bluuebunny/crossref_metadata_2025 huggingface dataset:
NMR chemical shift analysis decodes olefin oligo- and polymerization activity of d
0
group 4 metal complexes
Authors: Gordon Christopher P. , Shirase Satoru , Yamamoto Keishi , Andersen Richard A. , Eisenstein Odile , Copéret Christophe
Published: June 2018

Significance

The rational understanding and design of catalysts pose major challenges to chemists. While catalysts are involved in around 90% of industrial chemical processes, their discovery and development are usually based on screening and serendipity. Here, we show through a detailed analysis of the NMR chemical shift that the activity of olefin polymerization and oligomerization catalysts is directly related to the chemical shift of the carbon atom bound to the metal center. This relation is traced to specific frontier molecular orbitals, which induce π-character in the metal-alkyl bond, thereby favoring insertion. This result not only reveals a surprising analogy between olefin polymerization and metathesis, but also establishes chemical shift as a predictive descriptor for catalytic activity in these industrially relevant processes.
Confining electrodeposition of metals in structured electrolytes
Authors: Choudhury Snehashis , Vu Duylinh , Warren Alexander , Tikekar Mukul D. , Tu Zhengyuan , Archer Lynden A.
Published: June 2018

Significance

Electrochemical cells based on lithium and sodium metal anodes are considered among the most versatile platforms for high-energy electrical energy storage. Unfortunately, unstable dendritic metal deposition at currents below the diffusion limit lead to premature cell failure by internal short circuits. In a volatile electrolyte, the ohmic heat generated by these shorts pose significant safety risks. The article reports that electrodeposition of metals can be stabilized by confining ion transport to length scales below a few hundred nanometers. It is also shown that dendrite growth can be arrested in electrolytes with mechanical moduli well below that of the metal. This finding contradicts current orthodoxy, which holds that solid-state electrolytes with moduli higher than the metal are required for preventing dendrite growth.
A stress recovery signaling network for enhanced flooding tolerance inArabidopsis thaliana
Authors: Yeung Elaine , van Veen Hans , Vashisht Divya , Sobral Paiva Ana Luiza , Hummel Maureen , Rankenberg Tom , Steffens Bianka , Steffen-Heins Anja , Sauter Margret , de Vries Michel , Schuurink Robert C. , Bazin Jérémie , Bailey-Serres Julia , Voesenek Laurentius A. C. J. , Sasidharan Rashmi
Published: June 2018

Significance

Flooding due to extreme weather events can be highly detrimental to plant development and yield. Speedy recovery following stress removal is an important determinant of tolerance, yet mechanisms regulating this remain largely uncharacterized. We identified a regulatory network inArabidopsis thalianathat controls water loss and senescence to influence recovery from prolonged submergence. Targeted control of the molecular mechanisms facilitating stress recovery identified here could potentially improve performance of crops in flood-prone areas.
Potent laminin-inspired antioxidant regenerative dressing accelerates wound healing in diabetes
Authors: Zhu Yunxiao , Cankova Zdravka , Iwanaszko Marta , Lichtor Sheridan , Mrksich Milan , Ameer Guillermo A.
Published: June 2018

Significance

The clinical management of nonhealing ulcers requires advanced materials that improve wound-closure rates without relying on the release of drugs or other growth factors that could potentially lead to concerns regarding systemic deleterious side effects. We report the synthesis, characterization, and performance of a biodegradable antioxidant shape-conforming regenerative dressing that exploits α3β1 and α6β1 integrin-binding interactions to promote dermal tissue regeneration. A laminin-derived peptide grafted onto a thermoresponsive citrate-based macromolecular scaffold facilitates the adhesion and spreading of skin cells throughout the hydrogel and also significantly increases cell proliferation and migration in an integrin-dependent manner. We use a splinted excisional wound diabetic mouse model to demonstrate that application of this thermoresponsive regenerative dressing significantly accelerates wound closure in vivo.
River landscapes and optimal channel networks
Authors: Balister Paul , Balogh József , Bertuzzo Enrico , Bollobás Béla , Caldarelli Guido , Maritan Amos , Mastrandrea Rossana , Morris Robert , Rinaldo Andrea
Published: June 2018

Significance

Optimal channel networks (OCNs) are a well-studied static model of river network structures. We present exact results showing that every OCN is a natural river tree where a landscape exist such that the flow directions are always directed along its steepest descent. We characterize the family of natural river trees in terms of certain forbidden structures, called “

k

-path obstacles.” We thus determine conditions for river landscapes to imply a rooted tree as its network of topographic gradients. Our results are significant in particular for applications where OCNs may be used to produce statistically identical replicas of realistic matrices for ecological interactions.
Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells
Authors: Shen Erxia , Wang Qin , Rabe Hardis , Liu Wenquan , Cantor Harvey , Leavenworth Jianmei W.
Published: June 2018

Significance

Production of high-affinity antibody responses after infection or vaccination requires precise control of germinal center B cells by follicular helper T cells and follicular regulatory T cells. Although the Bcl6 transcription factor plays a central role in follicular T cell differentiation, the molecular basis of Bcl6 control has been clouded in uncertainty. Here we report that Bcl6-dependent control reflects the formation of a macromolecular complex between Bcl6 and the Mi-2β-nucleosome remodeling deacetylase complex (Mi-2β-NuRD). The repressive activity of this intranuclear complex potentiates the follicular T cell phenotype and inhibits alternative T cell fates. Identification of this intracellular complex may facilitate new targeted approaches to the treatment of autoimmune disorders.
Competition for mates and the improvement of nonsexual fitness
Authors: Yun Li , Chen Patrick J. , Kwok Kevin E. , Angell Christopher S. , Rundle Howard D. , Agrawal Aneil F.
Published: June 2018

Significance

Competition for mates is often intense. The resulting selection can have pervasive effects across the genome, potentially affecting components of nonsexual fitness. There is controversy over whether these effects on nonsexual fitness occur and, if so, their direction. Past studies have yielded variable results but without providing insight into why outcomes vary. Here, we show that when mate competition occurs in an environment in which male harassment is weak, there are substantial benefits in terms of the rate of adaptation to novel larval conditions as well as the purging of inbreeding depression. In contrast, these benefits are absent when mate competition occurs in an environment in which male harassment is strong.
A noncanonical PPARγ/RXRα-binding sequence regulates leptin expression in response to changes in adipose tissue mass
Authors: Zhang Yinxin , Dallner Olof Stefan , Nakadai Tomoyoshi , Fayzikhodjaeva Gulya , Lu Yi-Hsueh , Lazar Mitchell A. , Roeder Robert G. , Friedman Jeffrey M.
Published: June 2018

Significance

Leptin gene expression is highly correlated with the lipid content of individual fat cells, suggesting that it is regulated by a “fat-sensing” signal transduction pathway. This possibility is thus analogous to the identification of a cholesterol-sensing pathway by studying the regulation of the LDL receptor gene by intracellular cholesterol. Several lines of investigation have suggested that, in addition to adipocytes, liver, neurons, and other cell types can sense changes in lipid content, although the molecular mechanisms are unknown. The data here provide a critical step toward elucidating the components of this putative system, which would be of great importance. These studies also identify a previously underappreciated role of the PPARγ/RXRα complex to regulate leptin expression.
Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis
Authors: Amin Palak , Florez Marcus , Najafov Ayaz , Pan Heling , Geng Jiefei , Ofengeim Dimitry , Dziedzic Slawomir A. , Wang Huibing , Barrett Vica Jean , Ito Yasushi , LaVoie Matthew J. , Yuan Junying
Published: June 2018

Significance

This study demonstrates a distinct mode of RIPK1 activation mediated by a detergent-insoluble, highly ubiquitinated, activated RIPK1 species (iuRIPK1) which functions as a critical intermediate between TNF-receptor-associated complex I and assembly of the cytosolic caspase activation platform complex II in RIPK1-dependent apoptosis (RDA). By conducting a systematic screen for RDA regulators, we reveal the regulation of iuRIPK1 by Parkinson’s disease (PD)-associated LRRK2, E3 ubiquitin ligase c-Cbl, and ALS-associated NEK1. These results point to possible mechanistic links between RIPK1-mediated apoptosis and neurodegenerative diseases such as ALS and PD.
The significance of the discursive strategies in al-Baghdadi’s and al-Zawahiri’s hortatory speeches
Authors: Mohammed Al-Rikaby Ali Badeen , Mahadi Tengku Sepora Tengku
Published: June 2018

Recently, jihadi rhetoric has been employed extensively to ordain a justified violence and to incorporate radical groups’ identifications. In this article, the researchers take Reisigl’s and Wodak’s discourse – historical approach (2001; 2009), van Dijk’s ideological square (1998: 267) and Chilton’s binary concepts in political discourse (2004: 197–205) to show the significance of the discursive strategies in Abu Bakr al-Baghdadi’s and Ayman al-Zawahiri’s jihadi rhetoric used to establish their so-called Islamic State. We present two exemplary calls for jihad by al-Zawahiri (2006) and al-Baghdadi (2015) to exemplify their jihadist ideology giving much focus to in-group and out-group representations in their speeches and to their social impacts on Muslim societies over the last ten years. We argue further that such calls are abusive to Islamic religion and are designed in historical, pragmatic and communicative contexts (as mental models) to gain political legitimacy.
The Reception of Annius of Viterbo’s Forgeries: TheAntiquitiesin Renaissance France
Authors: Rothstein Marian
Published: June 2018

Annius of Viterbo’s 1498 “Antiquitatum Variarum Volumina XVII” (“Antiquities”), created to enhance the reputation of his native Viterbo, was a collection of spurious texts and commentary attributed to early Near Eastern authors of whom only fragments survive. Quickly spotted as spuria, they nonetheless flourished in France. This essay traces the use of Annius’s forgeries by Jean Lemaire de Belges, for whose “Illustrations” they were seminal; mid-sixteenth-century historians followed Lemaire’s lead. The “Antiquities” captivated Guillaume Postel and Guy Le Fèvre de la Boderie. They supported a history grounded on chronology, etymology, and genealogy, becoming essential to proofs of the glory and antiquity of France.
What Preferences Really Are
Authors: Angner Erik
Published: June 2018

Daniel M. Hausman holds that preferences in economics are total subjective comparative evaluations—subjective judgments to the effect that something is better than something else all things told—and that economists are right to employ this conception of preference. Here, I argue against both parts of Hausman’s thesis. The failure of Hausman’s account, I continue, reflects a deeper problem, that is, that preferences in economics do not need an explicit definition of the kind that he seeks. Nonetheless, Hausman’s labors were not in vain: his accomplishment is that he has articulated a useful model of the theory.
Neural Basis of Sensorimotor Plasticity in Speech Motor Adaptation
Authors: Darainy Mohammad , Vahdat Shahabeddin , Ostry David J
Published: June 2018

When we speak, we get correlated sensory feedback from speech sounds and from the muscles and soft tissues of the vocal tract. Here we dissociate the contributions of auditory and somatosensory feedback to identify brain networks that underlie the somatic contribution to speech motor learning. The technique uses a robotic device that selectively alters somatosensory inputs in combination with resting-state fMRI scans that reveal learning-related changes in functional connectivity. A partial correlation analysis is used to identify connectivity changes that are not explained by the time course of activity in any other learning-related areas. This analysis revealed changes related to behavioral improvements in movement and separately, to changes in auditory perception: Speech motor adaptation itself was associated with connectivity changes that were primarily in non-motor areas of brain, specifically, to a strengthening of connectivity between auditory and somatosensory cortex and between presupplementary motor area and the inferior parietal lobule. In contrast, connectively changes associated with alterations to auditory perception were restricted to speech motor areas, specifically, primary motor cortex and inferior frontal gyrus. Overall, our findings show that during adaptation, somatosensory inputs result in a broad range of changes in connectivity in areas associated with speech motor control and learning.
Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications
Authors: Ferdinandy Péter , Baczkó István , Bencsik Péter , Giricz Zoltán , Görbe Anikó , Pacher Pál , Varga Zoltán V , Varró András , Schulz Rainer
Published: June 2018

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.
On the Mean Euler Characteristic of Gorenstein Toric Contact Manifolds
Authors: Abreu Miguel , Macarini Leonardo
Published: June 2018

We prove that the mean Euler characteristic of a Gorenstein toric contact manifold, that is, a good toric contact manifold with zero 1st Chern class, is equal to half the normalized volume of the corresponding toric diagram and give some applications. A particularly interesting one, obtained using a result of Batyrev and Dais, is the following: twice the mean Euler characteristic of a Gorenstein toric contact manifold is equal to the Euler characteristic of any crepant toric symplectic filling, that is, any toric symplectic filling with zero 1st Chern class.
Does cross-Strait tourism induce peace? Evidence from survey data on Chinese tourists and non-tourists
Authors: Pan Hsin-Hsin , Wu Wen-Chin , Chang Yu-Tzung
Published: June 2018

Recent studies revisit the debate over whether tourism promotes peace via intergroup contacts. In this article, we examine the case of China-Taiwan confrontation and argue that the increase of Chinese tourists visiting Taiwan contributes to peace across the Taiwan Strait. Specifically, the touristic experiences and interactions with Taiwanese improve Chinese people’s understanding of Taiwan, fostering a patient and peaceful attitude toward the prospect of cross-Strait relations. With the survey data collected during July and September 2013, we find that Chinese people who were visiting Taiwan for the first time were less likely to support a rapid pace to the unification between China and Taiwan or unification by force than those who had never visited Taiwan. Additionally, the attitude is stronger among independent tourists than those who came in escorted tour groups. Our findings suggest that contacts between tourists and locals are effective in alleviating political tension across the Taiwan Strait.
Design and implementation of pragmatic clinical trials using the electronic medical record and an adaptive design
Authors: Simon Kelly Claire , Tideman Samuel , Hillman Laura , Lai Rebekah , Jathar Raman , Ji Yuan , Bergman-Bock Stuart , Castle James , Franada Tiffani , Freedom Thomas , Marcus Revital , Mark Angela , Meyers Steven , Rubin Susan , Semenov Irene , Yucus Chad , Pham Anna , Garduno Lisette , Szela Monika , Frigerio Roberta , Maraganore Demetrius M
Published: June 2018

Objectives

To demonstrate the feasibility of pragmatic clinical trials comparing the effectiveness of treatments using the electronic medical record (EMR) and an adaptive assignment design.

Methods

We have designed and are implementing pragmatic trials at the point-of-care using custom-designed structured clinical documentation support and clinical decision support tools within our physician’s typical EMR workflow. We are applying a subgroup based adaptive design (SUBA) that enriches treatment assignments based on baseline characteristics and prior outcomes. SUBA uses information from a randomization phase (phase 1, equal randomization, 120 patients), to adaptively assign treatments to the remaining participants (at least 300 additional patients total) based on a Bayesian hierarchical model. Enrollment in phase 1 is underway in our neurology clinical practices for 2 separate trials using this method, for migraine and mild cognitive impairment (MCI).

Results

We are successfully collecting structured data, in the context of the providers’ clinical workflow, necessary to conduct our trials. We are currently enrolling patients in 2 point-of-care trials of non-inferior treatments. As of March 1, 2018, we have enrolled 36% of eligible patients into our migraine study and 63% of eligible patients into our MCI study. Enrollment is ongoing and validation of outcomes has begun.

Discussion

This proof of concept article demonstrates the feasibility of conducting pragmatic trials using the EMR and an adaptive design.

Conclusion

The demonstration of successful pragmatic clinical trials based on a customized EMR and adaptive design is an important next step in achieving personalized medicine and provides a framework for future studies of comparative effectiveness.
Can the Provision of Long-Term Liquidity Help to Avoid a Credit Crunch? Evidence from the Eurosystem’s LTRO
Authors: Andrade Philippe , Cahn Christophe , Fraisse Henri , Mésonnier Jean-Stéphane
Published: June 2018

We exploit the Eurosystem’s longer-term refinancing operations (LTROs) of 2011–2012 to assess whether a large provision of central bank liquidity to banks during a financial crisis has a positive impact on banks’ credit supply to firms. We control for credit demand by examining firms that borrow from several banks, in addition to controlling for confounding factors at the level of banks. We find that the LTROs enhanced loan supply: according to our baseline estimate, banks borrowing 1 billion euros from the facility increased their loan supply by 186 million euros over one year. We also find that the transmission mostly took place with the first operation of December 2011, in which banks that were more capital constrained bid more. Moreover, we show that the opportunity to substitute long-term central bank liquidity for short-term liquidity enhanced this transmission. Lastly, the operations benefited larger borrowers more and did not lead banks to increase their lending to riskier firms.
Diverse novel residentWolbachiastrains in Culicine mosquitoes from Madagascar
Authors: Jeffries Claire Louise , Tantely Luciano M , Raharimalala Fara Nantenaina , Hurn Eliot , Boyer Sébastien , Walker Thomas
Published: June 2018

Wolbachiaendosymbiotic bacteria are widespread throughout insect species andWolbachiatransinfected inAedesmosquito species has formed the basis for biocontrol programs asWolbachiastrains inhibit arboviral replication and can spread through populations. Resident strains in wild Culicine mosquito populations (the vectors of most arboviruses) requires further investigation given resident strains can also affect arboviral transmission. As Madagascar has a large diversity of both Culicine species and has had recent arboviral outbreaks, an entomology survey was undertaken, in five ecologically diverse sites, to determine theWolbachiaprevalence. We detected diverse novel residentWolbachiastrains within theAedeomyia, Culex, Ficalbia, MansoniaandUranotaeniagenera.Wolbachiaprevalence rates and strain characterisation through Sanger sequencing with multilocus sequence typing (MLST) and phylogenetic analysis revealed significant diversity and we detected co-infections with the environmentally acquired bacterial endosymbiontAsaia. Mosquitoes were screened for major arboviruses to investigate if any evidence could be provided for their potential role in transmission and we report the presence of Rift Valley fever virus in threeCulexspecies:Culex tritaeniorhynchus, Culex antennatusandCulex decens. The implications of the presence of residentWolbachiastrains are discussed and how the discovery of novel strains can be utilized for applications in the development of biocontrol strategies.
An Atlas of Human and Murine Genetic Influences on Osteoporosis
Authors: Morris John A. , Kemp John P. , Youlten Scott E. , Laurent Laetitia , Logan John G. , Chai Ryan , Vulpescu Nicholas A. , Forgetta Vincenzo , Kleinman Aaron , Mohanty Sindhu , Sergio C. Marcelo , Quinn Julian , Nguyen-Yamamoto Loan , Luco Aimee Lee , Vijay Jinchu , Simon Marie-Michelle , Pramatarova Albena , Medina-Gomez Carolina , Trajanoska Katerina , Ghirardello Elena J. , Butterfield Natalie C. , Curry Katharine F. , Leitch Victoria D. , Sparkes Penny C. , Adoum Anne-Tounsia , Mannan Naila S. , Komla-Ebri Davide , Pollard Andrea S. , Dewhurst Hannah F. , Hassall Thomas , Beltejar Michael-John G , Adams Douglas J , Vaillancourt Suzanne M. , Kaptoge Stephen , Baldock Paul , Cooper Cyrus , Reeve Jonathan , Ntzani Evangelia , Evangelou Evangelos , Ohlsson Claes , Karasik David , Rivadeneira Fernando , Kiel Douglas P. , Tobias Jonathan H. , Gregson Celia L. , Harvey Nicholas C. , Grundberg Elin , Goltzman David , Adams David J. , Lelliott Christopher J. , Hinds David A. , Ackert-Bicknell Cheryl L. , Hsu Yi-Hsiang , Maurano Matthew T. , Croucher Peter I. , Williams Graham R. , Bassett J. H. Duncan , Evans David M. , Richards J. Brent
Published: June 2018

Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10−75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene,DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
Analysis of phage-resistant mechanisms inStaphylococcus aureusSA003 reveals a different binding mechanism for the closely related Twort-like phages ϕSA012 and ϕSA039
Authors: Azam Aa Haeruman , Hoshiga Fumiya , Takeuchi Ippei , Miyanaga Kazuhiko , Tanji Yasunori
Published: June 2018

We have previously generated strains ofStaphylococcus aureusSA003 resistant to its specific phage ϕSA012 through long-term coevolution experiment. However, the DNA mutations responsible for the phenotypic change of phage resistance are unknown. Whole-genome analysis revealed six genes that acquired unique point mutations: five missense mutations and one nonsense mutation. Moreover, one deletion, 1.779-bp, resulted in the deletion of the genes encoding glycosyltransferase, TarS, and iron-sulfure repair protein, ScdA. The deletion occurred from the second round of coculture (SA003R2) and remained through the last round. The ϕSA012 infection toward SA003R2 had decreased to 79.77±7.50% according to plating efficiency. Complementation of the phage-resistant strain by the wild-type allele showed two mutated host genes were linked to the inhibition of post-adsorption, and five genes were linked to phage adsorption of ϕSA012. Unlike ϕSA012, infection by ϕSA039, a close relative of ϕSA012, onto SA003R2 was impaired drastically. Complementation of SA003R2 by wild-typetarSrestores the infectivity of ϕSA039. Thus, we concluded that ϕSA039 requires β-GlcNAc in Wall Teichoic Acid (WTA) for its binding. In silico analysis of the ϕSA039 genome revealed that several proteins in the tail and baseplate region were different from ϕSA012; notably the partial deletion oforf96of ϕSA039, a homolog oforf99of ϕSA012.Orf100of ϕSA039, a homolog ofOrf103of ϕSA012, a previously reported receptor binding protein (RBP), had low similarity (86%) to that of ϕSA012. The difference in tail and baseplate proteins might be the factor for specificity difference between ϕSA012 and ϕSA039.
The Global State of Genome Editing
Authors: Siwo Geoffrey H.
Published: June 2018

Genome editing technologies hold great promise in fundamental biomedical research, development of treatments for animal and plant diseases, and engineering biological organisms for food and industrial applications. Therefore, a global understanding of the growth of the field is needed to identify challenges, opportunities and biases that could shape the impact of the technology. To address this, this work applies automated literature mining of scientific publications on genome editing in the past year to infer research trends in 2 key genome editing technologies-CRISPR/Cas systems and TALENs. The study finds that genome editing research is disproportionately distributed between and within countries, with researchers in the US and China accounting for 50% of authors in the field whereas countries across Africa are underrepresented. Furthermore, genome editing research is also disproportionately being explored on diseases such as cancer, Duchene Muscular Dystrophy, sickle cell disease and malaria. Gender biases are also evident in genome editing research with considerably fewer women as principal investigators. The results of this study suggest that automated mining of scientific literature could help identify biases in genome editing research as a means to mitigate future inequalities and tap the full potential of the technology.
Reliable Multiplex Sequencing with Rare Index Mis-Assignment on DNB-Based NGS Platform
Authors: Li Qiaoling , Zhao Xia , Zhang Wenwei , Wang Lin , Wang Jingjing , Xu Dongyang , Mei Zhiying , Liu Qiang , Du Shiyi , Li Zhanqing , Liang Xinming , Wang Xiaman , Wei Hanmin , Liu Pengjuan , Zou Jing , Shen Hanjie , Chen Ao , Drmanac Snezana , Liu Jia Sophie , Li Li , Jiang Hui , Zhang Yongwei , Wang Jian , Yang Huanming , Xu Xun , Drmanac Radoje , Jiang Yuan
Published: June 2018

Background

Massively-parallel-sequencing, coupled with sample multiplexing, has made genetic tests broadly affordable. However, intractable index mis-assignments (commonly exceeds 1%) were repeatedly reported on some widely used sequencing platforms.

Results

Here, we investigated this quality issue on BGI sequencers using three library preparation methods: whole genome sequencing (WGS) with PCR, PCR-free WGS, and two-step targeted PCR. BGI’s sequencers utilize a unique DNB technology which uses rolling circle replication for DNA-nanoball preparation; this linear amplification is PCR free and can avoid error accumulation. We demonstrated that single index mis-assignment from free indexed oligos occurs at a rate of one in 36 million reads, suggesting virtually no index hopping during DNB creation and arraying. Furthermore, the DNB-based NGS libraries have achieved an unprecedentedly low sample-to-sample mis-assignment rate of 0.0001% to 0.0004% under recommended procedures.

Conclusions

Single indexing with DNB technology provides a simple but effective method for sensitive genetic assays with large sample numbers.
A Novel Compound, ML336, Inhibits VEEV Replication by Interfering with Viral RNA Synthesis
Authors: Skidmore Andrew M. , Adcock Robert S. , Lee Jasper , Jonsson Colleen B. , Golden Jennifer E. , Chung Dong-Hoon
Published: June 2018

Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is endemic to Central and South America. VEEV is known to cause periodic outbreaks of encephalitis in both humans and equids. There are currently no treatments or preventatives for VEEV disease. Our group has previously reported on the development of a novel VEEV inhibitor, ML336, which showed a potent antiviral effect in cell culture models. However, the mechanism of action had yet to be elucidated. Based on the discovery of mutations conferring resistance within nonstructural proteins, we hypothesized that ML336 inhibits viral RNA synthesis. We found that ML336 was able to inhibit VEEV RNA synthesis with an IC50value of 1.1 nM in a metabolic labelling assay. ML336 marginally affected cellular transcription at levels 20,000-fold above the IC50, and did not show any cytotoxicity up to 50 µM. Using a combination of fluorography, strand-specific qRT-PCR, and a metabolic labelling assay, we found that ML336 inhibits the synthesis of all forms of VEEV RNA. Structural analogues of ML336 showed a correlation between their RNA synthesis inhibitory activity and their antiviral activity in cells, leading us to propose that the primary mechanism of action of this class of compounds is viral RNA synthesis inhibition. The activities of ML336 were highly specific to VEEV, without measurable activity against Chikungunya virus. ML336 was efficacious even in a cell-free viral RNA synthesis assay, suggesting a direct interaction with viral proteins.

Importance

Venezuelan equine encephalitis virus (VEEV) is a pathogenic alphavirus that circulates in the Americas which can cause a lethal encephalitis in humans and equids. There are currently no licensed treatments or vaccines for VEEV. Due to the high potential for aerosol infection and severe outcomes, it is classified as an NIAID Category B agent. To address the unmet need for VEEV antivirals, we continue to advance a novel amidine compound, ML336, through medicinal chemistry and mechanism of action (MOA) studies. Here, we present the molecular MOA by which ML336 inhibits VEEV replication using cellular and biochemical approaches. Our data suggest that ML336 is a direct-acting antiviral that inhibits viral RNA synthesis by interfering with the viral replicase complex. Our studies provide new insights into approaches for the development of novel RNA virus replication inhibitors and the molecular mechanism of alphavirus RNA synthesis.
Bacterial cell lysis: geometry, elasticity, and implications
Authors: Wong Felix , Amir Ariel
Published: June 2018

Membrane lysis, or rupture, is a cell death pathway in bacteria frequently caused by cell wall-targeting antibiotics. Although several studies have clarified biochemical mechanisms of antibiotic action, a physical understanding of the processes leading to lysis remains lacking. Here, we analyze the dynamics of membrane bulging and lysis inEscherichia coli, where, strikingly, the formation of an initial bulge (“bulging”) after cell wall digestion occurs on a characteristic timescale as fast as 100 ms and the growth of the bulge (“swelling”) occurs on a slower characteristic timescale of 10-100 s. We show that bulging can be energetically favorable due to the relaxation of the entropic and stretching energies of the inner membrane, cell wall, and outer membrane and that experimentally observed bulge shapes are consistent with model predictions. We then show that swelling can involve both the continued flow of water into the cytoplasm and the enlargement of wall defects, after which cell lysis is consistent with both the inner and outer membranes exceeding characteristic estimates of the yield areal strains of biological membranes. Our results contrast biological membrane physics and the physics of thin shells, reveal principles of how all bacteria likely function in their native states, and may have implications for cellular morphogenesis and antibiotic discovery across different species of bacteria.
A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain
Authors: Olah Marta , Menon Vilas , Habib Naomi , Taga Mariko , Yung Christina , Cimpean Maria , Khairalla Anthony , Dionne Danielle , Hopp Sarah , Frosch Matthew P. , Hyman Bradley T. , Beach Thomas , Sarkis Rani , Cosgrove Garth R , Helgager Jeffrey , Golden Jeffrey A. , Pennell Page B. , Schneider Julie A. , Bennett David A. , Regev Aviv , Elyaman Wassim , Bradshaw Elizabeth M. , De Jager Philip L.
Published: June 2018

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.
Detoxification of endogenous serine prevents cell lysis upon glucose depletion in bacteria
Authors: Kriner Michelle A. , Subramaniam Arvind R.
Published: June 2018

The amino acid serine, despite its diverse metabolic roles, can become toxic when present in excess. Indeed, many bacteria rapidly deaminate exogenously supplied serine into pyruvate and ammonia, even at the expense of biomass production. Here we report a surprising case in which endogenously produced serine must be detoxified in order for the bacteriumEscherichia colito survive. Specifically, we show thatE. colicells lacking thesdaCBoperon, which encodes a serine transporter and a serine deaminase, lyse upon glucose depletion when serine is absent from the growth medium. Lysis can be prevented by omission of glycine or by inhibition of the glycine cleavage system, suggesting that activation of glycine catabolism upon glucose depletion causes a transient increase in intracellular serine levels. Heterologous expression of the serine transporter SdaC is sufficient to prevent lysis, indicating a dominant role for serine export, rather than deamination, in mitigating serine toxicity. Since lysis can be modulated by altering alanine availability, we further propose that mis-incorporation of serine instead of alanine into peptidoglycan crosslinks is the cause of lysis. Together, our results reveal that SdaC-mediated detoxification of intracellularly produced serine plays a protective role during sudden shifts in nutrient availability in bacteria.

Author summary

The amino acid serine is a building block used to make many types of macromolecules, yet bacteria actively degrade serine that is provided in growth media. Serine degradation is thought to prevent toxic serine accumulation, but the biological role of this process is not fully understood. We observed that cells lacking thesdaCBoperon, which encodes a serine transporter and an enzyme that converts serine to pyruvate, suddenly lyse upon depletion of glucose from the growth medium. This surprising phenotype occurs only in media lacking serine, suggesting thatsdaCBis required to detoxify intracellularly produced serine. Expression of the serine transporter SdaC is sufficient to prevent lysis, providing the first evidence that serine export can be an essential function of this protein. Our results reveal that sudden shifts in nutrient availability can increase the intracellular concentration of useful metabolites to toxic levels and suggest that increasing intracellular serine levels by manipulating SdaC activity may be a possible antimicrobial strategy.
GLnexus: joint variant calling for large cohort sequencing
Authors: Lin Michael F. , Rodeh Ohad , Penn John , Bai Xiaodong , Reid Jeffrey G. , Krasheninina Olga , Salerno William J.
Published: June 2018

As ever-larger cohorts of human genomes are collected in pursuit of genotype/phenotype associations, sequencing informatics must scale up to yield complete and accurate genotypes from vast raw datasets. Joint variant calling, a data processing step entailing simultaneous analysis of all participants sequenced, exhibits this scaling challenge acutely. We present GLnexus (GL, Genotype Likelihood), a system for joint variant calling designed to scale up to the largest foreseeable human cohorts. GLnexus combines scalable joint calling algorithms with a persistent database that grows efficiently as additional participants are sequenced. We validate GLnexus using 50,000 exomes to show it produces comparable or better results than existing methods, at a fraction of the computational cost with better scaling. We provide a standalone open-source version of GLnexus and a DNAnexus cloud-native deployment supporting very large projects, which has been employed for cohorts of >240,000 exomes and >22,000 whole-genomes.
Codon usage influences fitness through RNA toxicity
Authors: Mittal Pragya , Brindle James , Stephen Julie , Plotkin Joshua B. , Kudla Grzegorz
Published: June 2018

Many organisms are subject to selective pressure that gives rise to unequal usage of synonymous codons, known as codon bias. To experimentally dissect the mechanisms of selection on synonymous sites, we expressed several hundred synonymous variants of the GFP gene inEscherichia coli, and used quantitative growth and viability assays to estimate bacterial fitness. Unexpectedly, we found many synonymous variants whose expression was toxic toE. coli. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We identified RNA sequence determinants of toxicity, and evolved suppressor strains that can tolerate the expression of toxic GFP variants. Genome sequencing of these suppressor strains revealed a cluster of promoter mutations that prevented toxicity by reducing mRNA levels. We conclude that translation-independent RNA toxicity is a previously unrecognized obstacle in bacterial gene expression.

Significance statement

Synonymous mutations in genes do not change protein sequence, but they may affect gene expression and cellular function. Here we describe an unexpected toxic effect of synonymous mutations inEscherichia coli, with potentially large implications for bacterial physiology and evolution. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We hypothesize that the mechanism we identified influences the evolution of endogenous genes in bacteria, by imposing selective constraints on synonymous mutations that arise in the genome. Of interest for biotechnology and synthetic biology, we identify bacterial strains and growth conditions that alleviate RNA toxicity, thus allowing efficient overexpression of heterologous proteins.
Structural Aspects of Homologous DNA-DNA Interactions Revealed by Partitioning of RIP Mutations
Authors: Mazur Alexey K. , Gladyshev Eugene
Published: June 2018

In some fungi, a process known as Repeat-Induced Point mutation (RIP) can accurately identify and mutate nearly all genesized DNA repeats present in the haploid premeiotic nuclei. Studies of RIP inNeurospora crassahave suggested that the sequence homology is detected between intact double helices without strand separation and participation of RecA homologs. These studies relied on the aggregated number of mutations as a simple quantitative readout of RIP activity and did not try interpret the distributions of mutations along DNA. Important additional information can be extracted by transforming these distributions into profiles of a new parameter called partitioned RIP propensity (PRP) which takes into account the site density as well as the sequence context. This approach revealed surprising systematic variations of PRP due to the position of a given DNA segment relative to the homology boundaries and its topology. Notably, identical pairs of direct versus inverted repeats produce very distinct PRP profiles. This effect could be rationalized assuming a specific redistribution of the supercoiling stress produced by the previously discovered untwisting of paired of DNA homologs. Similar mechanisms account for other persistent features of PRP profiles, and this general topological model raises an intriguing possibility that local DNA supercoiling provoked by homologous dsDNA-dsDNA pairing can modulate the overall structure and properties of repetitive DNA. These effects can be particularly strong in the context of long tandem repeat arrays that are typically present at the (peri)centromeric regions of chromosomes.
G-quadruplex forming sequences in the genome of all known human viruses: a comprehensive guide
Authors: Lavezzo Enrico , Berselli Michele , Frasson Ilaria , Perrone Rosalba , Palù Giorgio , Brazzale Alessandra R. , Richter Sara N. , Toppo Stefano
Published: June 2018

G-quadruplexes are non-canonical nucleic acid structures that control transcription, replication, and recombination in organisms. G-quadruplexes are present in eukaryotes, prokaryotes, and viruses. In the latter, mounting evidence indicates their key biological activity. Since data on viruses are scattered, we here present a comprehensive analysis of putative G-quadruplexes in the genome of all known viruses that can infect humans. We show that the presence, distribution, and location of G-quadruplexes are features characteristic of each virus class and family. Our statistical analysis proves that their presence within the viral genome is orderly arranged, as indicated by the possibility to correctly assign up to two-thirds of viruses to their exact class based on the G-quadruplex classification. For each virus we provide: i) the list of all G-quadruplexes formed by GG-, GGG- and GGGG-islands present in the genome (positive and negative strands), ii) their position in the viral genome along with the known function of that region, iii) the degree of conservation among strains of each G-quadruplex in its genome context, iv) the statistical significance of G-quadruplex formation. This information is accessible from a database (http://www.medcomp.medicina.unipd.it/main_site/doku.php?id=g4virus) to allow the easy and interactive navigation of the results. The availability of these data will greatly expedite research on G-quadruplex in viruses, with the possibility to accelerate finding therapeutic opportunities to numerous and some fearsome human diseases.
Rhamnolipids fromPseudomonas aeruginosaDisperse the Biofilms of Sulfate-Reducing Bacteria
Authors: Wood Thammajun L. , Zhu Lei , Miller James , Miller Daniel S. , Yin Bei , Wood Thomas K.
Published: June 2018

Biofilm formation is an important problem for many industries.Desulfovibrio vulgarisis the representative sulfate-reducing bacterium (SRB) which causes metal corrosion in oil wells and drilling equipment, and the corrosion is related to its biofilm formation. Biofilms are extremely difficult to remove since the cells are cemented in a polymer matrix. In an effort to eliminate SRB biofilms, we examined the ability of supernatants fromPseudomonas aeruginosaPA14 to disperse SRB biofilms. We found that theP. aeruginosasupernatants dispersed more than 98% of the biofilm. To determine the genetic basis of this SRB biofilm dispersal, we examined a series ofP. aeruginosamutants and found that mutantsrhlA,rhlB,rhlI, andrhlR,defective in rhamnolipids production, had significantly reduced levels of SRB biofilm dispersal. Corroborating these results, purified rhamnolipids dispersed SRB biofilms, and rhamnolipids were detected in theP. aeruginosasupernatants. Hence,P. aeruginosasupernatants disperse SRB biofilms via rhamnolipids. In addition, the supernatants ofP. aeruginosadispersed the SRB biofilms more readily than protease in M9 glucose minimum medium and were also effective against biofilms ofEscherichia coliandBacillus subtilis.
clonealign: statistical integration of independent single-cell RNA & DNA-seq from human cancers
Authors: Campbell Kieran R , Steif Adi , Laks Emma , Zahn Hans , Lai Daniel , McPherson Andrew , Farahani Hossein , Kabeer Farhia , O’Flanagan Ciara , Biele Justina , Brimhall Jazmine , Wang Beixi , Walters Pascale ,   IMAXT Consortium, Bouchard-Côté Alexandre , Aparicio Samuel , Shah Sohrab P
Published: June 2018

Measuring gene expression of genomically defined tumour clones at single cell resolution would associate functional consequences to somatic alterations, as a prelude to elucidating pathways driving cell population growth, resistance and relapse. In the absence of scalable methods to simultaneously assay DNA and RNA from the same single cell, independent sampling of cell populations for parallel measurement of single cell DNA and single cell RNA must be computationally mapped for genome-transcriptome association. Here we presentclonealign, a robust statistical framework to assign gene expression states to cancer clones using single-cell RNA-seq and DNA-seq independently sampled from an heterogeneous cancer cell population. We applyclonealignto triple-negative breast cancer patient derived xenografts and high-grade serous ovarian cancer cell lines and discover clone-specific dysregulated biological pathways not visible using either DNA-Seq or RNA-Seq alone.