bluuebunny/crossref_metadata_2025 huggingface dataset:
An “International Crime” Exception to the Immunity of State Officials from Foreign Criminal Jurisdiction: Not Currently, Not Likely
Authors: O’Keefe Roger
Published: June 2017

The happiest outcomes of the work of the International Law Commission (ILC) result when those charged with reporting on a topic elucidate the existing law with maximum objectivity and accuracy and when, where desired, they formulate such possibilities for its avowed progressive development as find a solid basis in emerging practice or international jurisprudence and are unlikely to arouse implacable opposition among members of the Commission or member states of the General Assembly. This history should be foremost in the minds of those presently leading the Commission’s work on the immunity of state officials from foreign criminal jurisdiction as they come next session to report on possible limitations on and exceptions to such immunity. Whether the eventual aim is codification or reform, any consideration of this most controverted and combustible of contemporary questions of international law that is not based on an impartial and convincing assessment of relevant state practice and international case-law and that misreads the political temper of the times will end in tears, in the Commission itself and even more so in the Sixth Committee of the General Assembly.
Considering the Role of the State: Comment on “Criminalizing Sexual Violence Against Women in Intimate Relationships”
Authors: Goldscheid Julie
Published: June 2017

International human rights frameworks offer powerful support for a range of reforms to address marital rape. Melanie Randall and Vasanthi Venkatesh’s valuable commentary, Criminalizing Sexual Violence against Women in Intimate Relationships, correctly shines a spotlight on the extent to which marital rape is still accepted in too many countries around the world, and calls for its explicit criminalization under international human rights laws. The commentary serves as an important reminder of the challenges and enduring stereotypes that prevent marital rape from being recognized globally as a human rights violation. But the commentary’s focus on criminalization as the fundamental response is unduly limited. While criminalization, whether explicit or implicit, is a core part of states’ obligations under international human rights law, centering criminal justice risks both shortchanging other approaches and obscuring the problems with criminal justice interventions. Although Randall and Venkatesh acknowledge that criminalization is but one element of a broader strategy, this essay urges a broader view. International human rights laws’ due diligence framework requires a range of responses that include the obligation to prevent, protect, and provide redress, along with the obligation to prosecute and punish. Explicitly framing states’ obligations in terms of that more comprehensive approach would reach broadly to address the cultural and social barriers that allow marital rape to continue without sanction.
Meet KELT-9b, the Hottest Exoplanet Ever Discovered
Authors: Wendel JoAnna
Published: June 2017

The exoplanet’s host star blasts it with so much radiation that it will someday evaporate.
Identifying the core seed bank of a complex boreal bacterial metacommunity
Authors: Ruiz-González Clara , Niño-García Juan Pablo , Kembel Steven W , del Giorgio Paul A
Published: June 2017

Seed banks are believed to contribute to compositional changes within and across microbial assemblages, but the application of this concept to natural communities remains challenging. Here we describe the core seed bank of a bacterial metacommunity from a boreal watershed, using the spatial distribution of bacterial operational taxonomic units (OTUs) across 223 heterogeneous terrestrial, aquatic and phyllosphere bacterial assemblages. Taxa were considered potential seeds if they transitioned from rare to abundant somewhere within the metacommunity and if they were ubiquitous and able to persist under unfavorable conditions, the latter assessed by checking their presence in three deeply sequenced samples (one soil, one river and one lake, 2.2–3 million reads per sample). We show that only a small fraction (13%) of all detected OTUs constitute a metacommunity seed bank that is shared between all terrestrial and aquatic communities, but not by phyllosphere assemblages, which seem to recruit from a different taxa pool. Our results suggest directional recruitment driven by the flow of water in the landscape, since most aquatic sequences were associated to OTUs found in a single deeply-sequenced soil sample, but only 45% of terrestrial sequences belonged to OTUs found in the two deeply-sequenced aquatic communities. Finally, we hypothesize that extreme rarity, and its interplay with water residence time and growth rates, may further constrain the size of the potential seed bank.
Linking rhizosphere microbiome composition of wild and domesticated Phaseolus vulgaris to genotypic and root phenotypic traits
Authors: Pérez-Jaramillo Juan E , Carrión Víctor J , Bosse Mirte , Ferrão Luiz F V , de Hollander Mattias , Garcia Antonio A F , Ramírez Camilo A , Mendes Rodrigo , Raaijmakers Jos M
Published: June 2017

Plant domestication was a pivotal accomplishment in human history, but also led to a reduction in genetic diversity of crop species compared to their wild ancestors. How this reduced genetic diversity affected plant–microbe interactions belowground is largely unknown. Here, we investigated the genetic relatedness, root phenotypic traits and rhizobacterial community composition of modern and wild accessions of common bean (Phaseolus vulgaris) grown in agricultural soil from the highlands of Colombia, one of the centers of common bean diversification. Diversity Array Technology-based genotyping and phenotyping of local common bean accessions showed significant genetic and root architectural differences between wild and modern accessions, with a higher specific root length for the wild accessions. Canonical Correspondence Analysis indicated that the divergence in rhizobacterial community composition between wild and modern bean accessions is associated with differences in specific root length. Along the bean genotypic trajectory, going from wild to modern, we observed a gradual decrease in relative abundance of Bacteroidetes, mainly Chitinophagaceae and Cytophagaceae, and an increase in relative abundance of Actinobacteria and Proteobacteria, in particular Nocardioidaceae and Rhizobiaceae, respectively. Collectively, these results establish a link between common bean domestication, specific root morphological traits and rhizobacterial community assembly.
Letting go: bacterial genome reduction solves the dilemma of adapting to predation mortality in a substrate-restricted environment
Authors: Baumgartner Michael , Roffler Stefan , Wicker Thomas , Pernthaler Jakob
Published: June 2017

Resource limitation and predation mortality are major determinants of microbial population dynamics, and optimization for either aspect is considered to imply a trade-off with respect to the other. Adaptation to these selective factors may, moreover, lead to disadvantages at rich growth conditions. We present an example of a concomitant evolutionary optimization to both, substrate limitation and predation in an aggregate-forming freshwater bacterial isolate, and we elucidate an underlying genomic mechanism. Bacteria were propagated in serial batch culture in a nutrient-restricted environment either with or without a bacterivorous flagellate. Strains isolated after 26 growth cycles of the predator–prey co-cultures formed as much total biomass as the ancestor at ancestral growth conditions, albeit largely reallocated to cell aggregates. A ~273 kbp genome fragment was lost in three strains that had independently evolved with predators. These strains had significantly higher growth yield on substrate-restricted media than others that were isolated from the same treatment before the excision event. Under predation pressure, the isolates with the deletion outcompeted both, the ancestor and the strains evolved without predators even at rich growth conditions. At the same time, genome reduction led to a growth disadvantage in the presence of benzoate due to the loss of the respective degradation pathway, suggesting that niche constriction might be the price for the bidirectional optimization.
Nitrogen cost minimization is promoted by structural changes in the transcriptome of N-deprivedProchlorococcuscells
Authors: Read Robert W , Berube Paul M , Biller Steven J , Neveux Iva , Cubillos-Ruiz Andres , Chisholm Sallie W , Grzymski Joseph J
Published: June 2017

Prochlorococcus is a globally abundant marine cyanobacterium with many adaptations that reduce cellular nutrient requirements, facilitating growth in its nutrient-poor environment. One such genomic adaptation is the preferential utilization of amino acids containing fewer N-atoms, which minimizes cellular nitrogen requirements. We predicted that transcriptional regulation might further reduce cellular N budgets during transient N limitation. To explore this, we compared transcription start sites (TSSs) in Prochlorococcus MED4 under N-deprived and N-replete conditions. Of 64 genes with primary and internal TSSs in both conditions, N-deprived cells initiated transcription downstream of primary TSSs more frequently than N-replete cells. Additionally, 117 genes with only an internal TSS demonstrated increased internal transcription under N-deprivation. These shortened transcripts encode predicted proteins with an average of 21% less N content compared to full-length transcripts. We hypothesized that low translation rates, which afford greater control over protein abundances, would be beneficial to relatively slow-growing organisms like Prochlorococcus. Consistent with this idea, we found that Prochlorococcus exhibits greater usage of glycine–glycine motifs, which causes translational pausing, when compared to faster growing microbes. Our findings indicate that structural changes occur within the Prochlorococcus MED4 transcriptome during N-deprivation, potentially altering the size and structure of proteins expressed under nutrient limitation.
Shifts in rhizosphere fungal community during secondary succession following abandonment from agriculture
Authors: Hannula S Emilia , Morriën Elly , de Hollander Mattias , van der Putten Wim H , van Veen Johannes A , de Boer Wietse
Published: June 2017

Activities of rhizosphere microbes are key to the functioning of terrestrial ecosystems. It is commonly believed that bacteria are the major consumers of root exudates and that the role of fungi in the rhizosphere is mostly limited to plant-associated taxa, such as mycorrhizal fungi, pathogens and endophytes, whereas less is known about the role of saprotrophs. In order to test the hypothesis that the role of saprotrophic fungi in rhizosphere processes increases with increased time after abandonment from agriculture, we determined the composition of fungi that are active in the rhizosphere along a chronosequence of ex-arable fields in the Netherlands. Intact soil cores were collected from nine fields that represent three stages of land abandonment and pulse labeled with 13CO2. The fungal contribution to metabolization of plant-derived carbon was evaluated using phospholipid analysis combined with stable isotope probing (SIP), whereas fungal diversity was analyzed using DNA-SIP combined with 454-sequencing. We show that in recently abandoned fields most of the root-derived 13C was taken up by bacteria but that in long-term abandoned fields most of the root-derived 13C was found in fungal biomass. Furthermore, the composition of the active functional fungal community changed from one composed of fast-growing and pathogenic fungal species to one consisting of beneficial and slower-growing fungal species, which may have essential consequences for the carbon flow through the soil food web and consequently nutrient cycling and plant succession.
Compaction of quasi-one-dimensional elastoplastic materials
Authors: Shaebani M. Reza , Najafi Javad , Farnudi Ali , Bonn Daniel , Habibi Mehdi
Published: June 2017

Insight into crumpling or compaction of one-dimensional objects is important for understanding biopolymer packaging and designing innovative technological devices. By compacting various types of wires in rigid confinements and characterizing the morphology of the resulting crumpled structures, here, we report how friction, plasticity and torsion enhance disorder, leading to a transition from coiled to folded morphologies. In the latter case, where folding dominates the crumpling process, we find that reducing the relative wire thickness counter-intuitively causes the maximum packing density to decrease. The segment size distribution gradually becomes more asymmetric during compaction, reflecting an increase of spatial correlations. We introduce a self-avoiding random walk model and verify that the cumulative injected wire length follows a universal dependence on segment size, allowing for the prediction of the efficiency of compaction as a function of material properties, container size and injection force.
Organic hydrogen peroxide-driven low charge potentials for high-performance lithium-oxygen batteries with carbon cathodes
Authors: Wu Shichao , Qiao Yu , Yang Sixie , Ishida Masayoshi , He Ping , Zhou Haoshen
Published: June 2017

Reducing the high charge potential is a crucial concern in advancing the performance of lithium-oxygen batteries. Here, for water-containing lithium-oxygen batteries with lithium hydroxide products, we find that a hydrogen peroxide aqueous solution added in the electrolyte can effectively promote the decomposition of lithium hydroxide compounds at the ultralow charge potential on a catalyst-free Ketjen Black-based cathode. Furthermore, for non-aqueous lithium-oxygen batteries with lithium peroxide products, we introduce a urea hydrogen peroxide, chelating hydrogen peroxide without any water in the organic, as an electrolyte additive in lithium-oxygen batteries with a lithium metal anode and succeed in the realization of the low charge potential of ∼3.26 V, which is among the best levels reported. In addition, the undesired water generally accompanying hydrogen peroxide solutions is circumvented to protect the lithium metal anode and ensure good battery cycling stability. Our results should provide illuminating insights into approaches to enhancing lithium-oxygen batteries.
Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents
Authors: Cho Choi-Fong , Wolfe Justin M. , Fadzen Colin M. , Calligaris David , Hornburg Kalvis , Chiocca E. Antonio , Agar Nathalie Y. R. , Pentelute Bradley L. , Lawler Sean E.
Published: June 2017

Culture-based blood–brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility ofin vitrobarrier properties and permeability remain as major challenges. Here, we report that self-assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robustin vitroBBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics.
Tailoring protein nanomechanics with chemical reactivity
Authors: Beedle Amy E. M. , Mora Marc , Lynham Steven , Stirnemann Guillaume , Garcia-Manyes Sergi
Published: June 2017

The nanomechanical properties of elastomeric proteins determine the elasticity of a variety of tissues. A widespread natural tactic to regulate protein extensibility lies in the presence of covalent disulfide bonds, which significantly enhance protein stiffness. The prevalent in vivo strategy to form disulfide bonds requires the presence of dedicated enzymes. Here we propose an alternative chemical route to promote non-enzymatic oxidative protein folding via disulfide isomerization based on naturally occurring small molecules. Using single-molecule force-clamp spectroscopy, supported by DFT calculations and mass spectrometry measurements, we demonstrate that subtle changes in the chemical structure of a transient mixed-disulfide intermediate adduct between a protein cysteine and an attacking low molecular-weight thiol have a dramatic effect on the protein’s mechanical stability. This approach provides a general tool to rationalize the dynamics of S-thiolation and its role in modulating protein nanomechanics, offering molecular insights on how chemical reactivity regulates protein elasticity.
Conserved linear dynamics of single-molecule Brownian motion
Authors: Serag Maged F. , Habuchi Satoshi
Published: June 2017

Macromolecular diffusion in homogeneous fluid at length scales greater than the size of the molecule is regarded as a random process. The mean-squared displacement (MSD) of molecules in this regime increases linearly with time. Here we show that non-random motion of DNA molecules in this regime that is undetectable by the MSD analysis can be quantified by characterizing the molecular motion relative to a latticed frame of reference. Our lattice occupancy analysis reveals unexpected sub-modes of motion of DNA that deviate from expected random motion in the linear, diffusive regime. We demonstrate that a subtle interplay between these sub-modes causes the overall diffusive motion of DNA to appear to conform to the linear regime. Our results show that apparently random motion of macromolecules could be governed by non-random dynamics that are detectable only by their relative motion. Our analytical approach should advance broad understanding of diffusion processes of fundamental relevance.
Single-mutation fitness landscapes for an enzyme on multiple substrates reveal specificity is globally encoded
Authors: Wrenbeck Emily E. , Azouz Laura R. , Whitehead Timothy A.
Published: June 2017

Our lack of total understanding of the intricacies of how enzymes behave has constrained our ability to robustly engineer substrate specificity. Furthermore, the mechanisms of natural evolution leading to improved or novel substrate specificities are not wholly defined. Here we generate near-comprehensive single-mutation fitness landscapes comprising >96.3% of all possible single nonsynonymous mutations for hydrolysis activity of an amidase expressed in E. coli with three different substrates. For all three selections, we find that the distribution of beneficial mutations can be described as exponential, supporting a current hypothesis for adaptive molecular evolution. Beneficial mutations in one selection have essentially no correlation with fitness for other selections and are dispersed throughout the protein sequence and structure. Our results further demonstrate the dependence of local fitness landscapes on substrate identity and provide an example of globally distributed sequence-specificity determinants for an enzyme.
Structural basis of HypK regulating N-terminal acetylation by the NatA complex
Authors: Weyer Felix Alexander , Gumiero Andrea , Lapouge Karine , Bange Gert , Kopp Jürgen , Sinning Irmgard
Published: June 2017

In eukaryotes, N-terminal acetylation is one of the most common protein modifications involved in a wide range of biological processes. Most N-acetyltransferase complexes (NATs) act co-translationally, with the heterodimeric NatA complex modifying the majority of substrate proteins. Here we show that the Huntingtin yeast two-hybrid protein K (HypK) binds tightly to the NatA complex comprising the auxiliary subunit Naa15 and the catalytic subunit Naa10. The crystal structures of NatA bound to HypK or to a N-terminal deletion variant of HypK were determined without or with a bi-substrate analogue, respectively. The HypK C-terminal region is responsible for high-affinity interaction with the C-terminal part of Naa15. In combination with acetylation assays, the HypK N-terminal region is identified as a negative regulator of the NatA acetylation activity. Our study provides mechanistic insights into the regulation of this pivotal protein modification.
Erratum: Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations
Authors: Brown David , Smeets Dominiek , Székely Borbála , Larsimont Denis , Szász A. Marcell , Adnet Pierre-Yves , Rothé Françoise , Rouas Ghizlane , Nagy Zsófia I , Faragó Zsófia , Tőkés Anna-Mária , Dank Magdolna , Szentmártoni Gyöngyvér , Udvarhelyi Nóra , Zoppoli Gabriele , Pusztai Lajos , Piccart Martine , Kulka Janina , Lambrechts Diether , Sotiriou Christos , Desmedt Christine
Published: June 2017

Nature Communications 8: Article number: 14944 (2017); Published: 21 Apr 2017; Updated: 6 Jun 2017 The HTML version of this Article previously published had an incorrect publication date of 20 April 2017; it should have been 21 April 2017. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication.
Mechanism of microtubule stabilization by taccalonolide AJ
Authors: Wang Yuxi , Yu Yamei , Li Guo-Bo , Li Shu-Ang , Wu Chengyong , Gigant Benoît , Qin Wenming , Chen Hao , Wu Yangping , Chen Qiang , Yang Jinliang
Published: June 2017

As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin–AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.
Lipidomic analysis of skeletal muscle tissues of p53 knockout mice by nUPLC-ESI-MS/MS
Authors: Park Se Mi , Byeon Seul Kee , Lee Hojun , Sung Hyerim , Kim Il Yong , Seong Je Kyung , Moon Myeong Hee
Published: June 2017

Tumour suppressor p53 is known to be associated with the maintenance of mitochondrial functional properties in the skeletal muscles. As deactivation or mutation of p53 can affect the synthesis of lipids, investigating the relationship between p53-related energy generation metabolism and perturbation of lipid profile is critical. In this study, 329 lipid species (among 412 identified species) in two different skeletal muscle tissues (the gastrocnemius and soleus) from p53 knockout (KO) mice were quantitatively analysed using nanoflow ultrahigh performance liquid chromatography tandem mass spectrometry (nUPLC-MS/MS). Overall, lipids from the soleus tissues were more affected by p53 KO than those from the gastrocnemius in most lipid profiles. In p53 KO, lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), phosphatidic acid (PA), sphingomyelin (SM), and triacylglycerol (TAG), including 6 TAG (44:2, 46:0, 58:5, 58:8, 58:9, and 50:0), were significantly increased (p < 0.05) by 1.4–2-fold only in the soleus tissue. Overall monohexosylceramide (MHC) levels, including those of 3 MHC species (d18:0/24:0, d18:1/22:0, and d18:1/24:0), were significantly increased (p < 0.05) by 2–4 fold, only in the gastrocnemius tissue. The results suggest that lipid profiles are significantly altered by the lack of p53 in muscle tissues.
A Novel Strategy to Engineer Pre-Vascularized Full-Length Dental Pulp-like Tissue Constructs
Authors: Athirasala Avathamsa , Lins Fernanda , Tahayeri Anthony , Hinds Monica , Smith Anthony J. , Sedgley Christine , Ferracane Jack , Bertassoni Luiz E.
Published: June 2017

The requirement for immediate vascularization of engineered dental pulp poses a major hurdle towards successful implementation of pulp regeneration as an effective therapeutic strategy for root canal therapy, especially in adult teeth. Here, we demonstrate a novel strategy to engineer pre-vascularized, cell-laden hydrogel pulp-like tissue constructs in full-length root canals for dental pulp regeneration. We utilized gelatin methacryloyl (GelMA) hydrogels with tunable physical and mechanical properties to determine the microenvironmental conditions (microstructure, degradation, swelling and elastic modulus) that enhanced viability, spreading and proliferation of encapsulated odontoblast-like cells (OD21), and the formation of endothelial monolayers by endothelial colony forming cells (ECFCs). GelMA hydrogels with higher polymer concentration (15% w/v) and stiffness enhanced OD21 cell viability, spreading and proliferation, as well as endothelial cell spreading and monolayer formation. We then fabricated pre-vascularized, full-length, dental pulp-like tissue constructs by dispensing OD21 cell-laden GelMA hydrogel prepolymer in root canals of extracted teeth and fabricating 500 µm channels throughout the root canals. ECFCs seeded into the microchannels successfully formed monolayers and underwent angiogenic sprouting within 7 days in culture. In summary, the proposed approach is a simple and effective strategy for engineering of pre-vascularized dental pulp constructs offering potentially beneficial translational outcomes.
Coral lipid bodies as the relay center interconnecting diel-dependent lipidomic changes in different cellular compartments
Authors: Chen Hung-Kai , Wang Li-Hsueh , Chen Wan-Nan U. , Mayfield Anderson B. , Levy Oren , Lin Chan-Shing , Chen Chii-Shiarng
Published: June 2017

Lipid bodies (LBs) in the coral gastrodermal tissues are key organelles in the regulation of endosymbiosis and exhibit a diel rhythmicity. Using the scleractinian Euphyllia glabrescens collected across the diel cycle, we observed temporally dynamic lipid profiles in three cellular compartments: host coral gastrodermal cells, LBs, and in hospite Symbiodinium. Particularly, the lipidome varied over time, demonstrating the temporally variable nature of the coral–Symbiodinium endosymbiosis. The lipidome-scale data highlight the dynamic, light-driven metabolism of such associations and reveal that LBs are not only lipid storage organelles but also act as a relay center in metabolic trafficking. Furthermore, lipogenesis in LBs is significantly regulated by coral hosts and the lipid metabolites within holobionts featured predominantly triacylglycerols, sterol esters, and free fatty acids. Given these findings through a time-varied lipidome status, the present study provided valuable insights likely to be crucial to understand the cellular biology of the coral–Symbiodinium endosymbiosis.
Early oxygen therapy does not protect the brain from vasogenic edema following acute ischemic stroke in adult male rats
Authors: Pasban Elmira , Panahpour Hamdollah , Vahdati Akbar
Published: June 2017

Brain edema aggravates primary brain injury and increases its mortality rate after ischemic stroke. It is believed that normobaric oxygen therapy (NBO) may produce neuroprotective effects against ischemic stroke; however, reports have been controversial, and its effects on vasogenic brain edema as a major complication of brain ischemia have not been clarified. The present study investigates the effects of NBO on cerebral edema and blood – brain barrier integrity using rat model of ischemic stroke. Transient focal cerebral ischemia was induced in adult male Sprague-Dawley rats by left middle cerebral artery occlusion (MCAO) for 90 min followed by 24 h reperfusion. Early NBO supplementation was started 15 min after MCAO and continued for 90 min. The results of the present study show that early oxygen therapy following acute ischemic stroke does not reduce vasogenic brain edema, nor does it protect against oxidative stress-induced BBB destruction. Additionally, cerebral edema formation occurs in conjunction with an increased mortality rate, serious brain injury, and impairment of brain antioxidant power. These findings suggest that further experimental studies should be carried out to clarify the beneficial effects and potential side effects of early oxygen therapy in acute ischemic stroke before its clinical use.
Cerebrospinal fluid microRNAs are potential biomarkers of temporal lobe epilepsy and status epilepticus
Authors: Raoof Rana , Jimenez-Mateos Eva M. , Bauer Sebastian , Tackenberg Björn , Rosenow Felix , Lang Johannes , Onugoren Müjgan Dogan , Hamer Hajo , Huchtemann Tessa , Körtvélyessy Peter , Connolly Niamh M. C. , Pfeiffer Shona , Prehn Jochen H. M. , Farrell Michael A. , O’Brien Donncha F. , Henshall David C. , Mooney Catherine
Published: June 2017

There is a need for diagnostic biomarkers of epilepsy and status epilepticus to support clinical examination, electroencephalography and neuroimaging. Extracellular microRNAs may be potentially ideal biomarkers since some are expressed uniquely within specific brain regions and cell types. Cerebrospinal fluid offers a source of microRNA biomarkers with the advantage of being in close contact with the target tissue and sites of pathology. Here we profiled microRNA levels in cerebrospinal fluid from patients with temporal lobe epilepsy or status epilepticus, and compared findings to matched controls. Differential expression of 20 microRNAs was detected between patient groups and controls. A validation phase included an expanded cohort and samples from patients with other neurological diseases. This identified lower levels of miR-19b in temporal lobe epilepsy compared to controls, status epilepticus and other neurological diseases. Levels of miR-451a were higher in status epilepticus compared to other groups whereas miR-21-5p differed in status epilepticus compared to temporal lobe epilepsy but not to other neurological diseases. Targets of these microRNAs include proteins regulating neuronal death, tissue remodelling, gliosis and inflammation. The present study indicates cerebrospinal fluid contains microRNAs that can support differential diagnosis of temporal lobe epilepsy and status epilepticus from other neurological and non-neurological diseases.
Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
Authors: Cheng Shanmei , Song Wanling , Yuan Xiaojing , Xu Yechun
Published: June 2017

Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer’s disease. To facilitate the massive pass-through of the substrate and inhibitors, “breathing” motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer ofTorpedo californicaacetylcholinesterase (TcAChE) as well as the complex ofTcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Ω-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.
Two-step ATP-driven opening of cohesin head
Authors: Marcos-Alcalde Íñigo , Mendieta-Moreno Jesús I. , Puisac Beatriz , Gil-Rodríguez María Concepción , Hernández-Marcos María , Soler-Polo Diego , Ramos Feliciano J. , Ortega José , Pié Juan , Mendieta Jesús , Gómez-Puertas Paulino
Published: June 2017

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.
Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma
Authors: Wang Kun , Ge Yichen , Ni Chao , Cui Bomiao , Du Jintao , Zhang Bo , Hu Xiaoyu , Chen Jiao , Xiao Liying , Sun Chongkui , Li Yan
Published: June 2017

Telomerase Cajal body protein 1 (TCAB1), which is involved in Cajal body maintenance, telomere elongation and ribonucleoprotein biogenesis, has been linked to cancer predisposition, including nasopharyngeal carcinoma (NPC), due to its oncogenic properties. However, there are no specific reports to date on the functional relevance of TCAB1 and Epstein–Barr virus (EBV), which is considered to be a risk factor for NPC. In this study, we first examined NPC clinical tissues and found a notable overexpression of TCAB1 in EBV-positive specimens. Secondly, on a cellular level, we also observed that TCAB1 expression rose gradually along with the increased duration of EBV exposure in NPC cell lines. Additionally, EBV infection promoted cell proliferation and telomerase activity, but the activation was significantly inhibited after TCAB1 knockdown. Moreover, depletion of TCAB1 caused both cell cycle arrest and apoptosis, and suppressed the activation of ataxia telangiectasia and Rad3 related protein (ATR) induced by EBV, resulting in accumulation of DNA damage. Taken together, we here demonstrate that up-regulated expression of TCAB1, induced by EBV in the development of NPC, is involved in stimulating telomerase activity and regulating the DNA damage response within the context of EBV infection.
Functional characterization of Aquaporin-like genes in the human bed bug Cimex lectularius
Authors: Tsujimoto Hitoshi , Sakamoto Joyce M. , Rasgon Jason L.
Published: June 2017

The bed bug Cimex lectularius is a blood-feeding re-emerging annoyance pest insect that has the ability to transmit Trypanosoma cruzi under experimental laboratory conditions. Aquaporins (AQPs) are water channel proteins that are essential in biological organisms. C. lectularius are constantly exposed to water-related stress, suggesting that AQPs may offer novel control avenues. We identified and cloned four AQPs from C. lectularius, assessed tissue and lifestage-specific expression, and characterized biochemical functions in vitro and in vivo. We identified an efficient water-specific AQP (ClAQP1), two aquaglyceroporins (ClGlp1 and ClGlp2) and a homolog of Drosophila melanogaster big brain (ClBib). ClGlp1 was only functional when co-expressed with the water-specific AQP. Simultaneous RNAi gene silencing of ClAQP1 and ClGlp1 significantly reduced water and urea excretion post blood feeding. The Bib homologue was enriched in embryos, exclusively expressed in ovaries, and when silenced, dramatically increased bug fecundity. Our data demonstrate that AQPs have critical roles in excretion, water homeostasis and reproduction in C. lectularius, and could be potential targets for control in this notorious pest.
Early Gut Microbiota Intervention Suppresses DSS-Induced Inflammatory Responses by Deactivating TLR/NLR Signalling in Pigs
Authors: Xiao Yi , Yan Honglin , Diao Hui , Yu Bing , He Jun , Yu Jie , Zheng Ping , Mao Xiangbing , Luo Yuheng , Chen Daiwen
Published: June 2017

Recent metagenomic studies suggest that innate and adaptive immune phenotypes can be programmed via gut microbiota-host interactions mediated via activation of pattern recognition receptors (PRRs) on host cells. In this study, we used two extremely different pig lines (the Yorkshire and the Tibetan) to test the hypothesis that the transplantation of gut microbiota could transfer certain immunologic characteristics from donor to recipient. The faecal microbiota of these two pig lines was transplanted in healthy commercial hybrid newborn piglets to establish the “Tibetan-intervened” and “Yorkshire-intervened” porcine models. Then, acute colitis was induced using dextran sulphate sodium (DSS), which activated Toll-/NOD-like receptor (TLR/NLR) signalling in the colonic tissues of the “Yorkshire-intervened” piglets, leading to increases in pro-inflammatory cytokines and immune cells and causing intestinal injuries. Conversely, DSS administration had little influence on the “Tibetan-intervened” piglets, which showed no significant inflammation and no changes in cytokines, immune cells, or signalling molecules, including TLRs, NLRs, MYD88 and NF-κB, after DSS treatment. These results indicate that pigs inoculated with the Tibetan microbiota acquired relatively strong resistance to experimental colitis, suggesting that the genotype of the host contributes to the uniqueness of its intestinal microbial community, whereas the microbiota plays a vital role in programming the immune phenotypes of the host.
Irregular sleep/wake patterns are associated with poorer academic performance and delayed circadian and sleep/wake timing
Authors: Phillips Andrew J. K. , Clerx William M. , O’Brien Conor S. , Sano Akane , Barger Laura K. , Picard Rosalind W. , Lockley Steven W. , Klerman Elizabeth B. , Czeisler Charles A.
Published: June 2017

The association of irregular sleep schedules with circadian timing and academic performance has not been systematically examined. We studied 61 undergraduates for 30 days using sleep diaries, and quantified sleep regularity using a novel metric, the sleep regularity index (SRI). In the most and least regular quintiles, circadian phase and light exposure were assessed using salivary dim-light melatonin onset (DLMO) and wrist-worn photometry, respectively. DLMO occurred later (00:08 ± 1:54 vs. 21:32 ± 1:48; p < 0.003); the daily sleep propensity rhythm peaked later (06:33 ± 0:19 vs. 04:45 ± 0:11; p < 0.005); and light rhythms had lower amplitude (102 ± 19 lux vs. 179 ± 29 lux; p < 0.005) in Irregular compared to Regular sleepers. A mathematical model of the circadian pacemaker and its response to light was used to demonstrate that Irregular vs. Regular group differences in circadian timing were likely primarily due to their different patterns of light exposure. A positive correlation (r = 0.37; p < 0.004) between academic performance and SRI was observed. These findings show that irregular sleep and light exposure patterns in college students are associated with delayed circadian rhythms and lower academic performance. Moreover, the modeling results reveal that light-based interventions may be therapeutically effective in improving sleep regularity in this population.
Reproductive Isolation through Experimental Manipulation of Sexually Antagonistic Coevolution in Drosophila melanogaster
Authors: Syed Zeeshan Ali , Chatterjee Martik , Samant Manas Arun , Prasad Nagaraj Guru
Published: June 2017

Promiscuity can drive the evolution of sexual conflict before and after mating occurs. Post mating, the male ejaculate can selfishly manipulate female physiology, leading to a chemical arms race between the sexes. Theory suggests that drift and sexually antagonistic coevolution can cause allopatric populations to evolve different chemical interactions between the sexes, thereby leading to postmating reproductive barriers and speciation. There is, however, little empirical evidence supporting this form of speciation. We tested this theory by creating an experimental evolutionary model ofDrosophila melanogasterpopulations undergoing different levels of interlocus sexual conflict. We found that allopatric populations under elevated sexual conflict show assortative mating, indicating premating reproductive isolation. Further, these allopatric populations also show reduced copulation duration and sperm defense ability when mating happens between individuals across populations compared to that within the same population, indicating postmating prezygotic isolation. Sexual conflict can cause reproductive isolation in allopatric populations through the coevolution of chemical (postmating prezygotic) as well as behavioural (premating) interactions between the sexes. Thus, to our knowledge, we provide the first comprehensive evidence of postmating (as well as premating) reproductive isolation due to sexual conflict.
L12 ordering and δ′ precipitation in Al-Cu-Li
Authors: Neibecker Pascal , Leitner Michael , Kushaim Muna , Boll Torben , Anjum Dalaver , Al-Kassab Tala’at , Haider Ferdinand
Published: June 2017

The precipitation mechanism of the δ′ (Al3Li) phase in Al-Li alloys has been controversially discussed in recent decades, specifically with respect to a conjectured congruent ordering process. However, kinetics in the Al-Li system does not allow to resolve the intermediate stages of precipitation and hence to experimentally clarify this issue. In this paper, we are revisiting the subject in ternary Al-Cu-Li alloys with pronouncedly slower kinetics, employing Transmission Electron Microscopy, High-Angle Annular Dark-Field Scanning Transmission Electron Microscopy, Differential Scanning Calorimetry and Atom Probe Tomography. The results show clear evidence for congruent ordering in a selected compositional range, revealing an already strongly L12 ordered microstructure after natural aging with a chemically homogeneous Li distribution and a decomposition of the alloy upon annealing at elevated temperatures. The presented study of the δ′ precipitation evaluates the reaction pathway of this process and compares it to the predictions of the Bragg-Williams-Gorsky model with respect to decomposition and ordering in this alloy system.
Climate variability and trends at a national scale
Authors: Xu Zhenci , Tang Ying , Connor Thomas , Li Dapeng , Li Yunkai , Liu Jianguo
Published: June 2017

Climate variability and trends have significant environmental and socioeconomic impacts. Global challenges such as food security, biodiversity loss, water scarcity and human health are affected by reference evapotranspiration, temperature, solar radiation, and precipitation together, but nonlinear dynamics of these four climatic factors have not been assessed simultaneously at the national scale. This leads to unclear climatic dynamics and limited applications. To address this knowledge gap, we analyzed the daily variability and trends of four climatic factors (reference evapotranspiration, temperature, solar radiation, and precipitation) in China simultaneously using high spatial resolution data from 1960 to 2013. The results indicate that the daily variability of climate system dynamics (quantified by multiplying fractal dimensions of the four climatic factors) in north China was higher than that in south China. For example, the climate system dynamics were more chaotic and with higher nonlinear variation in north China, most notably in Heilongjiang Province, the major grain base of China, posing threats to food security in the context of growing national population. Spatial distribution of variability varies among different climatic factors. Our study highlights the need for a more holistic study of climate variability and trends in other countries with multiple climate types to address challenges of sustainable development.
Non-iterative Directional Dark-field Tomography
Authors: Schaff Florian , Prade Friedrich , Sharma Yash , Bech Martin , Pfeiffer Franz
Published: June 2017

Dark-field imaging is a scattering-based X-ray imaging method that can be performed with laboratory X-ray tubes. The possibility to obtain information about unresolvable structures has already seen a lot of interest for both medical and material science applications. Unlike conventional X-ray attenuation, orientation dependent changes of the dark-field signal can be used to reveal microscopic structural orientation. To date, reconstruction of the three-dimensional dark-field signal requires dedicated, highly complex algorithms and specialized acquisition hardware. This severely hinders the possible application of orientation-dependent dark-field tomography. In this paper, we show that it is possible to perform this kind of dark-field tomography with common Talbot-Lau interferometer setups by reducing the reconstruction to several smaller independent problems. This allows for the reconstruction to be performed with commercially available software and our findings will therefore help pave the way for a straightforward implementation of orientation-dependent dark-field tomography.
A translational approach to capture gait signatures of neurological disorders in mice and humans
Authors: Broom Lauren , Ellison Brian A. , Worley Audrey , Wagenaar Lara , Sörberg Elina , Ashton Christine , Bennett David A. , Buchman Aron S. , Saper Clifford B. , Shih Ludy C. , Hausdorff Jeffrey M. , VanderHorst Veronique G.
Published: June 2017

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species. In mice, we represented spatial and temporal gait parameters as a function of velocity and established regression models that reproducibly capture the signatures of these relationships during walking. In experimental parkinsonism models, regression curves representing these relationships shifted from baseline, implicating changes in gait signatures, but with marked differences between models. Gait parameters in healthy human subjects followed similar strict velocity dependent relationships which were altered in Parkinson’s patients in ways that resemble some but not all mouse models. This novel approach is suitable to quantify qualitative walking abnormalities related to CNS circuit dysfunction across species, identify appropriate animal models, and it provides important translational opportunities.