bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ceramide-induced BOK promotes mitochondrial fission in preeclampsia
Authors: Ausman Jonathan , Abbade Joelcio , Ermini Leonardo , Farrell Abby , Tagliaferro Andrea , Post Martin , Caniggia Isabella 
Published: February 2018

AbstractMitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss- and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia.
Magnolol restores the activity of meropenem against NDM-1-producing Escherichia coli by inhibiting the activity of metallo-beta-lactamase
Authors: Liu Shui , Zhou Yonglin , Niu Xiaodi , Wang Tingting , Li Jiyun , Liu Zhongjie , Wang Jianfeng , Tang Shusheng , Wang Yang , Deng Xuming 
Published: February 2018

AbstractThe emergence of plasmid-mediated New Delhi metallo-β-lactamase-1 (NDM-1) in carbapenem-resistant Gram-negative pathogens is an increasing clinical threat. Here we report the discovery of an NDM-1 inhibitor, magnolol, through enzyme inhibition screening. We showed that magnolol significantly inhibited NDM enzyme activity (IC50 = 6.47 µg/mL), and it restored the activity of meropenem against Escherichia coli ZC-YN3, an NDM-1-producing E. coli isolate, in in vitro antibacterial activity assays. Magnolol lacked direct antibacterial activity, but compared with meropenem alone, it reduced the MICs of meropenem against E. coli ZC-YN3 by 4-fold and killed almost all the bacteria within 3 h. Molecular modeling and a mutational analysis demonstrated that magnolol binds directly to the catalytic pocket (residues 110 to 200) of NDM-1, thereby blocking the binding of the substrate to NDM-1 and leading to its inactivation. Our results demonstrate that the combination of magnolol and meropenem may have the potential to treat infections caused by NDM-1-positive, carbapenem-resistant Gram-negative pathogens.
Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages
Authors: Datta Debika , Khatri Preeti , Singh Ambika , Saha Dhira Rani , Verma Gaurav , Raman Rajagopal , Mazumder Shibnath 
Published: February 2018

AbstractMycobacterium fortuitum is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, Clarias sp though the mechanism remains largely unknown. We observed M. fortuitum triggers calcium (Ca2+) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER-stress in the pathogenesis of M. fortuitum. ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation. The study documents the primal role of calpain/caspase-12 axis on caspase-9 activation in M. fortuitum-pathogenesis. Mobilization of Ca2+ from ER to mitochondria led to increased mitochondrial Ca2+ (Ca2+)m load,, mitochondrial permeability transition (MPT) pore opening, altered mitochondrial membrane potential (ΔΨm) and cytochrome c release eventually activating the caspase-9/-3 cascade. Ultra-structural studies revealed close apposition of ER and mitochondria and pre-treatment with (Ca2+)m-uniporter (MUP) blocker ruthenium red, reduced Ca2+ overload suggesting (Ca2+)m fluxes are MUP-driven and the ER-mitochondria tethering orchestrates the process. This is the first report implicating role of sub-cellular Ca2+ in the pathogenesis of M. fortuitum. We summarize, the dynamics of Ca2+ in sub-cellular compartments incites ER-stress and mitochondrial dysfunction, leading to activation of pro-apoptotic calpain/caspase-12/caspase-9 axis in M. fortuitum-infected HKM.
A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state
Authors: Fahrner Marc , Stadlbauer Michael , Muik Martin , Rathner Petr , Stathopulos Peter , Ikura Mitsu , Müller Norbert , Romanin Christoph 
Published: February 2018

AbstractSTIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.
Agrochemicals increase risk of human schistosomiasis by supporting higher densities of intermediate hosts
Authors: Halstead Neal T. , Hoover Christopher M. , Arakala Arathi , Civitello David J. , De Leo Giulio A. , Gambhir Manoj , Johnson Steve A. , Jouanard Nicolas , Loerns Kristin A. , McMahon Taegan A. , Ndione Raphael A. , Nguyen Karena , Raffel Thomas R. , Remais Justin V. , Riveau Gilles , Sokolow Susanne H. , Rohr Jason R. 
Published: February 2018

AbstractSchistosomiasis is a snail-borne parasitic disease that ranks among the most important water-based diseases of humans in developing countries. Increased prevalence and spread of human schistosomiasis to non-endemic areas has been consistently linked with water resource management related to agricultural expansion. However, the role of agrochemical pollution in human schistosome transmission remains unexplored, despite strong evidence of agrochemicals increasing snail-borne diseases of wildlife and a projected 2- to 5-fold increase in global agrochemical use by 2050. Using a field mesocosm experiment, we show that environmentally relevant concentrations of fertilizer, a herbicide, and an insecticide, individually and as mixtures, increase densities of schistosome-infected snails by increasing the algae snails eat and decreasing densities of snail predators. Epidemiological models indicate that these agrochemical effects can increase transmission of schistosomes. Identifying agricultural practices or agrochemicals that minimize disease risk will be critical to meeting growing food demands while improving human wellbeing.
How ligand binds to the type 1 insulin-like growth factor receptor
Authors: Xu Yibin , Kong Geoffrey K.-W. , Menting John G. , Margetts Mai B. , Delaine Carlie A. , Jenkin Lauren M. , Kiselyov Vladislav V. , De Meyts Pierre , Forbes Briony E. , Lawrence Michael C. 
Published: February 2018

AbstractHuman type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor’s primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor.
Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Authors: Ryan Tammy , Bamm Vladimir V. , Stykel Morgan G. , Coackley Carla L. , Humphries Kayla M. , Jamieson-Williams Rhiannon , Ambasudhan Rajesh , Mosser Dick D. , Lipton Stuart A. , Harauz George , Ryan Scott D. 
Published: February 2018

AbstractNeuronal loss in Parkinson’s disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.
Clonally diverse CD38+HLA-DR+CD8+ T cells persist during fatal H7N9 disease
Authors: Wang Zhongfang , Zhu Lingyan , Nguyen Thi H. O. , Wan Yanmin , Sant Sneha , Quiñones-Parra Sergio M. , Crawford Jeremy Chase , Eltahla Auda A. , Rizzetto Simone , Bull Rowena A. , Qiu Chenli , Koutsakos Marios , Clemens E. Bridie , Loh Liyen , Chen Tianyue , Liu Lu , Cao Pengxing , Ren Yanqin , Kedzierski Lukasz , Kotsimbos Tom , McCaw James M. , La Gruta Nicole L. , Turner Stephen J. , Cheng Allen C. , Luciani Fabio , Zhang Xiaoyan , Doherty Peter C. , Thomas Paul G. , Xu Jianqing , Kedzierska Katherine 
Published: February 2018

AbstractSevere influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8+ T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38+HLA-DR+PD-1+ CD8+ T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38+HLA-DR+CD8+ T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38+HLA-DR+CD8+ T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38+HLA-DR+CD8+ T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.
Allelic decomposition and exact genotyping of highly polymorphic and structurally variant genes
Authors: Numanagić Ibrahim , Malikić Salem , Ford Michael , Qin Xiang , Toji Lorraine , Radovich Milan , Skaar Todd C. , Pratt Victoria M. , Berger Bonnie , Scherer Steve , Sahinalp S. Cenk 
Published: February 2018

AbstractHigh-throughput sequencing provides the means to determine the allelic decomposition for any gene of interest—the number of copies and the exact sequence content of each copy of a gene. Although many clinically and functionally important genes are highly polymorphic and have undergone structural alterations, no high-throughput sequencing data analysis tool has yet been designed to effectively solve the full allelic decomposition problem. Here we introduce a combinatorial optimization framework that successfully resolves this challenging problem, including for genes with structural alterations. We provide an associated computational tool Aldy that performs allelic decomposition of highly polymorphic, multi-copy genes through using whole or targeted genome sequencing data. For a large diverse sequencing data set, Aldy identifies multiple rare and novel alleles for several important pharmacogenes, significantly improving upon the accuracy and utility of current genotyping assays. As more data sets become available, we expect Aldy to become an essential component of genotyping toolkits.
High spin cycles: topping the spin record for a single molecule verging on quantum criticality
Authors: Baniodeh Amer , Magnani Nicola , Lan Yanhua , Buth Gernot , Anson Christopher E. , Richter Johannes , Affronte Marco , Schnack Jürgen , Powell Annie K. 
Published: February 2018

AbstractThe cyclisation of a short chain into a ring provides fascinating scenarios in terms of transforming a finite array of spins into a quasi-infinite structure. If frustration is present, theory predicts interesting quantum critical points, where the ground state and thus low-temperature properties of a material change drastically upon even a small variation of appropriate external parameters. This can be visualised as achieving a very high and pointed summit where the way down has an infinity of possibilities, which by any parameter change will be rapidly chosen, in order to reach the final ground state. Here we report a mixed 3d/4f cyclic coordination cluster that turns out to be very near or even at such a quantum critical point. It has a ground state spin of S = 60, the largest ever observed for a molecule (120 times that of a single electron). [Fe10Gd10(Me-tea)10(Me-teaH)10(NO3)10]·20MeCN forms a nano-torus with alternating gadolinium and iron ions with a nearest neighbour Fe–Gd coupling and a frustrating next-nearest neighbour Fe–Fe coupling. Such a spin arrangement corresponds to a cyclic delta or saw-tooth chain, which can exhibit unusual frustration effects. In the present case, the quantum critical point bears a ‘flatland’ of tens of thousands of energetically degenerate states between which transitions are possible at no energy costs with profound caloric consequences. Entropy-wise the energy flatland translates into the pointed summit overlooking the entropy landscape. Going downhill several target states can be reached depending on the applied physical procedure which offers new prospects for addressability.
Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs
Authors: Vallecillo-Hernández Jorge , Barrachina Maria Dolores , Ortiz-Masiá Dolores , Coll Sandra , Esplugues Juan Vicente , Calatayud Sara , Hernández Carlos 
Published: February 2018

AbstractNSAIDs inhibit tumorigenesis in gastrointestinal tissues and have been proposed as coadjuvant agents to chemotherapy. The ability of cancer epithelial cells to adapt to the tumour environment and to resist cytotoxic agents seems to depend on rescue mechanisms such as autophagy. In the present study we aimed to determine whether an NSAID with sensitizing properties such as indomethacin modulates autophagy in gastric cancer epithelial cells. We observed that indomethacin causes lysosomal dysfunction in AGS cells and promotes the accumulation of autophagy substrates without altering mTOR activity. Indomethacin enhanced the inhibitory effects of the lysosomotropic agent chloroquine on lysosome activity and autophagy, but lacked any effect when both functions were maximally reduced with another lysosome inhibitor (bafilomycin B1). Indomethacin, alone and in combination with chloroquine, also hindered the autophagic flux stimulated by the antineoplastic drug oxaliplatin and enhanced its toxic effect, increasing the rate of apoptosis/necrosis and undermining cell viability. In summary, our results indicate that indomethacin disrupts autophagic flux by disturbing the normal functioning of lysosomes and, by doing so, increases the sensitivity of gastric cancer cells to cytotoxic agents, an effect that could be used to overcome cancer cell resistance to antineoplastic regimes.
Skew in ovarian activation depends on domicile size in phyllode-glueing thrips
Authors: Gilbert J. D. J. , Wells A. , Simpson S. J. 
Published: February 2018

AbstractCosts and benefits of group living are a fundamental topic in behavioural ecology. Resource availability affects individuals’ breeding prospects alone and in groups, as well as how reproduction is distributed within groups (“reproductive skew”). Here, in facultatively social thrips, we provide correlational evidence that breeding resources are associated with (1) whether solitary or social living is favoured, and (2) the degree of ovarian skew.Dunatothrips aneurae(Thysanoptera, Phlaeothripidae) cooperatively build silk “domiciles” on Australian Acacias, feeding exclusively from internal phyllode surfaces.Per capitaproductivity scaled differently with group size depending on domicile volume — females in small domiciles did better alone than in groups, whereas in large domiciles single and group-nesting females did equally well. Ovarian dissections revealed that in small domiciles some females were nonreproductive, indicating ovarian (i.e. reproductive) skew. Skew increased as domicile size decreased and group size increased. Breeders had smaller oocyte volume in smaller domiciles, especially those containing nonreproductives. These findings suggest group formation and reproductive skew inD. aneuraemay be influenced by reproductive competition for breeding resources. Nonreproductive females in small domiciles may be reproductively suppressed, subfertile, or accumulating resources to reproduce.
Oligonucleotide conjugated multi-functional adeno-associated viruses
Authors: Katrekar Dhruva , Moreno Ana M. , Chen Genghao , Worlikar Atharv , Mali Prashant 
Published: February 2018

AbstractRecombinant adeno-associated viruses (AAVs) are among the most commonly used vehicles for in vivo gene delivery. However, their tropism is limited, and additionally their efficacy can be negatively affected by prevalence of neutralizing antibodies in sera. Methodologies to systematically engineer AAV capsid properties would thus be of great relevance. In this regard, we develop here multi-functional AAVs by engineering precision tethering of oligonucleotides onto the AAV surface, and thereby enabling a spectrum of nucleic-acid programmable functionalities. Towards this, we engineered genetically encoded incorporation of unnatural amino acids (UAA) bearing bio-orthogonal chemical handles onto capsid proteins. Via these we enabled site-specific coupling of oligonucleotides onto the AAV capsid surface using facile click chemistry. The resulting oligo-AAVs could be sequence specifically labeled, and also patterned in 2D using DNA array substrates. Additionally, we utilized these oligo conjugations to engineer viral shielding by lipid-based cloaks that efficaciously protected the AAV particles from neutralizing serum. We confirmed these ‘cloaked AAVs’ retained full functionality via their ability to transduce a range of cell types, and also enable robust delivery of CRISPR-Cas9 effectors. Taken together, we anticipate this programmable oligo-AAV system will have broad utility in synthetic biology and AAV engineering applications.
Increased mechanical loading through controlled swimming exercise induces bone formation and mineralization in adult zebrafish
Authors: Suniaga Santiago , Rolvien Tim , vom Scheidt Annika , Fiedler Imke A. K. , Bale Hrishikesh A. , Huysseune Ann , Witten P. Eckhard , Amling Michael , Busse Björn 
Published: February 2018

AbstractExercise promotes gain in bone mass through adaptive responses of the vertebrate skeleton. This mechanism counteracts age- and disease-related skeletal degradation, but remains to be fully understood. In life sciences, zebrafish emerged as a vertebrate model that can provide new insights into the complex mechanisms governing bone quality. To test the hypothesis that musculoskeletal exercise induces bone adaptation in adult zebrafish and to characterize bone reorganization, animals were subjected to increased physical exercise for four weeks in a swim tunnel experiment. Cellular, structural and compositional changes of loaded vertebrae were quantified using integrated high-resolution analyses. Exercise triggered rapid bone adaptation with substantial increases in bone-forming osteoblasts, bone volume and mineralization. Clearly, modeling processes in zebrafish bone resemble processes in human bone. This study highlights how exercise experiments in adult zebrafish foster in-depth insight into aging-related bone diseases and can thus catalyze the search for appropriate prevention and new treatment options.
Characterization of the quinol-dependent nitric oxide reductase from the pathogen Neisseria meningitidis, an electrogenic enzyme
Authors: Gonska Nathalie , Young David , Yuki Riki , Okamoto Takuya , Hisano Tamao , Antonyuk Svetlana , Hasnain S. Samar , Muramoto Kazumasa , Shiro Yoshitsugu , Tosha Takehiko , Ädelroth Pia 
Published: February 2018

AbstractBacterial nitric oxide reductases (NORs) catalyse the reduction of NO to N2O and H2O. NORs are found either in denitrification chains, or in pathogens where their primary role is detoxification of NO produced by the immune defense of the host. Although NORs belong to the heme-copper oxidase superfamily, comprising proton-pumping O2-reducing enzymes, the best studied NORs, cNORs (cytochrome c-dependent), are non-electrogenic. Here, we focus on another type of NOR, qNOR (quinol-dependent). Recombinant qNOR from Neisseria meningitidis, a human pathogen, purified from Escherichia coli, showed high catalytic activity and spectroscopic properties largely similar to cNORs. However, in contrast to cNOR, liposome-reconstituted qNOR showed respiratory control ratios above two, indicating that NO reduction by qNOR was electrogenic. Further, we determined a 4.5 Å crystal structure of the N. meningitidis qNOR, allowing exploration of a potential proton transfer pathway from the cytoplasm by mutagenesis. Most mutations had little effect on the activity, however the E-498 variants were largely inactive, while the corresponding substitution in cNOR was previously shown not to induce significant effects. We thus suggest that, contrary to cNOR, the N. meningitidis qNOR uses cytoplasmic protons for NO reduction. Our results allow possible routes for protons to be discussed.