bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between minimum inter‐event time and the number of rainfall events in Peninsular Malaysia
Authors: Chin Ren Jie , Lai Sai Hin , Chang Kian Boon , Jaafar Wan Zurina Wan , Othman Faridah
Published: September 2016

The minimum inter‐event time (MIT) between two wet periods has to be set in order to separate rainfall events. The objective of this study is to analyse the effect of MIT on rainfall events in Peninsular Malaysia. Rainfall event data from 16 rainfall stations, containing the annual number of rainfall events together with the number of events that exceed a certain range of duration values, have been extracted using RainEMT. It is found that the average total number of rainfall events will be higher with smaller MIT values.
Variability of antithrombotics use in patients with hypoplastic left heart syndrome and its variants following first- and second-stage palliation surgery: a national report using the National Pediatric Cardiology Quality Improvement Collaborative registry
Authors: Ramachandran Preeti , King Eileen , Nebbia Ashley , Beekman Robert H. , Anderson Jeffrey B.
Published: September 2016

Purpose

Patients with hypoplastic left heart syndrome and its variants following palliation surgery are at risk for thrombosis. This study examines variability of antithrombotic practice, the incidence of interstage shunt thrombosis, and other adverse events following Stage I and Stage II palliation within the National Pediatric Cardiology Quality Improvement Collaborative registry.

Methods

We carried out a multicentre, retrospective review using the National Pediatric Cardiology Quality Improvement Collaborative registry including patients from 2008 to 2013 across 52 surgical sites. Antithrombotic medications used at Stage I and Stage II discharge were evaluated. Variability of antithrombotics use at the individual patient level and intersite variability, incidence of shunt thrombosis, and other adverse events such as cardiac arrest, seizure, stroke, and need for cardiac catheterisation intervention in the interstage period were identified. Antithrombotic strategies for hybrid Stage I patients were evaluated but they were excluded from the variability and outcomes analysis.

Results

A total of 932 Stage I and 923 Stage II patients were included in the study: 93.8% of Stage I patients were discharged on aspirin and 4% were discharged on no antithrombotics, and 77% of Stage II patients were discharged on aspirin and 17.5% were discharged on no antithrombotics. Only three patients (0.2%) presented with interstage shunt thrombosis. The majority of patients who died during interstage or required shunt dilation and/or stenting were discharged home on aspirin.

Conclusion

Aspirin is the most commonly used antithrombotic following Stage I and Stage II palliation. There is more variability in the choice of antithrombotics following Stage II compared with Stage I. The incidence of interstage shunt thrombosis and associated adverse events was rare.
MRI evaluation of mitral-aortic intervalvular fibrosa aneurysm in a boy
Authors: Caro-Dominguez Pablo , Gill Navjot , Yoo Shi-Joon
Published: September 2016

Mitral-aortic intervalvular fibrosa aneurysm is a rare disease with a few cases documented in children. We present the case of a 12-year-old boy, without a history of infection or previous surgery, diagnosed with MRI.
A discussion of Stephen Macedo Just Married: Same-Sex Couples, Monogamy & the Future of Marriage
Authors: Fischel Joseph J.
Published: August 2016

On June 26, 2015, the U.S. Supreme Court ruled, in Obergefell v. Hodges, that the Fourteenth Amendment of the U.S. Constitution forbids legal discrimination against same-sex marriage. The decision sent shock waves throughout the country, with both supporters and opponents regarding it as signal of dramatic shifts in public opinion and a revolutionary development on the road to sex-gender equality. Just two days earlier, on June 24, 2015, Stephen Macedo’s Just Married: Same-Sex Couples, Monogamy, and the Future of Marriage was published. Macedo has always worked at the intersection of legal theory, normative theory, and public policy, and Just Married offers a nuanced liberal democratic defense of marriage equality with striking resonance in light of Obergefell. We have thus invited a range of scholars on LGBT rights, and LGBT politics more generally, to comment on his book.
Madelung and Hubbard interactions in polaron band model of doped organic semiconductors
Authors: Png Rui-Qi , Ang Mervin C.Y. , Teo Meng-How , Choo Kim-Kian , Tang Cindy Guanyu , Belaineh Dagmawi , Chua Lay-Lay , Ho Peter K.H.
Published: September 2016

The standard polaron band model of doped organic semiconductors predicts that density-of-states shift into the π–π* gap to give a partially filled polaron band that pins the Fermi level. This picture neglects both Madelung and Hubbard interactions. Here we show using ultrahigh workfunction hole-doped model triarylamine–fluorene copolymers that Hubbard interaction strongly splits the singly-occupied molecular orbital from its empty counterpart, while Madelung (Coulomb) interactions with counter-anions and other carriers markedly shift energies of the frontier orbitals. These interactions lower the singly-occupied molecular orbital band below the valence band edge and give rise to an empty low-lying counterpart band. The Fermi level, and hence workfunction, is determined by conjunction of the bottom edge of this empty band and the top edge of the valence band. Calculations are consistent with the observed Fermi-level downshift with counter-anion size and the observed dependence of workfunction on doping level in the strongly doped regime.
Virus-derived DNA drives mosquito vector tolerance to arboviral infection
Authors: Goic Bertsy , Stapleford Kenneth A. , Frangeul Lionel , Doucet Aurélien J. , Gausson Valérie , Blanc Hervé , Schemmel-Jofre Nidia , Cristofari Gael , Lambrechts Louis , Vignuzzi Marco , Saleh Maria-Carla
Published: September 2016

Mosquitoes develop long-lasting viral infections without substantial deleterious effects, despite high viral loads. This makes mosquitoes efficient vectors for emerging viral diseases with enormous burden on public health. How mosquitoes resist and/or tolerate these viruses is poorly understood. Here we show that two species of Aedes mosquitoes infected with two arboviruses from distinct families (dengue or chikungunya) generate a viral-derived DNA (vDNA) that is essential for mosquito survival and viral tolerance. Inhibition of vDNA formation leads to extreme susceptibility to viral infections, reduction of viral small RNAs due to an impaired immune response, and loss of viral tolerance. Our results highlight an essential role of vDNA in viral tolerance that allows mosquito survival and thus may be important for arbovirus dissemination and transmission. Elucidating the mechanisms of mosquito tolerance to arbovirus infection paves the way to conceptualize new antivectorial strategies to selectively eliminate arbovirus-infected mosquitoes.
The myosin X motor is optimized for movement on actin bundles
Authors: Ropars Virginie , Yang Zhaohui , Isabet Tatiana , Blanc Florian , Zhou Kaifeng , Lin Tianming , Liu Xiaoyan , Hissier Pascale , Samazan Frédéric , Amigues Béatrice , Yang Eric D. , Park Hyokeun , Pylypenko Olena , Cecchini Marco , Sindelar Charles V. , Sweeney H. Lee , Houdusse Anne
Published: September 2016

Myosin X has features not found in other myosins. Its structure must underlie its unique ability to generate filopodia, which are essential for neuritogenesis, wound healing, cancer metastasis and some pathogenic infections. By determining high-resolution structures of key components of this motor, and characterizing the in vitro behaviour of the native dimer, we identify the features that explain the myosin X dimer behaviour. Single-molecule studies demonstrate that a native myosin X dimer moves on actin bundles with higher velocities and takes larger steps than on single actin filaments. The largest steps on actin bundles are larger than previously reported for artificially dimerized myosin X constructs or any other myosin. Our model and kinetic data explain why these large steps and high velocities can only occur on bundled filaments. Thus, myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles.
Transition to and from the skyrmion lattice phase by electric fields in a magnetoelectric compound
Authors: Okamura Y. , Kagawa F. , Seki S. , Tokura Y.
Published: September 2016

Dissipation-less electric control of magnetic state variable is an important target of contemporary spintronics. The non-volatile control of magnetic skyrmions, nanometre-sized spin-swirling objects, with electric fields may exemplify this goal. The skyrmion-hosting magnetoelectric chiral magnet Cu2OSeO3 provides a unique platform for the implementation of such control; however, the hysteresis that accompanies the first-order transition associated with the skyrmion phase is negligibly narrow in practice. Here we demonstrate another method that functions irrespective of the transition boundary. Combination of magnetic-susceptibility measurements and microwave spectroscopy reveals that although the metastable skyrmion lattice is normally hidden behind a more thermodynamically stable conical phase, it emerges under electric fields and persists down to the lowest temperature. Once created, this metastable skyrmion lattice remains without electric fields, establishing a bistability distinct from the transition hysteresis. This bistability thus enables non-volatile electric-field control of the skyrmion lattice even in temperature/magnetic-field regions far from the transition boundary.
ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Authors: Zhong Wenbin , Yi Qing , Xu Bing , Li Shiqian , Wang Tong , Liu Fupei , Zhu Biying , Hoffmann Peter R. , Ji Guangju , Lei Pingsheng , Li Guoping , Li Jiwei , Li Jian , Olkkonen Vesa M. , Yan Daoguang
Published: September 2016

Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca2+ release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment.
Strong cooperative coupling of pressure-induced magnetic order and nematicity in FeSe
Authors: Kothapalli K. , Böhmer A. E. , Jayasekara W. T. , Ueland B. G. , Das P. , Sapkota A. , Taufour V. , Xiao Y. , Alp E. , Bud’ko S. L. , Canfield P. C. , Kreyssig A. , Goldman A. I.
Published: September 2016

A hallmark of the iron-based superconductors is the strong coupling between magnetic, structural and electronic degrees of freedom. However, a universal picture of the normal state properties of these compounds has been confounded by recent investigations of FeSe where the nematic (structural) and magnetic transitions appear to be decoupled. Here, using synchrotron-based high-energy x-ray diffraction and time-domain Mössbauer spectroscopy, we show that nematicity and magnetism in FeSe under applied pressure are indeed strongly coupled. Distinct structural and magnetic transitions are observed for pressures between 1.0 and 1.7 GPa and merge into a single first-order transition for pressures ≳1.7 GPa, reminiscent of what has been found for the evolution of these transitions in the prototypical system Ba(Fe1−xCox)2As2. Our results are consistent with a spin-driven mechanism for nematic order in FeSe and provide an important step towards a universal description of the normal state properties of the iron-based superconductors.
ge-CRISPR - An integrated pipeline for the prediction and analysis of sgRNAs genome editing efficiency for CRISPR/Cas system
Authors: Kaur Karambir , Gupta Amit Kumar , Rajput Akanksha , Kumar Manoj
Published: September 2016

Genome editing by sgRNA a component of CRISPR/Cas system emerged as a preferred technology for genome editing in recent years. However, activity and stability of sgRNA in genome targeting is greatly influenced by its sequence features. In this endeavor, a few prediction tools have been developed to design effective sgRNAs but these methods have their own limitations. Therefore, we have developed “ge-CRISPR” using high throughput data for the prediction and analysis of sgRNAs genome editing efficiency. Predictive models were employed using SVM for developing pipeline-1 (classification) and pipeline-2 (regression) using 2090 and 4139 experimentally verified sgRNAs respectively from Homo sapiens, Mus musculus, Danio rerio and Xenopus tropicalis. During 10-fold cross validation we have achieved accuracy and Matthew’s correlation coefficient of 87.70% and 0.75 for pipeline-1 on training dataset (T1840) while it performed equally well on independent dataset (V250). In pipeline-2 we attained Pearson correlation coefficient of 0.68 and 0.69 using best models on training (T3169) and independent dataset (V520) correspondingly. ge-CRISPR (http://bioinfo.imtech.res.in/manojk/gecrispr/) for a given genomic region will identify potent sgRNAs, their qualitative as well as quantitative efficiencies along with potential off-targets. It will be useful to scientific community engaged in CRISPR research and therapeutics development.
Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways
Authors: Lee Mei-Yueh , Tsai Kun-Bow , Hsu Jong-Hau , Shin Shyi-Jang , Wu Jiunn-Ren , Yeh Jwu-Lai
Published: September 2016

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.
Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models
Authors: Shen Xiujin , Jiang Hong , Ying Meike , Xie Zhoutao , Li Xiayu , Wang Haibing , Zhao Jie , Lin Chuan , Wang Yucheng , Feng Shi , Shen Jia , Weng Chunhua , Lin Weiqiang , Wang Huiping , Zhou Qin , Bi Yan , Li Meng , Wang Lingyan , Zhu Tongyu , Huang Xiaoru , Lan Hui-Yao , Zhou Jing , Chen Jianghua
Published: September 2016

Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway.
Time-resolved, single-cell analysis of induced and programmed cell death via non-invasive propidium iodide and counterstain perfusion
Authors: Krämer Christina E. M. , Wiechert Wolfgang , Kohlheyer Dietrich
Published: September 2016

Conventional propidium iodide (PI) staining requires the execution of multiple steps prior to analysis, potentially affecting assay results as well as cell vitality. In this study, this multistep analysis method has been transformed into a single-step, non-toxic, real-time method via live-cell imaging during perfusion with 0.1 μM PI inside a microfluidic cultivation device. Dynamic PI staining was an effective live/dead analytical tool and demonstrated consistent results for single-cell death initiated by direct or indirect triggers. Application of this method for the first time revealed the apparent antibiotic tolerance of wild-typeCorynebacterium glutamicumcells, as indicated by the conversion of violet fluorogenic calcein acetoxymethyl ester (CvAM). Additional implementation of this method provided insight into the induced cell lysis ofEscherichia colicells expressing a lytic toxin-antitoxin module, providing evidence for non-lytic cell death and cell resistance to toxin production. Finally, our dynamic PI staining method distinguished necrotic-like and apoptotic-like cell death phenotypes inSaccharomyces cerevisiaeamong predisposed descendants of nutrient-deprived ancestor cells using PO-PRO-1 or green fluorogenic calcein acetoxymethyl ester (CgAM) as counterstains. The combination of single-cell cultivation, fluorescent time-lapse imaging and PI perfusion facilitates spatiotemporally resolved observations that deliver new insights into the dynamics of cellular behaviour.
The efficacy and safety of proton-pump inhibitors in treating patients with non-erosive reflux disease: a network meta-analysis
Authors: Chen Lingxiao , Chen Yujie , Li Bo
Published: September 2016

Proton-pump inhibitors (PPIs) have been proved as safe and effective ways to treat patients with non-erosive reflux disease (NERD). However, less is known about the comparisons among different PPIs and their best dosage. We aimed to synthesize the available evidence through network meta-analysis to investigate the efficacy and safety of different PPIs in treating patients with NERD. Fifteen studies with 6309 patients were included in the meta-analyses. For the rate of symptomatic relief, compared with control groups, all interventions except rabeprazole 5 mg significantly increased rate of symptomatic relief. Among the comparisons of different interventions, omeprazole 20 mg group was associated with a higher rate of symptomatic relief in contrast to omeprazole 10 mg group (odds ratio, OR: 1.89, 95% confidence interval, CI: 1.34, 2.67; p-value: 0.0005) or rabeprazole 5 mg group (OR: 2.51, 95%CI: 1.16, 5.42; p-value: 0.019); dexlansoprazole 30 mg therapy significantly improved the rate of symptomatic relief compared with rabeprazole 5 mg group (OR: 2.64, 95%CI: 1.08, 6.43; p-value: 0.03). For the rate of adverse events, there was no significant difference among all interventions.
Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis
Authors: Wang Hai , Zhao Miaoyun , Sud Neetu , Christian Patricia , Shen Jing , Song Yongyan , Pashaj Anjeza , Zhang Kezhong , Carr Timothy , Su Qiaozhu
Published: September 2016

Insulin induced gene-2 (Insig-2) is an ER-resident protein that inhibits the activation of sterol regulatory element-binding proteins (SREBPs). However, cellular factors that regulate Insig-2 expression have not yet been identified. Here we reported that cyclic AMP-responsive element-binding protein H (CREBH) positively regulates mRNA and protein expression of a liver specific isoform of Insig-2, Insig-2a, which in turn hinders SREBP-1c activation and inhibits hepatic de novo lipogenesis. CREBH binds to the evolutionally conserved CRE-BP binding elements located in the enhancer region of Insig-2a and upregulates its mRNA and protein expression. Metabolic hormone glucagon and nutritional fasting activated CREBH, which upregulated expression of Insig-2a in hepatocytes and inhibited SREBP-1c activation. In contrast, genetic depletion of CREBH decreased Insig-2a expression, leading to the activation of SREBP-1c and its downstream lipogenic target enzymes. Compromising CREBH-Insig-2 signaling by siRNA interference against Insig-2 also disrupted the inhibitory effect of this signaling pathway on hepatic de novo triglyceride synthesis. These actions resulted in the accumulation of lipid droplets in hepatocytes and systemic hyperlipidemia. Our study identified CREBH as the first cellular protein that regulates Insig-2a expression. Glucagon activated the CREBH-Insig-2a signaling pathway to inhibit hepatic de novo lipogenesis and prevent the onset of hepatic steatosis and hypertriglyceridemia.
Single Molecule Fluorescence Microscopy and Machine Learning for Rhesus D Antigen Classification
Authors: Borgmann Daniela M. , Mayr Sandra , Polin Helene , Schaller Susanne , Dorfer Viktoria , Obritzberger Lisa , Endmayr Tanja , Gabriel Christian , Winkler Stephan M. , Jacak Jaroslaw
Published: September 2016

In transfusion medicine, the identification of the Rhesus D type is important to prevent anti-D immunisation in Rhesus D negative recipients. In particular, the detection of the very low expressed DEL phenotype is crucial and hence constitutes the bottleneck of standard immunohaematology. The current method of choice, adsorption-elution, does not provide unambiguous results. We have developed a complementary method of high sensitivity that allows reliable identification of D antigen expression. Here, we present a workflow composed of high-resolution fluorescence microscopy, image processing, and machine learning that - for the first time - enables the identification of even small amounts of D antigen on the cellular level. The high sensitivity of our technique captures the full range of D antigen expression (including D+, weak D, DEL, D−), allows automated population analyses, and results in classification test accuracies of up to 96%, even for very low expressed phenotypes.
Stimulatory effects of the degradation products from Mg-Ca-Sr alloy on the osteogenesis through regulating ERK signaling pathway
Authors: Li Mei , He Peng , Wu Yuanhao , Zhang Yu , Xia Hong , Zheng Yufeng , Han Yong
Published: September 2016

The influence of Mg-1Ca-xwt.% Sr (x = 0.2, 0.5, 1.0, 2.0) alloys on the osteogenic differentiation and mineralization of pre-osteoblast MC3T3-E1 were studied through typical differentiation markers, such as intracellular alkaline phosphatase (ALP) activity, extracellular collagen secretion and calcium nodule formation. It was shown that Mg-1Ca alloys with different content of Sr promoted cell viability and enhanced the differentiation and mineralization levels of osteoblasts and Mg-1Ca-2.0Sr alloy had the most remarkable and significant effect among all. To further investigate the underlying mechanisms, RT-PCR and Western Blotting assays were taken to analyze the mRNA expression level of osteogenesis-related genes and intracellular signaling pathways involved in osteogenesis, respectively. RT-PCR results showed that Mg-1Ca-2.0Sr alloy significantly up-regulated the expressions of the transcription factors of Runt-related transcription factor 2 (RUNX2) and Osterix (OSX), Integrin subunits, as well as alkaline phosphatase (ALP), Bone sialoprotein (BSP), Collagen I (COL I), Osteocalcin (OCN) and Osteopontin (OPN). Western Blotting results suggested that Mg-1Ca-2.0Sr alloy rapidly induced extracellular signal-regulated kinase (ERK) activation but showed no obvious effects on c-Jun N terminal kinase (JNK) and p38 kinase of MAPK. Taken together, our results demonstrated that Mg-1Ca-2.0Sr alloy had excellent biocompatibility and osteogenesis via the ERK pathway and is expected to be promising as orthopedic implants and bone repair materials.
dRHP-PseRA: detecting remote homology proteins using profile-based pseudo protein sequence and rank aggregation
Authors: Chen Junjie , Long Ren , Wang Xiao-long , Liu Bin , Chou Kuo-Chen
Published: September 2016

Protein remote homology detection is an important task in computational proteomics. Some computational methods have been proposed, which detect remote homology proteins based on different features and algorithms. As noted in previous studies, their predictive results are complementary to each other. Therefore, it is intriguing to explore whether these methods can be combined into one package so as to further enhance the performance power and application convenience. In view of this, we introduced a protein representation called profile-based pseudo protein sequence to extract the evolutionary information from the relevant profiles. Based on the concept of pseudo proteins, a new predictor, called “dRHP-PseRA”, was developed by combining four state-of-the-art predictors (PSI-BLAST, HHblits, Hmmer, and Coma) via the rank aggregation approach. Cross-validation tests on a SCOP benchmark dataset have demonstrated that the new predictor has remarkably outperformed any of the existing methods for the same purpose on ROC50 scores. Accordingly, it is anticipated that dRHP-PseRA holds very high potential to become a useful high throughput tool for detecting remote homology proteins. For the convenience of most experimental scientists, a web-server for dRHP-PseRA has been established at http://bioinformatics.hitsz.edu.cn/dRHP-PseRA/.
The onset of electrospray: the universal scaling laws of the first ejection
Authors: Gañán-Calvo A. M. , López-Herrera J. M. , Rebollo-Muñoz N. , Montanero J. M.
Published: September 2016

The disintegration of liquid drops with low electrical conductivity and subject to an electric field is investigated both theoretically and experimentally. This disintegration takes place through the development of a conical cusp that eventually ejects an ultrathin liquid ligament. A first tiny drop is emitted from the end of this ligament. Due to its exceptionally small size and large electric charge per unit volume, that drop has been the object of relevant recent studies. In this paper, universal scaling laws for the diameter and electric charge of the first issued droplet are proposed and validated both numerically and experimentally. Our analysis shows how charge relaxation is the mechanism that differentiates the onset of electrospray, including the first droplet ejection, from the classical steady cone-jet mode. In this way, our study identifies when and where charge relaxation and electrokinetic phenomena come into play in electrospray, a subject of live controversy in the field.
Substrate prediction of Ixodes ricinus salivary lipocalins differentially expressed during Borrelia afzelii infection
Authors: Valdés James J. , Cabezas-Cruz Alejandro , Sima Radek , Butterill Philip T. , Růžek Daniel , Nuttall Patricia A.
Published: September 2016

Evolution has provided ticks with an arsenal of bioactive saliva molecules that counteract host defense mechanisms. This salivary pharmacopoeia enables blood-feeding while enabling pathogen transmission. High-throughput sequencing of tick salivary glands has thus become a major focus, revealing large expansion within protein encoding gene families. Among these are lipocalins, ubiquitous barrel-shaped proteins that sequester small, typically hydrophobic molecules. This study was initiated by mining the Ixodes ricinus salivary gland transcriptome for specific, uncharacterized lipocalins: three were identified. Differential expression of these I. ricinus lipocalins during feeding at distinct developmental stages and in response to Borrelia afzelii infection suggests a role in transmission of this Lyme disease spirochete. A phylogenetic analysis using 803 sequences places the three I. ricinus lipocalins with tick lipocalins that sequester monoamines, leukotrienes and fatty acids. Both structural analysis and biophysical simulations generated robust predictions showing these I. ricinus lipocalins have the potential to bind monoamines similar to other tick species previously reported. The multidisciplinary approach employed in this study characterized unique lipocalins that play a role in tick blood-feeding and transmission of the most important tick-borne pathogen in North America and Eurasia.
Atmospheric drying as the main driver of dramatic glacier wastage in the southern Indian Ocean
Authors: Favier V. , Verfaillie D. , Berthier E. , Menegoz M. , Jomelli V. , Kay J. E. , Ducret L. , Malbéteau Y. , Brunstein D. , Gallée H. , Park Y.-H. , Rinterknecht V.
Published: September 2016

The ongoing retreat of glaciers at southern sub-polar latitudes is particularly rapid and widespread. Akin to northern sub-polar latitudes, this retreat is generally assumed to be linked to warming. However, no long-term and well-constrained glacier modeling has ever been performed to confirm this hypothesis. Here, we model the Cook Ice Cap mass balance on the Kerguelen Islands (Southern Indian Ocean, 49°S) since the 1850s. We show that glacier wastage during the 2000s in the Kerguelen was among the most dramatic on Earth. We attribute 77% of the increasingly negative mass balance since the 1960s to atmospheric drying associated with a poleward shift of the mid-latitude storm track. Because precipitation modeling is very challenging for the current generation of climate models over the study area, models incorrectly simulate the climate drivers behind the recent glacier wastage in the Kerguelen. This suggests that future glacier wastage projections should be considered cautiously where changes in atmospheric circulation are expected.
Novel Foxp3− IL-10− Regulatory T-cells Induced by B-Cells Alleviate Intestinal Inflammation in Vivo
Authors: Shao Tzu-Yu , Hsu Ling-Hui , Chien Chien-Hui , Chiang Bor-Luen
Published: September 2016

Recent studies have revealed various Foxp3− regulatory T (Treg) cell subsets effectively protect mice from colitis. In the present study, we demonstrated that B cells induced a particular subset of regulatory T (Treg-of-B) cells, expressing programmed cell death 1 (PD-1), inducible costimulator (ICOS), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced tumor necrosis factor receptor (GITR) and OX-40, did not express Foxp3. Treg-of-B cells produced abundant levels of IL-10 and low levels of IL-4 and TGF-β. Adoptive transfer of Treg-of-B cells protected mice from CD4+CD45RBhi T-cell-induced colitis, including infiltration of leukocytes, depletion of goblet cells, epithelial hyperplasia and inhibition of Th1 and Th17 cytokines. These features were similar to IL-10-producing type 1 regulatory T (Tr1) cells; however, IL-10-deficient Treg-of-B cells maintained their suppressive function in vitro as well as in vivo, while the regulation of Tr1 cells depended on IL-10. In conclusion, Treg-of-B cells protected against experimental colitis through an IL-10-independent mechanism. We reported a novel subpopulation of regulatory T cells was different from conventional Foxp3+ Treg and IL-10-producing Tr1 cells.
Genomic and transcriptomic analyses of the tangerine pathotype of Alternaria alternata in response to oxidative stress
Authors: Wang Mingshuang , Sun Xuepeng , Yu Dongliang , Xu Jianping , Chung Kuangren , Li Hongye
Published: September 2016

The tangerine pathotype of Alternaria alternata produces the A. citri toxin (ACT) and is the causal agent of citrus brown spot that results in significant yield losses worldwide. Both the production of ACT and the ability to detoxify reactive oxygen species (ROS) are required for A. alternata pathogenicity in citrus. In this study, we report the 34.41 Mb genome sequence of strain Z7 of the tangerine pathotype of A. alternata. The host selective ACT gene cluster in strain Z7 was identified, which included 25 genes with 19 of them not reported previously. Of these, 10 genes were present only in the tangerine pathotype, representing the most likely candidate genes for this pathotype specialization. A transcriptome analysis of the global effects of H2O2 on gene expression revealed 1108 up-regulated and 498 down-regulated genes. Expressions of those genes encoding catalase, peroxiredoxin, thioredoxin and glutathione were highly induced. Genes encoding several protein families including kinases, transcription factors, transporters, cytochrome P450, ubiquitin and heat shock proteins were found associated with adaptation to oxidative stress. Our data not only revealed the molecular basis of ACT biosynthesis but also provided new insights into the potential pathways that the phytopathogen A. alternata copes with oxidative stress.
Functional changes in Becker muscular dystrophy: implications for clinical trials in dystrophinopathies
Authors: Bello Luca , Campadello Paola , Barp Andrea , Fanin Marina , Semplicini Claudio , Sorarù Gianni , Caumo Luca , Calore Chiara , Angelini Corrado , Pegoraro Elena
Published: September 2016

We performed a 1-year longitudinal study of Six Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and timed function tests in Becker muscular dystrophy (BMD). Skeletal muscle dystrophin was quantified by immunoblot. We grouped deletions ending on exon 45 (“del 45-x”, n = 28) or 51 (“del x-51”, n = 10); isolated exon 48 deletion (“del 48”, n = 10); and other mutations (n = 21). Only patients in the “del 45-x” or “other” groups became non-ambulatory (n = 5, log-rank p = n.s.) or unable to run (n = 22, p < 0.001). All measures correlated positively with dystrophin quantity and negatively with age, and were significantly more impaired in the “del 45-x” and “other” groups. After one year, NSAA score decreased significantly (−0.9 ± 1.6, p < 0.001); in the “del 45-x” group, both NSAA (−1.3 ± 1.7, p = 0.001) and 6MWT (−12 ± 31 m, p = 0.059) decreased. We conclude that patients with “del x-51” or “del 48” mutations have mild or asymptomatic BMD, while “del 45-x” mutations cause comparatively severe weakness, and functional deterioration in 1 year. Furthermore, exon 51 skipping could be more effective than exon 45 skipping in Duchenne muscular dystrophy.
Assessing the contribution of thrombospondin-4 induction and ATF6α activation to endoplasmic reticulum expansion and phenotypic modulation in bladder outlet obstruction
Authors: Krawczyk Katarzyna K. , Ekman Mari , Rippe Catarina , Grossi Mario , Nilsson Bengt-Olof , Albinsson Sebastian , Uvelius Bengt , Swärd Karl
Published: September 2016

Phenotypic modulation of smooth muscle cells is a hallmark of disease. The associated expansion of endoplasmic reticulum (ER) volume remains unexplained. Thrombospondin-4 was recently found to promote ATF6α activation leading to ER expansion. Using bladder outlet obstruction as a paradigm for phenotypic modulation, we tested if thrombospondin-4 is induced in association with ATF6α activation and ER expansion. Thrombospondin-4 was induced and ATF6α was activated after outlet obstruction in rodents. Increased abundance of spliced of Xbp1, another ER-stress sensor, and induction of Atf4 and Creb3l2 was also seen. Downstream of ATF6α, Calr, Manf, Sdf2l1 and Pdi increased as did ER size, whereas contractile markers were reduced. Overexpression of ATF6α, but not of thrombospondin-4, increased Calr, Manf, Sdf2l1 and Pdi and caused ER expansion, but the contractile markers were inert. Knockout of thrombospondin-4 neither affected bladder growth nor expression of ATF6α target genes, and repression of contractile markers was the same, even if ATF6α activation was curtailed. Increases of Xbp1s, Atf4 and Creb3l2 were similar. Our findings demonstrate reciprocal regulation of the unfolded protein response, including ATF6α activation and ER expansion, and reduced contractile differentiation in bladder outlet obstruction occurring independently of thrombospondin-4, which however is a sensitive indicator of obstruction.
Transcriptional Analysis of The Adaptive Digestive System of The Migratory Locust in Response to Plant Defensive Protease Inhibitors
Authors: Spit Jornt , Holtof Michiel , Badisco Liesbet , Vergauwen Lucia , Vogel Elise , Knapen Dries , Vanden Broeck Jozef
Published: September 2016

Herbivorous insects evolved adaptive mechanisms to compensate for the presence of plant defensive protease inhibitors (PI) in their food. The underlying regulatory mechanisms of these compensatory responses remain largely elusive. In the current study, we investigated the initiation of this adaptive response in the migratory locust,Locusta migratoria, via microarray analysis of gut tissues. Four hours after dietary uptake of PIs, 114 and 150 transcripts were respectively found up- or downregulated. The results suggest a quick trade-off between compensating for potential loss of digestive activity on the one hand, and stress tolerance, defense, and structural integrity of the gut on the other hand. We additionally addressed the role of a group of related upregulated hexamerin-like proteins in the PI-induced response. Simultaneous knockdown of corresponding transcripts by means of RNA interference resulted in a reduced capacity of the locust nymphs to cope with the effects of PI. Moreover, since insect hexamerins have been shown to bind Juvenile Hormone (JH), we also investigated the effect of JH on the proteolytic digestion inL. migratoria. Our results indicate that JH has a stimulatory effect on the expression of three homologous chymotrypsin genes, while knocking down the JH receptor (methoprene tolerant) led to opposite effects.
The Combination of CRISPR/Cas9 and iPSC Technologies in the Gene Therapy of Human β-thalassemia in Mice
Authors: Ou Zhanhui , Niu Xiaohua , He Wenyin , Chen Yuchang , Song Bing , Xian Yexing , Fan Di , Tang Daolin , Sun Xiaofang
Published: September 2016

β-thalassemia results from point mutations or small deletions in the β-globin (HBB) gene that ultimately cause anemia. The generation of induced pluripotent stem cells (iPSCs) from the somatic cells of patients in combination with subsequent homologous recombination-based gene correction provides new approaches to cure this disease. CRISPR/Cas9 is a genome editing tool that is creating a buzz in the scientific community for treating human diseases, especially genetic disorders. Here, we reported that correction of β-thalassemia mutations in patient-specific iPSCs using the CRISPR/Cas9 tool promotes hematopoietic differentiation in vivo. CRISPR/Cas9-corrected iPSC-derived hematopoietic stem cells (HSCs) were injected into sublethally-irradiated NOD-scid-IL2Rg−/− (NSI) mice. HBB expression was observed in these HSCs after hematopoietic differentiation in the NSI mice. Importantly, no tumor was found in the livers, lungs, kidneys, or bone marrow at 10 weeks in the NSI mice after implantation with these HSCs. Collectively, our findings demonstrated that CRISPR/Cas9 successfully corrects β-thalassemia mutations in patient-specific iPSCs. These CRISPR/Cas9-corrected iPSC-derived HSCs express normal HBB in mice without tumorigenic potential, suggesting a safe strategy for personalized treatment of β-thalassemia.
ANGIOGENES: knowledge database for protein-coding and noncoding RNA genes in endothelial cells
Authors: Müller Raphael , Weirick Tyler , John David , Militello Giuseppe , Chen Wei , Dimmeler Stefanie , Uchida Shizuka
Published: September 2016

Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) is specific to various cell types. Although lncRNAs are speculated to be more numerous than protein-coding genes, the annotations of lncRNAs remain primitive due to the lack of well-structured schemes for their identification and description. Here, we introduce a new knowledge database “ANGIOGENES” (http://angiogenes.uni-frankfurt.de) to allow for in silico screening of protein-coding genes and lncRNAs expressed in various types of endothelial cells, which are present in all tissues. Using the latest annotations of protein-coding genes and lncRNAs, publicly-available RNA-seq data was analyzed to identify transcripts that are expressed in endothelial cells of human, mouse and zebrafish. The analyzed data were incorporated into ANGIOGENES to provide a one-stop-shop for transcriptomics data to facilitate further biological validation. ANGIOGENES is an intuitive and easy-to-use database to allow in silico screening of expressed, enriched and/or specific endothelial transcripts under various conditions. We anticipate that ANGIOGENES serves as a starting point for functional studies to elucidate the roles of protein-coding genes and lncRNAs in angiogenesis.
Genetic Diversity in Gorkhas: an Autosomal STR Study
Authors: Preet Kiran , Malhotra Seema , Shrivastava Pankaj , Jain Toshi , Rawat Shweta , Varte L. Robert , Singh Sayar , Singh Inderjeet , Sarkar Soma
Published: September 2016

Genotyping of highly polymorphic autosomal short tandem repeat (STR) markers is a potent tool for elucidating genetic diversity. In the present study, fifteen autosomal STR markers were analyzed in unrelated healthy male Gorkha individuals (n = 98) serving in the Indian Army by using AmpFlSTR Identifiler Plus PCR Amplification Kit. In total, 138 alleles were observed with corresponding allele frequencies ranging from 0.005 to 0.469. The studied loci were in Hardy-Weinberg Equilibrium (HWE). Heterozygosity ranged from 0.602 to 0.867. The most polymorphic locus was Fibrinogen Alpha (FGA) chain which was also the most discriminating locus as expected. Neighbor Joining (NJ) tree and principal component analysis (PCA) plot clustered the Gorkhas with those of Nepal and other Tibeto-Burman population while lowlander Indian population formed separate cluster substantiating the closeness of the Gorkhas with the Tibeto-Burman linguistic phyla. Furthermore, the dataset of STR markers obtained in the study presents a valuable information source of STR DNA profiles from personnel for usage in disaster victim identification in military exigencies and adds to the Indian database of military soldiers and military hospital repository.
Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins
Authors: Kudryashova Elena , Koneru Pratibha C. , Kvaratskhelia Mamuka , Strömstedt Adam A. , Lu Wuyuan , Kudryashov Dmitri S.
Published: September 2016

Human defensins are innate immune defense peptides with a remarkably broad repertoire of anti-pathogen activities. In addition to modulating immune response, inflammation and angiogenesis, disintegrating bacterial membranes and inactivating bacterial toxins, defensins are known to intercept various viruses at different stages of their life cycles, while remaining relatively benign towards human cells and proteins. Recently we have found that human defensins inactivate proteinaceous bacterial toxins by taking advantage of their low thermodynamic stability and acting as natural “anti-chaperones”, i.e. destabilizing the native conformation of the toxins. In the present study we tested various proteins produced by several viruses (HIV-1, PFV and TEV) and found them to be susceptible to destabilizing effects of human α-defensins HNP-1 and HD-5 and the synthetic θ-defensin RC-101, but not β-defensins hBD-1 and hBD-2 or structurally related plant-derived peptides. Defensin-induced unfolding promoted exposure of hydrophobic groups otherwise confined to the core of the viral proteins. This resulted in precipitation, an enhanced susceptibility to proteolytic cleavage and a loss of viral protein activities. We propose, that defensins recognize and target a common and essential physico-chemical property shared by many bacterial toxins and viral proteins – the intrinsically low thermodynamic protein stability.
Dual-mode operation of 2D material-base hot electron transistors
Authors: Lan Yann-Wen , Torres, Carlos M. , Zhu Xiaodan , Qasem Hussam , Adleman James R. , Lerner Mitchell B. , Tsai Shin-Hung , Shi Yumeng , Li Lain-Jong , Yeh Wen-Kuan , Wang Kang L.
Published: September 2016

Vertical hot electron transistors incorporating atomically-thin 2D materials, such as graphene or MoS2, in the base region have been proposed and demonstrated in the development of electronic and optoelectronic applications. To the best of our knowledge, all previous 2D material-base hot electron transistors only considered applying a positive collector-base potential (VCB > 0) as is necessary for the typical unipolar hot-electron transistor behavior. Here we demonstrate a novel functionality, specifically a dual-mode operation, in our 2D material-base hot electron transistors (e.g. with either graphene or MoS2 in the base region) with the application of a negative collector-base potential (VCB < 0). That is, our 2D material-base hot electron transistors can operate in either a hot-electron or a reverse-current dominating mode depending upon the particular polarity of VCB. Furthermore, these devices operate at room temperature and their current gains can be dynamically tuned by varying VCB. We anticipate our multi-functional dual-mode transistors will pave the way towards the realization of novel flexible 2D material-based high-density and low-energy hot-carrier electronic applications.
New concept for the prevention and treatment of metastatic lymph nodes using chemotherapy administered via the lymphatic network
Authors: Kodama Tetsuya , Matsuki Daisuke , Tada Asuka , Takeda Kazu , Mori Shiro
Published: September 2016

Intravenous chemotherapy has poor access to metastatic lymph nodes (LNs) and is limited by short-lived drug concentrations. Here, we describe the administration of chemotherapy via the lymphatic network as a new concept for the prevention and treatment of metastatic LNs. A metastatic LN can be treated by the injection of drugs into an upstream LN, either the sentinel LN (SLN) or another upstream LN. In a mouse model, tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). Two routes were used for drug delivery to the PALN, namely from the SiLN and from the accessory axillary LN (AALN). We found that tumor masses were formed in lymphatic vessels between the SiLN and PALN. The flow of fluorescent solution injected into the SiLN towards the PALN decreased with tumor mass formation. Delivery from the AALN (free of metastatic tumor cells) to the PALN was identified as an alternative route. Intranodal injection can deliver high concentrations of drugs to secondary metastatic LNs. The study advocates a new concept for the prevention and treatment of metastatic lymph nodes whereby drugs injected into upstream lymph nodes can reach metastatic lymph nodes via the lymphatic network.