mediated defense response was diminished inXid(Btkm) mice in which B1 cell numbers and activity are limited. Binding of fluorophore-labeled F1 to peritoneal B1b cells was detected as soon as 6 h post vaccination, emphasizing the high speed of this process. By assessing the ability to achieve rapid immunity with monomerized F1, we show that the natural polymeric structure of F1 is essential for (i) rapid association with peritoneal B1b cells, (ii) early induction of anti-F1 titers and (iii) rapid TI immunity in the mouse model of bubonic plague. These observations shed new light on the potential of novel as well as well-known protective antigens in generating rapid immunity and could be implemented in the rational design of future vaccines.
Author Correction: Expression of key genes affecting artemisinin content in five Artemisia species
Authors: Salehi Maryam , Karimzadeh Ghasem , Naghavi Mohammad Reza , Naghdi Badi Hassanali , Rashidi Monfared Sajad
Published: October 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Estimating the potential yield and ETc of winter wheat across Huang-Huai-Hai Plain in the future with the modified DSSAT model
Authors: Tang Xiaopei , Song Ni , Chen Zhifang , Wang Jinglei , He Jianqiang
Published: October 2018

The DSSAT model, integrated the calibrated Hargreaves ET model and dynamic crop coefficient, was run with the generated weather data by SDSM4.2 and CanESM2 to predict the potential yield and crop water requirement (ETC) of winter wheat in the Huang-Huai-Hai Plain in China under RCP4.5 and RCP8.5 scenarios. The results showed that the spatial distribution of potential yield in the future under RCP4.5 and RCP8.5 were similar, characterized by an increasing trend from the northwest inland to the southeast coast. The spatial distribution of ETCdecreased gradually from the Shandong Peninsula to the surrounding area, and the minimum ETCwas observed in the southern part of Huang-Huai-Hai Plain. The potential yield, ETC,and effective precipitation during winter wheat growing seasons might increase in the future under RCP4.5, while irrigation water requirements (IWR) would decrease. Under RCP8.5, the effective precipitation during the wheat growing seasons decreased first and then increased. However, the potential yield, ETC, and IWR of winter wheat increased first and then decreased. This study can provide some scientific evidence to mitigate the negative effects of climate change on agricultural production and water use in the Huang-Huai-Hai Plain.
Influence of the Occipital Orientation on Cervical Sagittal Alignment: A Prospective Radiographic Study on 335 Normal Subjects
Authors: Zhu Weiguo , Sha Shifu , Liu Zhen , Li Yang , Xu Leilei , Zhang Wen , Qiu Yong , Zhu Zezhang
Published: October 2018

Cervical sagittal alignment is considered to have a special role in the pathogenesis and evaluation of cervical diseases. Previous studies have demonstrated that cervical sagittal alignment is correlated with thoracolumbar and pelvic alignments. As the direct anatomical structures connect to the cervical region, however, no parameters in the occiput have been reported to be intimately related to the alignment of the cervical spine. A retrospective radiographic study of 335 individuals (182 males and 153 females) between 18 and 60 years of age was performed between January 2007 and January 2016. The occipital incidence (OI), occipital slope (OS), occipital tilt (OT), C0-C2 angle, C2-C7 angle, C0-C7 angle, T1 slope and thoracic kyphosis were measured in every individual. The mean values of the occipital parameters of the cohort were 34.6° ± 3.1° for OI, 23.4° ± 7.4° for OS, and 11.8° ± 3.3° for OT. OI was constant throughout three age groups. No significant differences were noted between males and females. In addition, strong correlations were found between the occipital parameters and cervical parameters. The occipital orientation was an important factor that influenced the cervical sagittal alignment.
Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
Authors: Portelli Stephanie , Phelan Jody E. , Ascher David B. , Clark Taane G. , Furnham Nicholas
Published: October 2018

Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the effects of point mutations conferring resistance to three major anti-tuberculosis drugs, isoniazid (n = 189), rifampicin (n = 201) and D-cycloserine (n = 48), within their primary targets, katG, rpoB, and alr. Notably, mild biophysical effects brought about by high incidence mutations were considered more tolerable, while different structural effects brought about by haplotype combinations reflected differences in their functional importance. Additionally, highly destabilising mutations such as alr Y388, highlighted a functional importance of the wildtype residue. Our qualitative analysis enabled us to relate resistance mutations onto a theoretical landscape linking enthalpic changes with phenotype. Such insights will aid the development of new resistance-resistant drugs and, via an integration into predictive tools, in pathogen surveillance.
All-optical fiber optic coherent amplifier
Authors: Goodarzi A. , Ghanaatshoar M. , Mozafari M.
Published: October 2018

A fiber optic-based all-optical amplifier is designed by using the coherent perfect absorption phenomenon. For this purpose, we use a deposited chromium thin layer as an absorbent material on the cross-section of a PM fiber. By placing another fiber in front of the deposited one, we show that by controlling the relative phase between the two counter-propagating beams, total absorbance can be controlled. In the interaction of two beams with unequal intensities, absorption control can be associated with amplification for the weaker beam. By using this mechanism, the effect of an external phase-shifting parameter can be amplified. Furthermore, it is possible to amplify a small signal riding on a CW background through this all-optical procedure.
Dynamical and Thermodynamical Influences of the Maritime Continent on ENSO Evolution
Authors: Zhang Tuantuan , Huang Bohua , Yang Song , Chen Junwen , Jiang Xingwen
Published: October 2018

El Niño-Southern Oscillation (ENSO) exerts tremendous influences on the global climate. Through dynamic lifting and thermal forcing, the Maritime Continent (MC) plays an important role in affecting global atmospheric circulation. In spite of the extensive studies on ENSO mechanisms, the influence of MC on the characteristics of ENSO life cycle remains unclear. Our coupled model experiments reveal that the absence of the MC land contributes to a strong ENSO asymmetry and a weakened nonlinear atmospheric response to the combined seasonal and interannual SST variations (i.e. the combination mode) that prolongs the warm events, resulting in a reduction of ENSO frequency. On the other hand, our experiments suggest that the global climate model applied (NCAR CESM) overestimates the MC topographic uplifting effect on ENSO simulation. Overall, this study provides a new physical insight into the nature of the MC influence on ENSO evolution.
Characterization of a novel AICARFT inhibitor which potently elevates ZMP and has anti-tumor activity in murine models
Authors: Brooks Harold B. , Meier Timothy I. , Geeganage Sandaruwan , Fales Kevin R. , Thrasher Kenneth J. , Konicek Susan A. , Spencer Charles D. , Thibodeaux Stefan , Foreman Robert T. , Hui Yu-Hua , Roth Kenneth D. , Qian Yue-Wei , Wang Tao , Luo Shuang , Torrado Alicia , Si Chong , Toth James L. , Mc Cowan Jefferson R. , Frimpong Kwame , Lee Matthew R. , Dally Robert D. , Shepherd Timothy A. , Durham Timothy B. , Wang Yong , Wu Zhipei , Iversen Philip W. , Njoroge F. George
Published: October 2018

AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent.
N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region
Authors: Williams Monique , Burlina Alberto , Rubert Laura , Polo Giulia , Ruijter George J. G. , van den Born Myrthe , Rüfenacht Véronique , Haskins Nantaporn , van Zutven Laura J. C. M. , Tuchman Mendel , Saris Jasper J. , Häberle Johannes , Caldovic Ljubica
Published: October 2018

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.
Current-driven production of vortex-antivortex pairs in planar Josephson junction arrays and phase cracks in long-range order
Authors: Estellés-Duart Francisco , Ortuño Miguel , Somoza Andrés M. , Vinokur Valerii M. , Gurevich Alex
Published: October 2018

Proliferation of topological defects like vortices and dislocations plays a key role in the physics of systems with long-range order, particularly, superconductivity and superfluidity in thin films, plasticity of solids, and melting of atomic monolayers. Topological defects are characterized by their topological charge reflecting fundamental symmetries and conservation laws of the system. Conservation of topological charge manifests itself in extreme stability of static topological defects because destruction of a single defect requires overcoming a huge energy barrier proportional to the system size. However, the stability of driven topological defects remains largely unexplored. Here we address this issue and investigate numerically a dynamic instability of moving vortices in planar arrays of Josephson junctions. We show that a single vortex driven by sufficiently strong current becomes unstable and destroys superconductivity by triggering a chain reaction of self-replicating vortex-antivortex pairs forming linear of branching expanding patterns. This process can be described in terms of propagating phase cracks in long-range order with far-reaching implications for dynamic systems of interacting spins and atoms hosting magnetic vortices and dislocations.
E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer
Authors: Teo Katy , Gómez-Cuadrado Laura , Tenhagen Milou , Byron Adam , Rätze Max , van Amersfoort Miranda , Renes Jojanneke , Strengman Eric , Mandoli Amit , Singh Abhishek A. , Martens Joost H. , Stunnenberg Hendrik G. , van Diest Paul J. , Brunton Valerie G. , Derksen Patrick W. B.
Published: October 2018

Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours develop resistance to anti-oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.
Electrodeposited metal-organic framework films as self-assembled hierarchically superstructured supports for stable omniphobic surface coatings
Authors: Sablowski Jakob , Linnemann Julia , Hempel Simone , Hoffmann Volker , Unz Simon , Beckmann Michael , Giebeler Lars
Published: October 2018

Superhierarchically rough films are rapidly synthesised on metal substrates via electrochemically triggered self-assembly of meso/macroporous-structured metal-organic framework (MOF) crystals. These coatings are applied to immobilise a functional oil with low surface energy to provide stable coatings repellent to a wide range of hydrophobic as well as hydrophilic fluids. Such omniphobic surfaces are highly interesting for several applications such as anti-fouling, anti-icing, and dropwise condensation, and become easily scalable with the presented bottom-up fabrication approach. As investigated by environmental scanning electron microscopy (ESEM), the presented perfluorinated oil-infused Cu-BTC coating constitutes of a flat liquid-covered surface with protruding edges of octahedral superstructured MOF crystals. Water and non-polar diiodomethane droplets form considerably high contact angles and even low-surface-tension fluids, e.g. acetone, form droplets on the infused coating. The repellent properties towards the test fluids do not change upon extended water spraying in contrast to oil-infused porous copper oxide or native copper surfaces. It is discussed in detail, how the presented electrodeposited MOF films grow and provide a proficient surface morphology to stabilise the functional oil film due to hemiwicking.
Evaluation of different mucosal microbiota leads to gut microbiota-based prediction of type 1 diabetes in NOD mice
Authors: Hu Youjia , Peng Jian , Li Fangyong , Wong F. Susan , Wen Li
Published: October 2018

Type 1 diabetes (T1D) is a progressive autoimmune disease in which the insulin-producing beta cells are destroyed by auto-reactive T cells. Recent studies suggest that microbiota are closely associated with disease development. We studied gut, oral and vaginal microbiota longitudinally in non-obese diabetic (NOD) mice. We showed that the composition of microbiota is very different at the different mucosal sites and between young and adult mice. Gut microbiota are more diverse than oral or vaginal microbiota and the changes were more evident in the mice before and after onset of diabetes. Using alpha-diversity, Gram-positive/Gram-negative ratio as well as the relative abundance ofBacteroidetesandErysipelotrichaceaein the gut microbiota, at 8 weeks of age, we formulated a predictive algorithm for T1D development in a cohort of 63 female NOD mice. Using this algorithm, we obtained 80% accuracy of prediction of diabetes onset, in two independent experiments, totaling 29 mice, with Area Under the Curve of 0.776 by ROC analysis. Interestingly, we did not find differences in peripheral blood mononuclear cells of the mice at 8 weeks of age, regardless of later diabetes development. Our results suggest that the algorithm could potentially be used in early prediction of future T1D development.
Coherent behavior of neuromuscular oscillations between isometrically interacting subjects: experimental study utilizing wavelet coherence analysis of mechanomyographic and mechanotendographic signals
Authors: Schaefer Laura V. , Bittmann Frank N.
Published: October 2018

Previous research has shown that electrical muscle activity is able to synchronize between muscles of one subject. The ability to synchronize the mechanical muscle oscillations measured by Mechanomyography (MMG) is not described sufficiently. Likewise, the behavior of myofascial oscillations was not considered yet during muscular interaction of two human subjects. The purpose of this study is to investigate the myofascial oscillations intra- and interpersonally. For this the mechanical muscle oscillations of the triceps and the abdominal external oblique muscles were measured by MMG and the triceps tendon was measured by mechanotendography (MTG) during isometric interaction of two subjects (n = 20) performed at 80% of the MVC using their arm extensors. The coherence of MMG/MTG-signals was analyzed with coherence wavelet transform and was compared with randomly matched signal pairs. Each signal pairing shows significant coherent behavior. Averagely, the coherent phases of n = 485 real pairings last over 82 ± 39 % of the total duration time of the isometric interaction. Coherent phases of randomly matched signal pairs take 21 ± 12 % of the total duration time (n = 39). The difference between real vs. randomly matched pairs is significant (U = 113.0, p = 0.000, r = 0.73). The results show that the neuromuscular system seems to be able to synchronize to another neuromuscular system during muscular interaction and generate a coherent behavior of the mechanical muscular oscillations. Potential explanatory approaches are discussed.
Blood immune transcriptome analysis of artificially fed dairy calves and naturally suckled beef calves from birth to 7 days of age
Authors: Surlis C. , Earley B. , McGee M. , Keogh K. , Cormican P. , Blackshields G. , Tiernan K. , Dunn A. , Morrison S. , Arguello A. , Waters S. M.
Published: October 2018

Neonatal calves possess a very immature and naïve immune system and are reliant on the intake of maternal colostrum for passive transfer of immunoglobulins. Variation in colostrum management of beef and dairy calves is thought to affect early immune development. Therefore, the objective of this study was to examine changes in gene expression and investigate molecular pathways involved in the immune-competence development of neonatal Holstein dairy calves and naturally suckled beef calves using next generation RNA-sequencing during the first week of life. Jugular whole blood samples were collected from Holstein (H) dairy calves (n = 8) artificially fed 5% B.W. colostrum, and from beef calves which were the progenies of Charolais-Limousin (CL; n = 7) and Limousin-Friesian beef suckler cows (LF; n = 7), for subsequent RNA isolation. In dairy calves, there was a surge in pro-inflammatory cytokine gene expression possibly due to the stress of separation from the dam. LF calves exhibited early signs of humoral immune development with observed increases in the expression genes coding for Ig receptors, which was not evident in the other breeds by 7 days of age. Immune and health related DEGs identified as upregulated in beef calves are prospective contender genes for the classification of biomarkers for immune-competence development, and will contribute towards a greater understanding of the development of an immune response in neonatal calves.
An analytical model for computing the sound power of an unbraced irregular-shaped plate of variable thickness
Authors: Lee Meng Koon , Hosseini Fouladi Mohammad , Narayana Namasivayam Satesh
Published: October 2018

An irregular-shaped plate with dimensions identical to a guitar soundboard is chosen for this study. It is well known that the classical guitar soundboard is a major contributor to acoustic radiation at high frequencies when compared to the bridge and sound hole. This paper focuses on using an analytical model to compute the sound power of an unbraced irregular-shaped plate of variable thickness up to frequencies of 5 kHz. The analytical model is an equivalent thin rectangular plate of variable thickness. Sound power of an irregular-shaped plate of variable thickness and with dimensions of an unbraced Torres’ soundboard is determined from computer analysis using ANSYS. The number of acoustic elements used in ANSYS for accurate simulation is six elements per wavelength. Here we show that the analytical model can be used to compute sound power of an unbraced irregular-shaped plate of variable thickness.
Alendronate release from calcium phosphate cement for bone regeneration in osteoporotic conditions
Authors: van Houdt Claire I. A. , Gabbai-Armelin Paulo R. , Lopez-Perez Paula M. , Ulrich Dietmar J. O. , Jansen John A. , Renno Ana Claudia M. , van den Beucken Jeroen J. J. P.
Published: October 2018

Osteoporosis represents a major health problem in terms of compromising bone strength and increasing the risk of bone fractures. It can be medically treated with bisphosphonates, which act systemically upon oral or venous administration. Further, bone regenerative treatments in osteoporotic conditions present a challenge. Here, we focused on the development of a synthetic bone substitute material with local diminishing effects on osteoporosis. Composites were created using calcium phosphate cement (CPC; 60 wt%) and polylactic-co-glycolic acid (PLGA; 40 wt%), which were loaded with alendronate (ALN). In vitro results showed that ALN-loaded CPC/PLGA composites presented clinically suitable properties, including setting times, appropriate compressive strength, and controlled release of ALN, the latter being dependent on composite degradation. Using a rat femoral condyle bone defect model in osteoporotic animals, ALN-loaded CPC/PLGA composites demonstrated stimulatory effects on bone formation both within and outside the defect region.
A Novel Target Pathogen Identification and Tracking System Using Capillary Electrophoresis-Random Amplified Polymorphic DNA
Authors: Lin Wei-Ju , Tung Chien-Yi , Yen Muh-Yong , Chan Yu-Jiun , Lin Chi-Hung , Hsueh Po-Ren
Published: October 2018

Rapid and accurate identification of pathogen is a major quarantine strategy for outbreak prevention. We used capillary electrophoresis-random amplified polymorphic DNA (CE-RAPD) to generate highly discriminatory pathogen profiles, reduced batch effects between profiles by novel normalization procedure and pattern of technical repeats, followed by target similarity evaluation using target identification score (TIS). A full target signature contains several patterns. TIS system was optimized by training set isolates that included three species, and validated using two hundred clinical Klebsiella pneumoniae isolates. Hierarchical clustering analysis showed CE-RAPD profiles arrange clusters according to the species or the source. Moreover, samples with similar profile may display similar antibiotic susceptibility. By using a signature of four patterns, the TIS system could accurately identify target among different isolates. The variation between isolates may be caused by small change in genome. TIS system provides a standardized tool for building of outbreak firewall and facilitate data exchange.
Optical control of spin-polarized photocurrent in topological insulator thin films
Authors: Takeno Hiroaki , Saito Shingo , Mizoguchi Kohji
Published: October 2018

Dirac electrons in topological insulators (TIs) provide one possible avenue to achieve control of photocurrents and spin currents without the need to apply external fields by utilizing characteristic spin-momentum locking. However, for TI crystals with electrodes it is actually difficult to characterize the net flow of spin-polarized photocurrents because of the coexistence of surface carriers and bulk carriers generated by optical excitations. We demonstrate here that the net flow directions of spin-polarized photocurrents in TI polycrystalline thin films without electrodes can be precisely and intentionally controlled by the polarization of the excitation pulse alone, which is characterized by performing time-domain terahertz (THz) wave measurements and time-resolved magneto-optical Kerr rotation measurements that are non-contact methods. We show that the amplitudes of s-polarized THz waves radiated from photocurrents under right- and left-circularly polarized excitations are inverted relative to one another. Moreover, we observe the inversion of time-resolved magneto-optical Kerr rotation signals between the two excitations. Our results will open the way as innovative methods to control spin-polarized electrons in optoelectronic and spintronic TI devices without the need to apply external fields.