bluuebunny/crossref_metadata_2025 huggingface dataset:
Coupling fission and exit of RAB6 vesicles at Golgi hotspots through kinesin-myosin interactions
Authors: Miserey-Lenkei Stéphanie , Bousquet Hugo , Pylypenko Olena , Bardin Sabine , Dimitrov Ariane , Bressanelli Gaëlle , Bonifay Raja , Fraisier Vincent , Guillou Catherine , Bougeret Cécile , Houdusse Anne , Echard Arnaud , Goud Bruno
Published: October 2017

The actin and microtubule cytoskeletons play important roles in Golgi structure and function, but how they are connected remain poorly known. In this study, we investigated whether RAB6 GTPase, a Golgi-associated RAB involved in the regulation of several transport steps at the Golgi level, and two of its effectors, Myosin IIA and KIF20A participate in the coupling between actin and microtubule cytoskeleton. We have previously shown that RAB6–Myosin IIA interaction is critical for the fission of RAB6-positive transport carriers from Golgi/TGN membranes. Here we show that KIF20A is also involved in the fission process and serves to anchor RAB6 on Golgi/TGN membranes near microtubule nucleating sites. We provide evidence that the fission events occur at a limited number of hotspots sites. Our results suggest that coupling between actin and microtubule cytoskeletons driven by Myosin II and KIF20A ensures the spatial coordination between RAB6-positive vesicles fission from Golgi/TGN membranes and their exit along microtubules.
Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses
Authors: Tusco Radu , Jacomin Anne-Claire , Jain Ashish , Penman Bridget S. , Larsen Kenneth Bowitz , Johansen Terje , Nezis Ioannis P.
Published: October 2017

Selective autophagy is a catabolic process with which cellular material is specifically targeted for degradation by lysosomes. The function of selective autophagic degradation of self-components in the regulation of innate immunity is still unclear. Here we show that Drosophila Kenny, the homolog of mammalian IKKγ, is a selective autophagy receptor that mediates the degradation of the IκB kinase complex. Selective autophagic degradation of the IκB kinase complex prevents constitutive activation of the immune deficiency pathway in response to commensal microbiota. We show that autophagy-deficient flies have a systemic innate immune response that promotes a hyperplasia phenotype in the midgut. Remarkably, human IKKγ does not interact with mammalian Atg8-family proteins. Using a mathematical model, we suggest mechanisms by which pathogen selection might have driven the loss of LIR motif functionality during evolution. Our results suggest that there may have been an autophagy-related switch during the evolution of the IKKγ proteins in metazoans.
Timing anthropogenic stressors to mitigate their impact on marine ecosystem resilience
Authors: Wu Paul Pao-Yen , Mengersen Kerrie , McMahon Kathryn , Kendrick Gary A. , Chartrand Kathryn , York Paul H. , Rasheed Michael A. , Caley M. Julian
Published: October 2017

Better mitigation of anthropogenic stressors on marine ecosystems is urgently needed to address increasing biodiversity losses worldwide. We explore opportunities for stressor mitigation using whole-of-systems modelling of ecological resilience, accounting for complex interactions between stressors, their timing and duration, background environmental conditions and biological processes. We then search for ecological windows, times when stressors minimally impact ecological resilience, defined here as risk, recovery and resistance. We show for 28 globally distributed seagrass meadows that stressor scheduling that exploits ecological windows for dredging campaigns can achieve up to a fourfold reduction in recovery time and 35% reduction in extinction risk. Although the timing and length of windows vary among sites to some degree, global trends indicate favourable windows in autumn and winter. Our results demonstrate that resilience is dynamic with respect to space, time and stressors, varying most strongly with: (i) the life history of the seagrass genus and (ii) the duration and timing of the impacting stress.
Quantitative microscopy of the Drosophila ovary shows multiple niche signals specify progenitor cell fate
Authors: Dai Wei , Peterson Amy , Kenney Thomas , Burrous Haley , Montell Denise J.
Published: October 2017

Adult stem cells commonly give rise to transit-amplifying progenitors, whose progeny differentiate into distinct cell types. It is unclear if stem cell niche signals coordinate fate decisions within the progenitor pool. Here we use quantitative analysis of Wnt, Hh, and Notch signalling reporters and the cell fate markers Eyes Absent (Eya) and Castor (Cas) to study the effects of hyper-activation and loss of niche signals on progenitor development in the Drosophila ovary. Follicle stem cell (FSC) progeny adopt distinct polar, stalk, and main body cell fates. We show that Wnt signalling transiently inhibits expression of the main body cell fate determinant Eya, and Wnt hyperactivity strongly biases cells towards polar and stalk fates. Hh signalling independently controls the proliferation to differentiation transition. Notch is permissive but not instructive for differentiation of multiple cell types. These findings reveal that multiple niche signals coordinate cell fates and differentiation of progenitor cells.
RNF8/UBC13 ubiquitin signaling suppresses synapse formation in the mammalian brain
Authors: Valnegri Pamela , Huang Ju , Yamada Tomoko , Yang Yue , Mejia Luis A. , Cho Ha Y. , Oldenborg Anna , Bonni Azad
Published: October 2017

Although ubiquitin ligases have been implicated in autism, their roles and mechanisms in brain development remain incompletely understood. Here, we report that in vivo knockdown or conditional knockout of the autism-linked ubiquitin ligase RNF8 or associated ubiquitin-conjugating enzyme UBC13 in rodent cerebellar granule neurons robustly increases the number of parallel fiber presynaptic boutons and functional parallel fiber/Purkinje cell synapses. In contrast to the role of nuclear RNF8 in proliferating cells, RNF8 operates in the cytoplasm in neurons to suppress synapse differentiation in vivo. Proteomics analyses reveal that neuronal RNF8 interacts with the HECT domain protein HERC2 and scaffold protein NEURL4, and knockdown of HERC2 or NEURL4 phenocopies the inhibition of RNF8/UBC13 signaling on synapse differentiation. In behavior analyses, granule neuron-specific knockout of RNF8 or UBC13 impairs cerebellar-dependent learning. Our study defines RNF8 and UBC13 as components of a novel cytoplasmic ubiquitin-signaling network that suppresses synapse formation in the brain.
History-based action selection bias in posterior parietal cortex
Authors: Hwang Eun Jung , Dahlen Jeffrey E. , Mukundan Madan , Komiyama Takaki
Published: October 2017

Making decisions based on choice-outcome history is a crucial, adaptive ability in life. However, the neural circuit mechanisms underlying history-dependent decision-making are poorly understood. In particular, history-related signals have been found in many brain areas during various decision-making tasks, but the causal involvement of these signals in guiding behavior is unclear. Here we addressed this issue utilizing behavioral modeling, two-photon calcium imaging, and optogenetic inactivation in mice. We report that a subset of neurons in the posterior parietal cortex (PPC) closely reflect the choice-outcome history and history-dependent decision biases, and PPC inactivation diminishes the history dependency of choice. Specifically, many PPC neurons show history- and bias-tuning during the inter-trial intervals (ITI), and history dependency of choice is affected by PPC inactivation during ITI and not during trial. These results indicate that PPC is a critical region mediating the subjective use of history in biasing action selection.
MicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors
Authors: Giacomazzi Giorgia , Holvoet Bryan , Trenson Sander , Caluwé Ellen , Kravic Bojana , Grosemans Hanne , Cortés-Calabuig Álvaro , Deroose Christophe M. , Huylebroeck Danny , Hashemolhosseini Said , Janssens Stefan , McNally Elizabeth , Quattrocelli Mattia , Sampaolesi Maurilio
Published: October 2017

Muscular dystrophies (MDs) are often characterized by impairment of both skeletal and cardiac muscle. Regenerative strategies for both compartments therefore constitute a therapeutic avenue. Mesodermal iPSC-derived progenitors (MiPs) can regenerate both striated muscle types simultaneously in mice. Importantly, MiP myogenic propensity is influenced by somatic lineage retention. However, it is still unknown whether human MiPs have in vivo potential. Furthermore, methods to enhance the intrinsic myogenic properties of MiPs are likely needed, given the scope and need to correct large amounts of muscle in the MDs. Here, we document that human MiPs can successfully engraft into the skeletal muscle and hearts of dystrophic mice. Utilizing non-invasive live imaging and selectively induced apoptosis, we report evidence of striated muscle regeneration in vivo in mice by human MiPs. Finally, combining RNA-seq and miRNA-seq data, we define miRNA cocktails that promote the myogenic potential of human MiPs.
Nigritoxin is a bacterial toxin for crustaceans and insects
Authors: Labreuche Yannick , Chenivesse Sabine , Jeudy Alexandra , Le Panse Sophie , Boulo Viviane , Ansquer Dominique , Pagès Sylvie , Givaudan Alain , Czjzek Mirjam , Le Roux Frédérique
Published: October 2017

The Tetraconata (Pancrustacea) concept proposes that insects are more closely related to aquatic crustaceans than to terrestrial centipedes or millipedes. The question therefore arises whether insects have kept crustacean-specific genetic traits that could be targeted by specific toxins. Here we show that a toxin (nigritoxin), originally identified in a bacterial pathogen of shrimp, is lethal for organisms within the Tetraconata and non-toxic to other animals. X-ray crystallography reveals that nigritoxin possesses a new protein fold of the α/β type. The nigritoxin N-terminal domain is essential for cellular translocation and likely encodes specificity for Tetraconata. Once internalized by eukaryotic cells, nigritoxin induces apoptotic cell death through structural features that are localized in the C-terminal domain of the protein. We propose that nigritoxin will be an effective means to identify a Tetraconata evolutionarily conserved pathway and speculate that nigritoxin holds promise as an insecticidal protein.
Structure-mediated modulation of mRNA abundance by A-to-I editing
Authors: Brümmer Anneke , Yang Yun , Chan Tracey W. , Xiao Xinshu
Published: October 2017

RNA editing introduces single nucleotide changes to RNA, thus potentially diversifying gene expression. Recent studies have reported significant changes in RNA editing profiles in disease and development. The functional consequences of these widespread alterations remain elusive because of the unknown function of most RNA editing sites. Here, we carry out a comprehensive analysis of A-to-I editomes in human populations. Surprisingly, we observe highly similar editing profiles across populations despite striking differences in the expression levels of ADAR genes. Striving to explain this discrepancy, we uncover a functional mechanism of A-to-I editing in regulating mRNA abundance. We show that A-to-I editing stabilizes RNA secondary structures and reduces the accessibility of AGO2-miRNA to target sites in mRNAs. The editing-dependent stabilization of mRNAs in turn alters the observed editing levels in the stable RNA repertoire. Our study provides valuable insights into the functional impact of RNA editing in human cells.
Chemical messages from an ancient buried bottle: metabolomics for wine archeochemistry
Authors: Roullier-Gall Chloé , Heinzmann Silke S. , Garcia Jean-Pierre , Schmitt-Kopplin Philippe , Gougeon Régis D.
Published: October 2017

Restoration works in the old Clunisian Saint-Vivant monastery in Burgundy revealed an unidentified wine bottle (SV1) dating between 1772 and 1860. Chemical evidence for SV1 origin and nature are presented here using non-targeted Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and Nuclear Magnetic Resonance analyses. The SV1 chemical diversity was compared to red wines (Pinot Noir) from the Romanée Saint Vivant appellation and from six different vintages spanning from 1915 to 2009. The close metabolomic signature between SV1 and Romanée Saint Vivant wines spoke in favor of a filiation between these wines, in particular considering the Pinot noir grape variety. A further statistical comparison with up to 77 Pinot noir wines from Burgundy and vintages from nearly all the 20th century, confirmed that SV1 must have been made more than one hundred years ago. The increasing number of detected high masses and of nitrogen containing compounds with the ageing of the wine was in accordance with known ageing mechanisms. Besides, resveratrol was shown here to be preserved for more than one hundred years in wine. For the first time, the age of an old unknown wine along with its grape variety have been assessed through non-targeted metabolomic analyses.
In vivo-like 3-D model for sodium nitrite- and acrylamide-induced hepatotoxicity tests utilizing HepG2 cells entrapped in micro-hollow fibers
Authors: Chu Qiang , Zhao Yiying , Shi Xuer , Han Wen , Zhang Yanzhen , Zheng Xiaodong , Zhu Jing
Published: October 2017

To address the need for a high throughput toxicity test in the modern food industry, an in vivo-like 3-D cell model was constructed in this study to provide an alternative to controversial long-term animal models and to improve the sensitivity and accuracy of the traditional monolayer model. The model formed cell cylindroids within polyvinylidene fluoride (PVDF) hollow fibers and therefore mimicked the microenvironment of liver tissue. Microscopy methods were used, and liver-specific functions were measured to demonstrate the superiority of the model compared to the monolayer model, as well as to optimize the model for best cell performances. Later, toxicity tests of sodium nitrite and acrylamide were conducted in both the 3-D model and the monolayer model to study the sensitivity of the 3-D model in toxicity responses. As expected, HepG2 cells within the 3-D model responded at lower concentrations and shorter exposure times compared to cells within the monolayer model. Furthermore, western blot analysis of apoptosis pathways also supported the argument.
Rapid Characterization of Local Shape Memory Properties through Indentation
Authors: Li Peizhen , Karaca Haluk E. , Cheng Yang-Tse
Published: October 2017

Abstarct

Shape memory alloys (SMAs) have the ability to show large recoverable shape changes upon temperature, stress or magnetic field cycling. Their shape memory, material and magnetic properties (e.g. transformation temperatures, strain, saturation magnetization and strength) determine their prospects for applications from small-scale microelectromechanical systems to large scale aerospace and biomedical systems. It should be noted that properties of SMAs are highly temperature dependent. Generally, the conventional mechanical characterization methods (e.g, tension, compression, and torsion) are used on bulk samples of SMAs to determine those properties. In this article, it will be shown that indentation technique can be used as an alternative rapid method to determine some of the important shape memory properties of SMAs. Indentation response of a high-temperature NiTiHf alloy was determined as a function of temperature. A clear relationship between the work recoverable ratio and transformation temperatures, superelastic and plastic behavior was observed. This work shows that indentation response can be used to measure local superelasticity response, determine phase transformation temperatures and reveal the temperature intervals of the deformation mechanisms of shape memory alloys.
Ant Droplet Dynamics Evolve via Individual Decision-Making
Authors: Sakiyama Tomoko
Published: October 2017

The droplets of a set of ants were studied while they constructed a bridge. A droplet is a group of ants derived from a larger group. Several experimental studies have revealed the droplet dynamics of ants that resemble the self-organising characteristics that are displayed in their physico-chemical systems. However, little is known regarding how these typical behaviours emerge from individual decision-making. In this study, I developed an agent-based model where artificial ants aggregated, thereby resulting in chain and droplet growth. In my proposed model, the agents tuned their weight thresholds according to the local pattern stability and propagation of negative information. As a result, it was revealed that the droplet dynamics of my proposed model partly matched the time series of droplets of real ants, as demonstrated in previous experimental studies that included the fluctuation function and interdrop increments that followed a scale-free distribution.
Identifying critical recruitment bottlenecks limiting seedling establishment in a degraded seagrass ecosystem
Authors: Statton John , Montoya Leonardo R. , Orth Robert J. , Dixon Kingsley W. , Kendrick Gary A.
Published: October 2017

Identifying early life-stage transitions limiting seagrass recruitment could improve our ability to target demographic processes most responsive to management. Here we determine the magnitude of life-stage transitions along gradients in physical disturbance limiting seedling establishment for the marine angiosperm, Posidonia australis. Transition matrix models and sensitivity analyses were used to identify which transitions were critical for successful seedling establishment during the first year of seed recruitment and projection models were used to predict the most appropriate environments and seeding densities. Total survival probability of seedlings was low (0.001), however, transition probabilities between life-stages differed across the environmental gradients; seedling recruitment was affected by grazing and bioturbation prevailing during the first life-stage transition (1 month), and 4–6 months later during the third life-stage transition when establishing seedlings are physically removed by winter storms. Models projecting population growth from different starting seed densities showed that seeds could replace other more labour intensive and costly methods, such as transplanting adult shoots, if disturbances are moderated sufficiently and if large numbers of seed can be collected in sufficient quantity and delivered to restoration sites efficiently. These outcomes suggest that by improving management of early demographic processes, we could increase recruitment in restoration programs.
Logistic growth of a surface contamination network and its role in disease spread
Authors: Lei Hao , Li Yuguo , Xiao Shenglan , Yang Xinyan , Lin ChaoHsin , Norris Sharon L. , Wei Daniel , Hu Zhongmin , Ji Shengcheng
Published: October 2017

Surfaces and objects surround us, and touching them is integral to everyday life. Pathogen contaminated surfaces (fomites) are known to transmit diseases. However, little is known about the ways and speed at which surfaces become contaminated. We found that under certain conditions, the number of contaminated surfaces grows logistically, corresponding to possible rapid transmission of infection. In such a surface network, pathogen can be transmitted great distances quickly—as far as people move. We found that the surface contamination network in aircraft cabins exhibits a community structure, with small communities connected by the aisle seatback surfaces and toilets, which are high-touch surfaces. In less than two to three hours, most high-touch surfaces in the cabin are contaminated, and within five to six hours nearly all touchable surfaces are contaminated. During short haul flight, aisle passengers have higher fomite exposure. This closely matches the spatial infection pattern of one reported inflight norovirus outbreaks. Our model is generally applicable to other crowded settings. The commonly repeated advice to “wash hands frequently” may be replaced in future by more strategic advice such as “clean surfaces right now”, or advice based on who should wash their hands, and when.
Dynamic fingerprinting of sub-cellular nanostructures by image mean square displacement analysis
Authors: Digiacomo Luca , D’Autilia Francesca , Durso William , Tentori Paolo Maria , Caracciolo Giulio , Cardarelli Francesco
Published: October 2017

Here we provide demonstration that image mean square displacement (iMSD) analysis is a fast and robust platform to address living matter dynamic organization at the level of sub-cellular nanostructures (e.g. endocytic vesicles, early/late endosomes, lysosomes), with no a-priori knowledge of the system, and no need to extract single trajectories. From each iMSD, a unique triplet of average parameters (namely: diffusivity, anomalous coefficient, size) are extracted and represented in a 3D parametric space, where clustering of single-cell points readily defines the structure “dynamic fingerprint”, at the whole-cell-population level. We demonstrate that different sub-cellular structures segregate into separate regions of the parametric space. The potency of this approach is further proved through application to two exemplary, still controversial, cases: i) the intracellular trafficking of lysosomes, comprising both free diffusion and directed motion along cytoskeletal components, and ii) the evolving dynamic properties of macropinosomes, passing from early to late stages of intracellular trafficking. We strongly believe this strategy may represent a flexible, multiplexed platform to address the dynamic properties of living matter at the sub-cellular level, both in the physiological and pathological state.
Multiple mechanisms are involved in new imazamox-resistant varieties of durum and soft wheat
Authors: Domínguez-Mendez Rafael , Alcántara-de la Cruz Ricardo , Rojano-Delgado Antonia M. , Fernández-Moreno Pablo T. , Aponte Raphael , De Prado Rafael
Published: October 2017

Weed control in wheat is one of the major goals of farmers in their efforts toward obtaining the highest crop yields for human foods. Several studies (dose-response, enzyme activity, absorption-translocation and metabolism) were conducted to characterize the resistance level of two new wheat cultivars called Rafalín (Triticum aestivum) and Antoñín (T. durum) that were obtained by conventional breeding based on Clearfield® technology; they are resistant (R) to imazamox compared to their sensitive (S) counterparts (Gazul and Simeto, respectively). The R-cultivars were 93.7-fold (Rafalín) and 43.7-fold (Antoñín) more resistant than their respective S-cultivars. The acetolactate synthase (ALS) enzyme activity revealed high resistance to imidazolinone (IMI) herbicides in R-cultivars, but no cross-resistance to other ALS herbicides was found. The Ser653Asn mutation that confers resistance to IMI herbicides was identified in the imi1 and imi2 genes of Rafalín and only in the imi1 gene of Antoñín. The 14C-imazamox absorption did not differ between the R- and S-cultivars. Imazamox was metabolized by Cyt-P450 into imazamox-hydroxyl and imazamox-glucoside in the R-cultivars, altering their translocation patterns. The differential sensitivity to imazamox between R-cultivars was due to the number of resistance genes that carry each genotype. The R-cultivars Rafalín and Antoñín could be excellent weed control tools.
Impact of Educational Interventions on Acceptance and Uptake of Male Circumcision in the General Population of Western China: A Multicenter Cohort Study
Authors: Zhou Bo , Ning Chuanyi , McCann Chase D. , Liao Yanyan , Yang Xiaobo , Zou Yunfeng , Jiang Junjun , Liang Bingyu , Abdullah Abu S. , Qin Bo , Upur Halmurat , Zhong Chaohui , Ye Li , Liang Hao
Published: October 2017

To compare different intervention models for promoting male circumcision (MC) to prevent HIV transmission in Western China. A total of 1690 male participants from multiple study sites were cluster randomly allocated to three-stage (Model A), two-stage (Model B), and one-stage (Model C) educational interventions. In all three interventions models, knowledge about MC significantly increased and the reported willingness to accept MC increased to 52.6% (255/485), 67.0% (353/527), and 45.5% (219/481) after intervention, respectively (P < 0.05). Rate of MC surgery uptake was highest (23.7%; 115/485) among those who received Model A intervention, compared to those who received Model B (17.1%; 90/527) or Model C (9.4%; 45/481) interventions (P < 0.05). Multivariable Cox regression analysis identified that Model A or Model B had twice the effect of Model C on MC uptake, with relative risks of 2.4 (95%CI, 1.5–3.8) and 2.2 (95%CI, 1.3–3.6), respectively. Model B was the most effective model for improving participants’ willingness to accept MC, while Model A was most successful at increasing uptake of MC surgery. Self-reported attitude towards MC uptake was not strongly correlated with actual behavior in this study focusing on the general male population in Western China.
Healthy Adults Display Long-Term Trait-Like Neurobehavioral Resilience and Vulnerability to Sleep Loss
Authors: Dennis Laura E. , Wohl Rachael J. , Selame Lauren A. , Goel Namni
Published: October 2017

Sleep loss produces well-characterized cognitive deficits, although there are large individual differences, with marked vulnerability or resilience among individuals. Such differences are stable with repeated exposures to acute total sleep deprivation (TSD) within a short-time interval (weeks). Whether such stability occurs with chronic sleep restriction (SR) and whether it endures across months to years in TSD, indicating a true trait, remains unknown. In 23 healthy adults, neurobehavioral vulnerability to TSD exposures, separated by 27–2,091 days (mean: 444 days; median: 210 days), showed trait-like stability in performance and subjective measures (82–95% across measures). Similarly, in 24 healthy adults, neurobehavioral vulnerability to SR exposures, separated by 78–3,058 days (mean: 935 days; median: 741 days), also showed stability (72–92% across measures). Cognitive performance outcomes and subjective ratings showed consistency across objective measures, and consistency across subjective measures, but not between objective and subjective domains. We demonstrate for the first time the stability of phenotypic neurobehavioral responses in the same individuals to SR and to TSD over long-time intervals. Across multiple measures, prior sleep loss responses are strong predictors of individual responses to subsequent sleep loss exposures chronically or intermittently, across months and years, thus validating the need for biomarkers and predictors.
High-concentration hydrogen protects mouse heart against ischemia/reperfusion injury through activation of thePI3K/Akt1 pathway
Authors: Chen Ouyang , Cao Zhiyong , Li He , Ye Zhouheng , Zhang Rongjia , Zhang Ning , Huang Junlong , Zhang Ting , Wang Liping , Han Ling , Liu Wenwu , Sun Xuejun
Published: October 2017

The study investigated the role of Akt1 through the cardioprotection of high-concentration hydrogen (HCH). C57BL/6 mice were randomly divided into the following groups: sham, I/R, I/R + HCH, I/R + HCH + LY294002 (PI3K inhibitor), I/R + HCH + wortmannin (PI3K inhibitor), I/R + LY294002, and I/R + wortmannin. After 45 min of ischemia, HCH (67% H2 and 33% O2) was administered to mice during a 90-min reperfusion. To investigate the role of Akt1 in the protective effects of HCH, mice were divided into the following groups: I/R + A-674563 (Akt1 selective inhibitor), I/R + HCH + A-674563, I/R + CCT128930 (Akt2 selective inhibitor), and I/R + HCH + CCT128930. After a 4-h reperfusion, serum biochemistry, histological, western blotting, and immunohistochemical analyses were performed to evaluate the role of the PI3K-Akt1 pathway in the protection of HCH. In vitro, 75% hydrogen was administered to cardiomyocytes during 4 h of reoxygenation after 3-h hypoxia. Several analyses were performed to evaluate the role of the Akt1 in the protective effects of hydrogen. HCH resulted in the phosphorylation of Akt1 but not Akt2, and Akt1 inhibition markedly abolished HCH-induced cardioprotection. Our findings reveal that HCH may exert cardioprotective effects through a PI3K-Akt1-dependent mechanism.
HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication
Authors: Cabrera Alvaro Cortes , Melo Esther , Roth Doris , Topp Andreas , Delobel Frederic , Stucki Corinne , Chen Chia-yi , Jakob Peter , Banfai Balazs , Dunkley Tom , Schilling Oliver , Huber Sylwia , Iacone Roberto , Petrone Paula
Published: October 2017

The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Among these, HtrA1 is implicated in several cancers, cerebrovascular disease and age-related macular degeneration. Currently, HtrA1 activation is not fully characterized and relevant for drug-targeting this protease. Our work provides a mechanistic step-by-step description of HtrA1 activation and regulation. We report that the HtrA1 trimer is regulated by an allosteric mechanism by which monomers relay the activation signal to each other, in a PDZ-domain independent fashion. Notably, we show that inhibitor binding is precluded if HtrA1 monomers cannot communicate with each other. Our study establishes how HtrA1 trimerization plays a fundamental role in proteolytic activity. Moreover, it offers a structural explanation for HtrA1-defective pathologies as well as mechanistic insights into the degradation of complex extracellular fibrils such as tubulin, amyloid beta and tau that belong to the repertoire of HtrA1.
Extraction of the Rashba spin-orbit coupling constant from scanning gate microscopy conductance maps for quantum point contacts
Authors: Kolasiński K. , Sellier H. , Szafran B.
Published: October 2017

We study the possibility for the extraction of the Rashba spin-orbit coupling constant for a two-dimensional electron gas with the conductance microscopy technique. Due to the interplay between the effective magnetic field due to the Rashba spin-orbit coupling and the external magnetic field applied within the plane of confinement, the electron backscattering induced by a charged tip of an atomic force microscope located above the sample leads to the spin precession and spin mixing of the incident and reflected electron waves between the QPC and the tip-induced 2DEG depletion region. This mixing leads to a characteristic angle-dependent beating pattern visible in the conductance maps. We show that the structure of the Fermi level, bearing signatures of the spin-orbit coupling, can be extracted from the Fourier transform of the interference fringes in the conductance maps as a function of the magnetic field direction. We propose a simple analytical model which can be used to fit the experimental data in order to obtain the spin-orbit coupling constant.
VP2 of Chicken Anaemia Virus Interacts with Apoptin for Down-regulation of Apoptosis through De-phosphorylated Threonine 108 on Apoptin
Authors: Lai Guan-Hua , Lien Yi-Yang , Lin Ming-Kuem , Cheng Jai-Hong , Tzen Jason TC , Sun Fang-Chun , Lee Meng-Shiunn , Chen Hsi-Jien , Lee Meng-Shiou
Published: October 2017

Chicken anaemia virus (CAV) is an important contagious agent that causes immunosuppressive disease in chickens. CAV Apoptin is a nucleoplasmic shuffling protein that induces apoptosis in chicken lymphoblastoid cells. In the present study, confocal microscopy revealed co-localisation of expressed CAV non-structural protein VP2 with Apoptin in the nucleus of MDCC-MSB1 cells and the nucleoplasmic compartment of CHO-K1 cells. In vitro pull-down and ex vivo biomolecular fluorescent complementation (BiFC) assays further showed that the VP2 protein directly interacts with Apoptin. Transient co-expression of VP2 and Apoptin in MDCC-MSB1 cells significantly decreased the rate of apoptosis compared with that in cells transfected with the Apoptin gene alone. In addition, the phosphorylation status of threonine 108 (Thr108) of Apoptin was found to decrease upon interaction with VP2. Although dephosphorylated Thr108 did not alter the subcellular distribution of Apoptin in the nucleus of MDCC-MSB1 cells, it did suppress apoptosis. These findings provide the first evidence that VP2 directly interacts with Apoptin in the nucleus to down-regulate apoptosis through alterations in the phosphorylation status of the latter. This information will be useful to further elucidate the underlying mechanism of viral replication in the CAV life cycle.
The genetic variation in the R1a clade among the Ashkenazi Levites’ Y chromosome
Authors: Behar Doron M. , Saag Lauri , Karmin Monika , Gover Meir G. , Wexler Jeffrey D. , Sanchez Luisa Fernanda , Greenspan Elliott , Kushniarevich Alena , Davydenko Oleg , Sahakyan Hovhannes , Yepiskoposyan Levon , Boattini Alessio , Sarno Stefania , Pagani Luca , Carmi Shai , Tzur Shay , Metspalu Ene , Bormans Concetta , Skorecki Karl , Metspalu Mait , Rootsi Siiri , Villems Richard
Published: October 2017

Approximately 300,000 men around the globe self-identify as Ashkenazi Levites, of whom two thirds were previously shown to descend from a single male. The paucity of whole Y-chromosome sequences precluded conclusive identification of this ancestor’s age, geographic origin and migration patterns. Here, we report the variation of 486 Y-chromosomes within the Ashkenazi and non-Ashkenazi Levite R1a clade, other Ashkenazi Jewish paternal lineages, as well as non-Levite Jewish and non-Jewish R1a samples. Cumulatively, the emerging profile is of a Middle Eastern ancestor, self-affiliating as Levite, and carrying the highly resolved R1a-Y2619 lineage, which was likely a minor haplogroup among the Hebrews. A star-like phylogeny, coalescing similarly to other Ashkenazi paternal lineages, ~1,743 ybp, suggests it to be one of the Ashkenazi paternal founders; to have expanded as part of the overall Ashkenazi demographic expansion, without special relation to the Levite affiliation; and to have subsequently spread to non-Ashkenazi Levites.
Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1α-dependent decay
Authors: Ko Jae Sung , Koh Jae Moon , So Jae-Seon , Jeon Yoon Kyung , Kim Hye Young , Chung Doo Hyun
Published: October 2017

Long chain fatty acids (LCFAs) exert pro-inflammatory effectsin vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors iniNKT cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-γ production and reducedgata-3andt-bettranscript levels iniNKT cells during TCR-mediated activation. IniNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1α RNase. Moreover, PA increased the degradation rates ofgata-3andt-betmRNA, which was restored by IRE1α inhibition or transfection with mutantgata-3ort-bet, indicating thatgata-3andt-betare cleaved via regulated IRE1α-dependent decay (RIDD). A PA-rich diet and PA injection suppressed IL-4 and IFN-γ production byiNKT cells in C57BL/6, but not Jα18 knockout mice, which was restored by injection of STF083010, an IRE1α-specific inhibitor. Furthermore, a PA-rich diet and PA injection attenuated arthritis in aniNKT cell-dependent manner. Taken together, our experiments demonstrate that a saturated LCFA induced RIDD-mediatedt-betandgata-3mRNA degradation iniNKT cells, thereby suppressing arthritis.
Identification of pharmacological agents that induce HMGB1 release
Authors: Liu Peng , Zhao Liwei , Loos Friedemann , Iribarren Kristina , Lachkar Sylvie , Zhou Heng , Gomes-da-Silva Lígia C. , Chen Guo , Bezu Lucillia , Boncompain Gaelle , Perez Franck , Zitvogel Laurence , Kepp Oliver , Kroemer Guido
Published: October 2017

The translocation of the protein high mobility group box 1 (HMGB1) from the nucleus to the cytoplasm and its secretion or passive release through the permeabilized plasma membrane, constitutes a major cellular danger signal. Extracellular HMGB1 can interact with pattern recognition receptors to stimulate pro-inflammatory and immunostimulatory pathways. Here, we developed a screening assay to identify pharmacological agents endowed with HMGB1 releasing properties. For this, we took advantage of the “retention using selective hooks” (RUSH) system in which a streptavidin-NLS3 fusion protein was used as a nuclear hook to sequestrate streptavidin-binding peptide (SBP) fused with HMGB1 and green fluorescent protein (GFP). When combined with biotin, which competitively disrupts the interaction between streptavidin-NLS3 and HMGB1-SBP-GFP, immunogenic cell death (ICD) inducers such as anthracyclines were able to cause the nucleo-cytoplasmic translocation of HMGB1-SBP-GFP. This system, was used in a high-content screening (HCS) campaign for the identification of HMGB1 releasing agents. Hits fell into three functional categories: known ICD inducers, microtubule inhibitors and epigenetic modifiers. These agents induced ICD through a panoply of distinct mechanisms. Their effective action was confirmed by multiple methods monitoring nuclear, cytoplasmic and extracellular HMGB1 pools, both in cultured human or murine cells, as well as in mouse plasma.
Author Correction: Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations
Authors: Kulemann Birte , Rösch Stephanie , Seifert Sindy , Timme Sylvia , Bronsert Peter , Seifert Gabriel , Martini Verena , Kuvendjiska Jasmina , Glatz Torben , Hussung Saskia , Fritsch Ralph , Becker Heiko , Pitman Martha B. , Hoeppner Jens
Published: October 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Proof-of-concept Raman spectroscopy study aimed to differentiate thyroid follicular patterned lesions
Authors: Rau Julietta V. , Fosca Marco , Graziani Valerio , Taffon Chiara , Rocchia Massimiliano , Caricato Marco , Pozzilli Paolo , Onetti Muda Andrea , Crescenzi Anna
Published: October 2017

Inter-observer variability and cancer over-diagnosis are emerging clinical problems, especially for follicular patterned thyroid lesions. This challenge strongly calls for a new clinical tool to reliably identify neoplastic lesions and to improve the efficiency of differentiation between benign and malignant neoplasms, especially considering the increased diagnosis of small carcinomas and the growing number of thyroid nodules. In this study, we employed a Raman spectroscopy (RS) microscope to investigate frozen thyroid tissues from fourteen patients with thyroid nodules. To generate tissue classification models, a supervised statistical analysis of the Raman spectra was performed. The results obtained demonstrate an accuracy of 78% for RS based diagnosis to discriminate between normal parenchyma and follicular patterned thyroid nodules, and 89% accuracy – for very challenging follicular lesions (carcinoma versus adenoma). RS translation into intraoperative diagnosis of frozen sections and in preoperative analysis of biopsies can be very helpful to reduce unnecessary surgery in patients with indeterminate cytological reports.
Spermine oxidase promotes bile canalicular lumen formation through acrolein production
Authors: Uemura Takeshi , Takasaka Tomokazu , Igarashi Kazuei , Ikegaya Hiroshi
Published: October 2017

Spermine oxidase (SMOX) catalyzes oxidation of spermine to generate spermidine, hydrogen peroxide (H2O2) and 3-aminopropanal, which is spontaneously converted to acrolein. SMOX is induced by a variety of stimuli including bacterial infection, polyamine analogues and acetaldehyde exposure. However, the physiological functions of SMOX are not yet fully understood. We investigated the physiological role of SMOX in liver cells using human hepatocellular carcinoma cell line HepG2. SMOX localized to the bile canalicular lumen, as determined by F-actin staining. Knockdown of SMOX reduced the formation of bile canalicular lumen. We also found that phospho-Akt (phosphorylated protein kinase B) was localized to canalicular lumen. Treatment with Akt inhibitor significantly reduced the formation of bile canalicular lumen. Acrolein scavenger also inhibited the formation of bile canalicular lumen. PTEN, phosphatase and tensin homolog and an inhibitor of Akt, was alkylated in a SMOX-dependent manner. Our results suggest that SMOX plays a central role in the formation of bile canalicular lumen in liver cells by activating Akt pathway through acrolein production.
Secretoneurin A regulates neurogenic and inflammatory transcriptional networks in goldfish (Carassius auratus) radial glia
Authors: Da Fonte Dillon F. , Martyniuk Christopher J. , Xing Lei , Pelin Adrian , Corradi Nicolas , Hu Wei , Trudeau Vance L.
Published: October 2017

Radial glial cells (RGCs) are the most abundant macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis; however, their transcriptome remains uncharacterized, which limits functional understanding of this important cell type. Using cultured goldfish RGCs, RNA sequencing and de novo transcriptome assembly were performed, generating the first reference transcriptome for fish RGCs with 17,620 unique genes identified. These data revealed that RGCs express a diverse repertoire of receptors and signaling molecules, suggesting that RGCs may respond to and synthesize an array of hormones, peptides, cytokines, and growth factors. Building upon neuroanatomical data and studies investigating direct neuronal regulation of RGC physiology, differential gene expression analysis was conducted to identify transcriptional networks that are responsive to the conserved secretogranin II-derived neuropeptide secretoneurin A (SNa). Pathway analysis of the transcriptome indicated that cellular processes related to the central nervous system (e.g., neurogenesis, synaptic plasticity, glial cell development) and immune functions (e.g., immune system activation, leukocyte function, macrophage response) were preferentially modulated by SNa. These data reveal an array of new functions that are proposed to be critical to neuronal-glial interactions through the mediator SNa.
iDNAProt-ES: Identification of DNA-binding Proteins Using Evolutionary and Structural Features
Authors: Chowdhury Shahana Yasmin , Shatabda Swakkhar , Dehzangi Abdollah
Published: October 2017

DNA-binding proteins play a very important role in the structural composition of the DNA. In addition, they regulate and effect various cellular processes like transcription, DNA replication, DNA recombination, repair and modification. The experimental methods used to identify DNA-binding proteins are expensive and time consuming and thus attracted researchers from computational field to address the problem. In this paper, we present iDNAProt-ES, a DNA-binding protein prediction method that utilizes both sequence based evolutionary and structure based features of proteins to identify their DNA-binding functionality. We used recursive feature elimination to extract an optimal set of features and train them using Support Vector Machine (SVM) with linear kernel to select the final model. Our proposed method significantly outperforms the existing state-of-the-art predictors on standard benchmark dataset. The accuracy of the predictor is 90.18% using jack knife test and 88.87% using 10-fold cross validation on the benchmark dataset. The accuracy of the predictor on the independent dataset is 80.64% which is also significantly better than the state-of-the-art methods. iDNAProt-ES is a novel prediction method that uses evolutionary and structural based features. We believe the superior performance of iDNAProt-ES will motivate the researchers to use this method to identify DNA-binding proteins. iDNAProt-ES is publicly available as a web server at:http://brl.uiu.ac.bd/iDNAProt-ES/.
Heparanase and macrophage interplay in the onset of liver fibrosis
Authors: Secchi Maria Francesca , Crescenzi Marika , Masola Valentina , Russo Francesco Paolo , Floreani Annarosa , Onisto Maurizio
Published: October 2017

The heparan sulfate endoglycosidase heparanase (HPSE) is involved in tumor growth, chronic inflammation and fibrosis. Since a role for HPSE in chronic liver disease has not been demonstrated to date, the current study was aimed at investigating the involvement of HPSE in the pathogenesis of chronic liver injury. Herein, we revealed that HPSE expression increased in mouse livers after carbon tetrachloride (CCl4)-mediated chronic induction of fibrosis, but with a trend to decline during progression of the disease. In mouse fibrotic liver tissues HPSE immunostaining was restricted in necro-inflammatory areas, co-localizing with F4/80 macrophage marker and TNF-α. TNF-α treatment induced HPSE expression as well as HPSE secretion in U937 macrophages. Moreover, macrophage-secreted HPSE regulated the expression of α-SMA and fibronectin in hepatic stellate LX-2 cells. Finally, HPSE activity increased in the plasma of patients with liver fibrosis but it inversely correlated with liver stiffness. Our results suggest the involvement of HPSE in early phases of reaction to liver damage and inflammatory macrophages as an important source of HPSE. HPSE seems to play a key role in the macrophage-mediated activation of hepatic stellate cells (HSCs), thus suggesting that HPSE targeting could be a new therapeutic option in the treatment of liver fibrosis.
Implications of mitochondrial network organization in mitochondrial stress signalling in NARP cybrid and Rho0 cells
Authors: Walczak Jarosław , Partyka Małgorzata , Duszyński Jerzy , Szczepanowska Joanna
Published: October 2017

Mitochondrial dysfunctions lead to the generation of signalling mediators that influence the fate of that organelle. Mitochondrial dynamics and their positioning within the cell are important elements of mitochondria-nucleus communication. The aim of this project was to examine whether mitochondrial shape, distribution and fusion/fission proteins are involved in the mitochondrial stress response in a cellular model subjected to specifically designed chronic mitochondrial stress: WT human osteosarcoma cells as controls, NARP cybrid cells as mild chronic stress and Rho0 as severe chronic stress. We characterized mitochondrial distribution in these cells using confocal microscopy and evaluated the level of proteins directly involved in the mitochondrial dynamics and their regulation. We found that the organization of mitochondria within the cell is correlated with changes in the levels of proteins involved in mitochondrial dynamics and proteins responsible for regulation of this process. Induction of the autophagy/mitophagy process, which is crucial for cellular homeostasis under stress conditions was also shown. It seems that mitochondrial shape and organization within the cell are implicated in retrograde signalling in chronic mitochondrial stress.