bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic policy and the double burden of malnutrition: cross-national longitudinal analysis of minimum wage and women’s underweight and obesity
Authors: Conklin Annalijn I , Ponce Ninez A , Crespi Catherine M , Frank John , Nandi Arijit , Heymann Jody
Published: December 2017

Objective

To examine changes in minimum wage associated with changes in women’s weight status.

Design

Longitudinal study of legislated minimum wage levels (per month, purchasing power parity-adjusted, 2011 constant US dollar values) linked to anthropometric and sociodemographic data from multiple Demographic and Health Surveys (2000–2014). Separate multilevel models estimated associations of a $10 increase in monthly minimum wage with the rate of change in underweight and obesity, conditioning on individual and country confounders. Post-estimation analysis computed predicted mean probabilities of being underweight or obese associated with higher levels of minimum wage at study start and end.

Setting

Twenty-four low-income countries.

Subjects

Adult non-pregnant women (n150 796).

Results

Higher minimum wages were associated (OR; 95 % CI) with reduced underweight in women (0·986; 0·977, 0·995); a decrease that accelerated over time (P-interaction=0·025). Increasing minimum wage was associated with higher obesity (1·019; 1·008, 1·030), but did not alter the rate of increase in obesity prevalence (P-interaction=0·8). A $10 rise in monthly minimum wage was associated (prevalence difference; 95 % CI) with an average decrease of about 0·14 percentage points (−0·14; −0·23, −0·05) for underweight and an increase of about 0·1 percentage points (0·12; 0·04, 0·20) for obesity.

Conclusions

The present longitudinal multi-country study showed that a $10 rise in monthly minimum wage significantly accelerated the decline in women’s underweight prevalence, but had no association with the pace of growth in obesity prevalence. Thus, modest rises in minimum wage may be beneficial for addressing the protracted underweight problem in poor countries, especially South Asia and parts of Africa.
Community junior sport sponsorship: an online experiment assessing children’s responses to unhealthy food v. pro-health sponsorship options
Authors: Dixon Helen , Scully Maree , Wakefield Melanie , Kelly Bridget , Pettigrew Simone
Published: December 2017

Objective

To explore children’s responses to sponsorship of community junior sport by unhealthy food brands and investigate the utility of alternative, pro-health sponsorship options.

Design

Between-subjects experiment, with four sponsorship conditions: A, non-food branding (control); B, unhealthy food branding; C, healthier food branding; D, obesity prevention campaign branding.

Setting

Online experiment conducted in schools. Participants were shown a junior sports pack for their favourite sport that contained merchandise with branding representing their assigned sponsorship condition. Participants viewed and rated the sports pack, completed a distractor task, then completed questions assessing brand awareness, brand attitudes and preference for food sponsors’ products.

Subjects

Students in grades 1 to 3 (aged 5–10 years; n 1124) from schools in metropolitan Melbourne, Australia.

Results

Compared with the control condition, there were no significant effects of unhealthy food branding on awareness of, attitudes towards or preference for these brands. Exposure to healthier food branding prompted a significant increase in the proportion of children aware of these brands, but did not impact attitudes towards or preference for these brands. Exposure to either healthier food branding or obesity prevention campaign branding prompted a significant reduction in the proportion of children showing a preference for unhealthy food sponsor products.

Conclusions

The sponsorship of children’s sport by healthier food brands may promote awareness of these brands and healthier sponsorship branding may reduce preferences for some unhealthy food products. Establishing and implementing healthy sponsor criteria in sports clubs could forge healthier sponsorship arrangements and help phase out unhealthy food and beverage sponsors.
The limits of practice: why realism can complement IR’s practice turn
Authors: Joseph Jonathan , Kurki Milja
Published: December 2017

This paper argues that the current calls for a practice turn in International Relations (IR) while positive in many respects, are problematic and potentially limiting because they are premised on a confused understanding of the role of philosophy and realist philosophy in particular and a restricted view of the role of sociological investigation. This arises from the problematic tendency to lapse into advocacy of an anti-realist philosophical and sociological imagination. We suggest that the problems that practice theorists point to should lead not to knee-jerk anti-realism but rather can motivate a reinvigorated conversation with realism. This entails revisiting the role of philosophy, realism, and sociology in the study of practices. We argue that far from being antithetical to practice theory, a reconsideration of realist philosophy helps make sense of the role of practice and provides those advocating practice theory with better tools to deal with the challenges which motivated the development of these theoretical stances. Reconsidering realism entails, however, a reconsideration of a wider social ontology within which practice takes place, and openness to the role of philosophical and theoretical abstractions in teasing out the role of practice.
A Midsouthern Consultant’s Survey on Weed Management Practices in Soybean
Authors: Schwartz-Lazaro Lauren M. , Norsworthy Jason K. , Steckel Lawrence E. , Stephenson Daniel O. , Bish Mandy D. , Bradley Kevin W. , Bond Jason A.
Published: December 2017

Soybean consultants from Arkansas, Louisiana, southeast Missouri, Mississippi, and Tennessee were surveyed in 2016 to assess weed management practices and the prevalence of herbicide-resistant weeds in midsouthern U.S. soybean production. The consultants surveyed represented 13%, 28%, 8%, 16%, and 5% of the total soybean area planted in Arkansas, Louisiana, southeast Missouri, Mississippi, and Tennessee, respectively. Of the total scouted area, 78% of the consultants said their growers planted glyphosate-resistant soybean in 2016, with 18% planting glufosinate-resistant (LibertyLink®), primarily due to familiarity with and cost of the technology. Although 94% of the consultants determined that glufosinate was most effective on killing Palmer amaranth, the primary concern associated with controlling herbicide-resistant weeds was the associated cost, followed by return profit and time constraints. Palmer amaranth, morningglory species, horseweed, barnyardgrass, and Italian ryegrass were the five most problematic weeds in soybean across the five states. Palmer amaranth was the most problematic and important weed in each state individually. The increased concern (77% of consultants) with this species was attributed to the rising concern with and occurrence of protoporphyrinogen oxidase–resistant Palmer amaranth. Consultants were of the opinion that more research was needed on cover crops and the new traited technologies in order to improve weed management in soybean.
Control of Protoporphyrinogen Oxidase Inhibiting Herbicide Resistant and Susceptible Palmer Amaranth (Amaranthus palmeri) with Soil-Applied Protoporphyrinogen Oxidase–Inhibiting Herbicides
Authors: Umphres Alinna M. , Steckel Lawrence E. , Mueller Thomas C.
Published: December 2017

Palmer amaranth resistance to protoporphyrinogen oxidase (PPO)-inhibiting herbicides has become an increasing problem to producers throughout the southeast region of the United States. Traditionally, these herbicides can be used as foliar-applied and soil-applied in glyphosate resistant (GR) cropping systems to control GR Palmer amaranth. Heavy reliance on PPO herbicides has contributed to the increased selection for PPO inhibitor-resistant (PPO-R) Palmer amaranth biotypes. Dose response greenhouse research was conducted to evaluate the efficacy of soil-applied flumioxazin, fomesafen, saflufenacil and sulfentrazone on a known susceptible (S) and resistant (R) Palmer amaranth biotype. Both R and S populations reached maximum germination at 14 d after treatment (DAT). The data from this study suggests complete control (100%) was achieved for the S biotype at 35 d after treatment (DAT) with all herbicides. The R biotype showed difference among herbicide treatments with flumioxazin and saflufenacil having similar responses in control and fomesafen and sulfentrazone resulting in less control of the R Palmer amaranth biotypes. The calculated relative resistance factor ranged from 3.5 to 6.0, and averaged 5X for the four herbicides. This research indicated that the PPO-R population was still responsive to all tested herbicides, but a low level of resistance was present.
A profile of traumatic spinal cord injury and medical complications in Latvia
Authors: Nulle Anda , Tjurina Uljana , Erts Renars , Vetra Anita
Published: December 2017

Study design

A single centre retrospective study.

Objectives

To collect data and analyse the epidemiological profile of traumatic spinal cord injury and its medical complications during the subacute rehabilitation period.

Setting

Spinal Cord Injury Rehabilitation Programme of the National Rehabilitation Centre, ‘Vaivari’, Jurmala, Latvia.

Methods

Information was collected in 2015 from the medical records of 134 patients with a traumatic spinal cord injury admitted for primary rehabilitation between January 2011 and December 2014.

Results

During this period, the median age of patients with a traumatic spinal cord injury was 39.5 years, and the male to female ratio was 5:1. The leading causes of traumatic spinal cord injuries were falls (37%), road traffic accidents (29%), sport and leisure activities (19%), other cause (8%), unidentified causes (5%), and assault (2%). The most common medical complications were pain (77%), spasticity (48%), urinary tract infections (45%), pressure ulcers (25%), and orthostatic hypotension (14%).

Conclusions

Preventive measures in Latvia should be aimed primarily to address falls, road traffic accidents, and sport and leisure activities in the young male population. Medical complications are varied, and they are an important factor following traumatic spinal cord injury. The results obtained in this study comply with the data from studies in countries of the Baltic and North Sea regions of Europe.
The relationship between dlPFC activity during unpredictable threat and CO2-induced panic symptoms
Authors: Balderston Nicholas L. , Liu Jeffrey , Roberson-Nay Roxann , Ernst Monique , Grillon Christian
Published: December 2017

Panic disorder is characterized by sudden, repeated, and unexpected attacks of intense fear and overwhelming anxiety about when another attack may strike. Patients with panic disorder and healthy individuals with a history of panic attacks show a hypersensitivity to unpredictable threats, suggesting a possible link between panic and sustained anxiety. The purpose of this study was to determine the degree to which induced symptoms of panic relate to fear and anxiety, as well as activity in the neural systems that mediate and regulate these affective states. Psychological and physiological symptoms of panic were assessed during an 8-min 7.5% CO2 challenge task. Psychological, physiological, and neural symptoms of fear and anxiety were measured during two sessions (one psychophysiology and one functional magnetic resonance imaging where subjects experienced several blocks of no threat (N), predictable shock (P), and unpredictable shock (U; NPU threat task). We used a principle component analysis to characterize panic susceptibility (PS), and found that PS significantly predicted dorsolateral prefrontal cortex (dlPFC) activity to the unpredictable cue during the NPU threat task. When examining the weighted beta coefficients from this analysis, we observed that self-reported fear/anxiety during the CO2 challenge negatively loaded onto dlPFC activity during the NPU task. Consistent with this observation, dlPFC activity during the unpredictable cue was also negatively correlated with anxiety during the NPU sessions. Together, these results suggest that panic symptoms and anxiety are regulated by the same prefrontal cognitive control system.
IRF8-dependent molecular complexes control the Th9 transcriptional program
Authors: Humblin Etienne , Thibaudin Marion , Chalmin Fanny , Derangère Valentin , Limagne Emeric , Richard Corentin , Flavell Richard A. , Chevrier Sandy , Ladoire Sylvain , Berger Hélène , Boidot Romain , Apetoh Lionel , Végran Frédérique , Ghiringhelli François
Published: December 2017

Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boostsIl9transcription. By contrast, IRF8 deficiency promotes the expression of other genes such asIl4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibitsIl4expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repressIl4expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy.
Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity
Authors: Winters Ian P. , Chiou Shin-Heng , Paulk Nicole K. , McFarland Christopher D. , Lalgudi Pranav V. , Ma Rosanna K. , Lisowski Leszek , Connolly Andrew J. , Petrov Dmitri A. , Kay Mark A. , Winslow Monte M.
Published: December 2017

Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice. Using this approach, we introduce a barcoded library of non-synonymous mutations into hotspot codons 12 and 13 of Kras in adult somatic cells to initiate tumors in the lung, pancreas, and muscle. High-throughput sequencing of barcoded Kras
HDR
alleles from bulk lung and pancreas reveals surprising diversity in Kras variant oncogenicity. Rapid, cost-effective, and quantitative approaches to simultaneously investigate the function of precise genomic alterations in vivo will help uncover novel biological and clinically actionable insights into carcinogenesis.
Insights into the structure and assembly of a bacterial cellulose secretion system
Authors: Krasteva Petya Violinova , Bernal-Bayard Joaquin , Travier Laetitia , Martin Fernando Ariel , Kaminski Pierre-Alexandre , Karimova Gouzel , Fronzes Rémi , Ghigo Jean-Marc
Published: December 2017

Secreted exopolysaccharides present important determinants for bacterial biofilm formation, survival, and virulence. Cellulose secretion typically requires the concerted action of a c-di-GMP-responsive inner membrane synthase (BcsA), an accessory membrane-anchored protein (BcsB), and several additional Bcs components. Although the BcsAB catalytic duo has been studied in great detail, its interplay with co-expressed subunits remains enigmatic. Here we show that E. coli Bcs proteins partake in a complex protein interaction network. Electron microscopy reveals a stable, megadalton-sized macromolecular assembly, which encompasses most of the inner membrane and cytosolic Bcs components and features a previously unobserved asymmetric architecture. Heterologous reconstitution and mutational analyses point toward a structure–function model, where accessory proteins regulate secretion by affecting both the assembly and stability of the system. Altogether, these results lay the foundation for more comprehensive models of synthase-dependent exopolysaccharide secretion in biofilms and add a sophisticated secretory nanomachine to the diverse bacterial arsenal for virulence and adaptation.
Endocytosis regulates TDP-43 toxicity and turnover
Authors: Liu Guangbo , Coyne Alyssa N. , Pei Fen , Vaughan Spencer , Chaung Matthew , Zarnescu Daniela C. , Buchan J. Ross
Published: December 2017

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.
Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors
Authors: Martin-Malpartida Pau , Batet Marta , Kaczmarska Zuzanna , Freier Regina , Gomes Tiago , Aragón Eric , Zou Yilong , Wang Qiong , Xi Qiaoran , Ruiz Lidia , Vea Angela , Márquez José A. , Massagué Joan , Macias Maria J.
Published: December 2017

Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene. The structures revealed a 5-bp consensus sequence GGC(GC)|(CG) as the binding site for both TGF-β and BMP-activated Smads and for Smad4. These 5GC motifs are highly represented as clusters in Smad-bound regions genome-wide. Our results provide a basis for understanding the functional adaptability of Smads in different cellular contexts, and their dependence on lineage-determining transcription factors to target specific genes in TGF-β and BMP pathways.
A modular synthesis of tetracyclic meroterpenoid antibiotics
Authors: Wildermuth Raphael , Speck Klaus , Haut Franz-Lucas , Mayer Peter , Karge Bianka , Brönstrup Mark , Magauer Thomas
Published: December 2017

Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels–Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2–sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.
Reproducible flaws unveil electrostatic aspects of semiconductor electrochemistry
Authors: Vogel Yan B. , Zhang Long , Darwish Nadim , Gonçales Vinicius R. , Le Brun Anton , Gooding J. Justin , Molina Angela , Wallace Gordon G. , Coote Michelle L. , Gonzalez Joaquin , Ciampi Simone
Published: December 2017

Predicting or manipulating charge-transfer at semiconductor interfaces, from molecular electronics to energy conversion, relies on knowledge generated from a kinetic analysis of the electrode process, as provided by cyclic voltammetry. Scientists and engineers encountering non-ideal shapes and positions in voltammograms are inclined to reject these as flaws. Here we show that non-idealities of redox probes confined at silicon electrodes, namely full width at half maximum <90.6 mV and anti-thermodynamic inverted peak positions, can be reproduced and are not flawed data. These are the manifestation of electrostatic interactions between dynamic molecular charges and the semiconductor’s space-charge barrier. We highlight the interplay between dynamic charges and semiconductor by developing a model to decouple effects on barrier from changes to activities of surface-bound molecules. These findings have immediate general implications for a correct kinetic analysis of charge-transfer at semiconductors as well as aiding the study of electrostatics on chemical reactivity.
Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels
Authors: Davies Luke C. , Rice Christopher M. , Palmieri Erika M. , Taylor Philip R. , Kuhns Douglas B. , McVicar Daniel W.
Published: December 2017

The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing.
High efficiency and long-term intracellular activity of an enzymatic nanofactory based on metal-organic frameworks
Authors: Lian Xizhen , Erazo-Oliveras Alfredo , Pellois Jean-Philippe , Zhou Hong-Cai
Published: December 2017

Enhancing or restoring enzymatic function in cells is highly desirable in applications ranging from ex vivo cellular manipulations to enzyme replacement therapies in humans. However, because enzymes degrade in biological milieus, achieving long-term enzymatic activities can be challenging. Herein we report on the in cellulo properties of nanofactories that consist of antioxidative enzymes encapsulated in metal–organic frameworks (MOFs). We demonstrate that, while free enzymes display weak activities for only a short duration, these efficient nanofactories protect human cells from toxic reactive oxygen species for up to a week. Remarkably, these results are obtained in spite of the nanofactories being localized in lysosomes, acidic organelles that contain a variety of proteases. The long-term persistence of the nanofactories is attributed to the chemical stability of MOF in low pH environment and to the protease resistance provided by the protective cage formed by the MOF around the encapsulated enzymes.
Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator
Authors: Carayol Jérôme , Chabert Christian , Di Cara Alessandro , Armenise Claudia , Lefebvre Gregory , Langin Dominique , Viguerie Nathalie , Metairon Sylviane , Saris Wim H. M. , Astrup Arne , Descombes Patrick , Valsesia Armand , Hager Jörg
Published: December 2017

Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of 1129 proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associatedcis-pQTLs andtrans-pQTLs at baseline and 3trans-pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validateFAM46Aas atransregulator for leptin.
Structure of outer membrane protein G in lipid bilayers
Authors: Retel Joren S. , Nieuwkoop Andrew J. , Hiller Matthias , Higman Victoria A. , Barbet-Massin Emeline , Stanek Jan , Andreas Loren B. , Franks W. Trent , van Rossum Barth-Jan , Vinothkumar Kutti R. , Handel Lieselotte , de Palma Gregorio Giuseppe , Bardiaux Benjamin , Pintacuda Guido , Emsley Lyndon , Kühlbrandt Werner , Oschkinat Hartmut
Published: December 2017

β-barrel proteins mediate nutrient uptake in bacteria and serve vital functions in cell signaling and adhesion. For the 14-strand outer membrane protein G of Escherichia coli, opening and closing is pH-dependent. Different roles of the extracellular loops in this process were proposed, and X-ray and solution NMR studies were divergent. Here, we report the structure of outer membrane protein G investigated in bilayers of E. coli lipid extracts by magic-angle-spinning NMR. In total, 1847 inter-residue 1H–1H and 13C–13C distance restraints, 256 torsion angles, but no hydrogen bond restraints are used to calculate the structure. The length of β-strands is found to vary beyond the membrane boundary, with strands 6–8 being the longest and the extracellular loops 3 and 4 well ordered. The site of barrel closure at strands 1 and 14 is more disordered than most remaining strands, with the flexibility decreasing toward loops 3 and 4. Loop 4 presents a well-defined helix.
Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase
Authors: Abplanalp Jeannette , Leutert Mario , Frugier Emilie , Nowak Kathrin , Feurer Roxane , Kato Jiro , Kistemaker Hans V. A. , Filippov Dmitri V. , Moss Joel , Caflisch Amedeo , Hottiger Michael O.
Published: December 2017

ADP-ribosylation is a posttranslational modification that exists in monomeric and polymeric forms. Whereas the writers (e.g. ARTD1/PARP1) and erasers (e.g. PARG, ARH3) of poly-ADP-ribosylation (PARylation) are relatively well described, the enzymes involved in mono-ADP-ribosylation (MARylation) have been less well investigated. While erasers for the MARylation of glutamate/aspartate and arginine have been identified, the respective enzymes with specificity for serine were missing. Here we report that, in vitro, ARH3 specifically binds and demodifies proteins and peptides that are MARylated. Molecular modeling and site-directed mutagenesis of ARH3 revealed that numerous residues are critical for both the mono- and the poly-ADP-ribosylhydrolase activity of ARH3. Notably, a mass spectrometric approach showed that ARH3-deficient mouse embryonic fibroblasts are characterized by a specific increase in serine-ADP-ribosylation in vivo under untreated conditions as well as following hydrogen peroxide stress. Together, our results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome.
H3K14ac is linked to methylation of H3K9 by the triple Tudor domain of SETDB1
Authors: Jurkowska Renata Z. , Qin Su , Kungulovski Goran , Tempel Wolfram , Liu Yanli , Bashtrykov Pavel , Stiefelmaier Judith , Jurkowski Tomasz P. , Kudithipudi Srikanth , Weirich Sara , Tamas Raluca , Wu Hong , Dombrovski Ludmila , Loppnau Peter , Reinhardt Richard , Min Jinrong , Jeltsch Albert
Published: December 2017

SETDB1 is an essential H3K9 methyltransferase involved in silencing of retroviruses and gene regulation. We show here that its triple Tudor domain (3TD) specifically binds to doubly modified histone H3 containing K14 acetylation and K9 methylation. Crystal structures of 3TD in complex with H3K14ac/K9me peptides reveal that peptide binding and K14ac recognition occurs at the interface between Tudor domains (TD) TD2 and TD3. Structural and biochemical data demonstrate a pocket switch mechanism in histone code reading, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2. Mutations in the K14ac/K9me binding sites change the sub-nuclear localization of 3TD. ChIP-seq analyses show that SETDB1 is enriched at H3K9me3 regions and K9me3/K14ac is enriched at SETDB1 binding sites overlapping with LINE elements, suggesting that recruitment of the SETDB1 complex to K14ac/K9me regions has a role in silencing of active genomic regions.
Inhibition of NHEJ repair by type II-A CRISPR-Cas systems in bacteria
Authors: Bernheim Aude , Calvo-Villamañán Alicia , Basier Clovis , Cui Lun , Rocha Eduardo P. C. , Touchon Marie , Bikard David
Published: December 2017

Type II CRISPR-Cas systems introduce double-strand breaks into DNA of invading genetic material and use DNA fragments to acquire novel spacers during adaptation. These breaks can be the substrate of several DNA repair pathways, paving the way for interactions. We report that non-homologous end-joining (NHEJ) and type II-A CRISPR-Cas systems only co-occur once among 5563 fully sequenced prokaryotic genomes. We investigated experimentally the possible molecular interactions using the NHEJ pathway from Bacillus subtilis and the type II-A CRISPR-Cas systems from Streptococcus thermophilus and Streptococcus pyogenes. Our results suggest that the NHEJ system has no effect on CRISPR immunity. On the other hand, we provide evidence for the inhibition of NHEJ repair by the Csn2 protein. Our findings give insights on the complex interactions between CRISPR-Cas systems and repair mechanisms in bacteria, contributing to explain the scattered distribution of CRISPR-Cas systems in bacterial genome.
Efficacy and safety of stereotactic radiosurgery for pulmonary metastases from osteosarcoma: Experience in 73 patients
Authors: Yu Wenxi , Liu Zimei , Tang Lina , Lin Feng , Yao Yang , Shen Zan
Published: December 2017

Osteosarcoma pulmonary metastases are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic radiosurgery (SRS) can be an alternative to surgery that can achieve high rates of local control with limited toxicity. From January 2005 to December 2013, 73 patients who developed pulmonary metastasis during period of adjuvant chemotherapy or follow-up were analyzed. 33 patients were treated by stereotactic radiosurgery using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 40 patients were treated by surgical resection. Four-year progression-free survival rate, four-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. Patients tolerated gamma knife radiosurgery well. Our study demonstrates that SRS is well-tolerated with excellent local control and less complications. SRS should be considered as a potential option in patients with pulmonary metastases from osteosarcoma, especially in those who are medically inoperable, refuse surgery.
Escherichia coli outer membrane vesicles can contribute to sepsis induced cardiac dysfunction
Authors: Svennerholm Kristina , Park Kyong-Su , Wikström Johannes , Lässer Cecilia , Crescitelli Rossella , Shelke Ganesh V. , Jang Su Chul , Suzuki Shintaro , Bandeira Elga , Olofsson Charlotta S. , Lötvall Jan
Published: December 2017

Sepsis induced cardiac dysfunction (SIC) is a severe complication to sepsis which significantly worsens patient outcomes. It is known that bacteria have the capacity to release outer membrane vesicles (OMVs), which are nano-sized bilayered vesicles composed of lipids and proteins, that can induce a fatal inflammatory response. The aim of this study was to determine whether OMVs from a uropathogenicEscherichia colistrain can induce cardiac dysfunction, and to elucidate any mechanisms involved. OMVs induced irregular Ca2+oscillations with a decreased frequency in cardiomyocytes through recordings of intracellular Ca2+dynamics. Mice were intraperitoneally injected with bacteria-free OMVs, which resulted in increased concentration of pro-inflammatory cytokine levels in blood. Cytokines were increased in heart lysates, and OMVs could be detected in the heart after OMVs injection. Troponin T was significantly increased in blood, and echocardiography showed increased heart wall thickness as well as increased heart rate. This study shows thatE. coliOMVs induce cardiac injuryin vitroandin vivo, in the absence of bacteria, and may be a causative microbial signal in SIC. The role of OMVs in clinical disease warrant further studies, as bacterial OMVs in addition to live bacteria may be good therapeutic targets to control sepsis.
Dynamic regulation of TREK1 gating by Polycystin 2 via a Filamin A-mediated cytoskeletal Mechanism
Authors: Li Fraine Steven , Patel Amanda , Duprat Fabrice , Sharif-Naeini Reza
Published: December 2017

Mechanosensing is essential for several physiological functions including touch and pain sensations, osmoregulation, and controlling the myogenic tone of resistance arteries. Understanding how mechanosensitive ion channels (MSCs) are gated can provide important information regarding these processes. We have previously demonstrated that during pathological conditions such as polycystic kidney disease, polycystin 2 (TRPP2) inhibits the activity of potassium-selective MSCs through a filamin A-mediated cytoskeletal effect, and renders tubular epithelial cells susceptible to apoptosis. However, the nature of this cytoskeletal inhibition remains poorly understood. In this study we use a combination of electrophysiology, structured illumination microscopy, and fluorescence recovery after photobleaching (FRAP) to examine the dynamic nature of the TRPP2-mediated cytoskeletal inhibition of the potassium-selective MSC TREK1. Our data indicate that this inhibition of MSC activity occurs through an accelerated cytoskeletal inhibition, and ultimately decreases the open probability of the TREK1 channel. These results shed light on a novel mode of regulation of MSCs gating, which may be at play in several physiological functions.
Oral immunotherapy combined with omalizumab for high–risk cow’s milk allergy: a randomized controlled trial
Authors: Takahashi Masaya , Soejima Kazuhiko , Taniuchi Shoichiro , Hatano Yasuko , Yamanouchi Sohsaku , Ishikawa Hideki , Irahara Makoto , Sasaki Youhei , Kido Hiroshi , Kaneko Kazunari
Published: December 2017

We evaluated the efficacy and safety of oral immunotherapy (OIT) combined with 24 weeks of omalizumab (OMB) at inducing desensitization in children with cow’s milk allergy (CM) compared with an untreated group. The present study was a prospective randomized controlled trial. Sixteen patients (age, 6–14 years) with high IgE levels to CM were enrolled in the present study. Patients were randomized 1:1 to receive OMB-OIT group or untreated group. The primary outcome was the induction of desensitization at 8 weeks after OMB was discontinued in OMB-OIT treated group and at 32 weeks after study entry. None of the 6 children in the untreated group developed desensitization to CM while all of the 10 children in the OIT-OMB treated group achieved desensitization (P < 0.001). A significantly decreased wheal diameter in response to a skin prick test using CM was found in the OMB-OIT treated group (P < 0.05). These data suggest that OIT combined with OMB using microwave heated CM may help to induce desensitization for children with high-risk CM allergy. This prospective randomized controlled trial was intended for 50 participants but was prematurely discontinued due to overwhelming superiority of OMB combined with microwave heated OIT over CM avoidance.
Dynamics of RIF1 SUMOylation is regulated by PIAS4 in the maintenance of Genomic Stability
Authors: Kumar Ramesh , Cheok Chit Fang
Published: December 2017

RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci. Mechanistically, we show that PIAS4 knockdown abrogates UHRF1-dependent ubiquitination of RIF1, compromising RIF1 protein turnover. We detected intense RPA foci that colocalize with RIF1 foci in PIAS4 knockdown cells. These data highlight an important role of PIAS4-dependent regulation of RIF1, likely mediated by SUMOylation, in the disassembly of RIF1 DNA damage response (DDR) foci. We propose that unresolved RIF1 protein at sites of DNA damage in PIAS4-depleted cells largely accumulates in S phase, and subsequently leads to DNA double strand breaks. Therefore, PIAS4 promotes genomic stability by regulating the timely removal of RIF1 from sites of DNA damage.
Sodium tanshinone IIA sulfate adjunct therapy reduces high-sensitivity C-reactive protein level in coronary artery disease patients: a randomized controlled trial
Authors: Li Siming , Jiao Yang , Wang Hanjay , Shang Qinghua , Lu Fang , Huang Li , Liu Jiangang , Xu Hao , Chen Keji
Published: December 2017

High-sensitivity C-reactive protein (hs-CRP) is independently associated with cardiovascular events in coronary artery disease (CAD) patients and reducing the hs-CRP level may further benefit this population. We conduct this parallel design, randomized-controlled trial to assess the effectiveness of adjunct sodium tanshinone IIA sulfate (STS) therapy on circulating inflammation markers in CAD patients. Unstable angina or non-ST-elevation myocardial infarction patients with increased hs-CRP level were randomly assigned to atorvastatin-based standard medical therapy or standard therapy plus STS injection (80 mg, once daily for 14 consecutive days). The primary outcome was hs-CRP level. After the 14-day treatment, the experimental group (n = 35) exhibited significantly lower levels of hs-CRP than the control group (n = 35) (1.72 vs 3.20 mg/L, p = 0.0191). Lower levels of interleukin-6, monocyte chemotactic protein-1 (MCP-1), and soluble CD40 ligand were also observed in the experimental group. Angina symptoms were also better controlled in the experimental group. At 30 days after treatment completion, MCP-1 levels remained lower in the experimental group than in the control group (313.88 vs 337.91 pg/mL, p = 0.0078). No serious adverse events occurred. Our study demonstrates that on the basis of standard medical therapy, STS further reduce elevated hs-CRP and other circulating inflammation markers in CAD patients. (Chictr.org number: ChiCTR-TRC-12002361).
Dual-energy micro-CT for quantifying the time-course and staining characteristics of ex-vivo animal organs treated with iodine- and gadolinium-based contrast agents
Authors: Martins de Souza e Silva Juliana , Utsch Julian , Kimm Melanie A. , Allner Sebastian , Epple Michael F. , Achterhold Klaus , Pfeiffer Franz
Published: December 2017

Chemical staining of soft-tissues can be used as a strategy to increase their low inherent contrast in X-ray absorption micro-computed tomography (micro-CT), allowing to obtain fast three-dimensional structural information of animal organs. Though some staining agents are commonly used in this context, little is known about the staining agents’ ability to stain specific types of tissues; the times necessary to provide a sufficient contrast; and the effect of staining solution in distorting the tissue. Here we contribute to studies of animal organs (mouse heart and lungs) using staining combined with dual-energy micro-CT (DECT). DECT was used in order to obtain an additional quantitative measure for the amount of staining agents within the sample in 3D maps. Our results show that the two staining solutions used in this work diffuse differently in the tissues studied, the staining times of some tens of minutes already produce high-quality micro-CT images and, at the concentrations applied in this work, the staining solutions tested do not cause relevant tissue distortions. While one staining solution provides images of the general morphology of the organs, the other reveals organs’ features in the order of a hundred micrometers.
Workflow assessing the effect of gait alterations on stresses in the medial tibial cartilage - combined musculoskeletal modelling and finite element analysis
Authors: Halonen K. S. , Dzialo C. M. , Mannisi M. , Venäläinen M. S. , de Zee M. , Andersen M. S.
Published: December 2017

Knee osteoarthritis (KOA) is most common in the medial tibial compartment. We present a novel method to study the effect of gait modifications and lateral wedge insoles (LWIs) on the stresses in the medial tibial cartilage by combining musculoskeletal (MS) modelling with finite element (FE) analysis. Subject’s gait was recorded in a gait laboratory, walking normally, with 5° and 10° LWIs, toes inward (‘Toe in’), and toes outward (‘Toe out wide’). A full lower extremity MRI and a detailed knee MRI were taken. Bones and most soft tissues were segmented from images, and the generic bone architecture of the MS model was morphed into the segmented bones. The output forces from the MS model were then used as an input in the FE model of the subject’s knee. During stance, LWIs failed to reduce medial peak pressures apart from Insole 10° during the second peak. Toe in reduced peak pressures by −11% during the first peak but increased them by 12% during the second. Toe out wide reduced peak pressures by −15% during the first and increased them by 7% during the second. The results show that the work flow can assess the effect of interventions on an individual level. In the future, this method can be applied to patients with KOA.
Analysis of the cervical microbiome and potential biomarkers from postpartum HIV-positive women displaying cervical intraepithelial lesions
Authors: Curty Gislaine , Costa Raquel L. , Siqueira Juliana D. , Meyrelles Angela I. , Machado Elizabeth S. , Soares Esmeralda A. , Soares Marcelo A.
Published: December 2017

The cervical microbiota composition and diversity of HIV-positive women in the postpartum period is unknown. Using a high-throughput bacterial 16S rRNA gene sequencing, we identified four community state types (CSTs). CST III (Lactobacillusdominant) and CST IV (IV-A, IV-B.1, IV-B.2; high-diversity) were found in 41% and 59% of samples, respectively. We did not find association of any CST to postpartum period (six or twelve months), HPV infection or cytology (normal or lesion). However, five bacterial genera were associated with cervical lesions (Gardnerella, Aerococcus, Schlegelella, Moryella and Bifidobacterium), with significant odds ratio (OR) of 40 (2.28–706) for the presence of Moryella and 3.5 (1.36–8.9) for Schlegelella. Longitudinal analysis of samples at postpartum that regressed (lesion to normal), progressed (normal to lesion) and maintained the cytology (lesion or normal) evidenced Gardnerella with a significantly higher abundance in regressing lesions. In the current study, we report the first data on the cervical microbiota of HIV-positive women in the postpartum period. Consistent with previous studies of HIV-negative cohorts, HIV-positive women present a stable cervical microbiota of high-diversity in the postpartum period. Our results highlight that specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with cervical lesions.
Adeno-associated virus serotype rh10 is a useful gene transfer vector for sensory nerves that innervate bone in immunodeficient mice
Authors: Park Sun H. , Eber Matthew R. , Tsuzuki Shunsuke , Booker Mary E. , Sunil Aaron G. , Widner D. Brooke , Parker Renee A. , Peters Christopher M. , Shiozawa Yusuke
Published: December 2017

Adeno-associated virus (AAV) is frequently used to manipulate gene expression in the sensory nervous system for the study of pain mechanisms. Although some serotypes of AAV are known to have nerve tropism, whether AAV can distribute to sensory nerves that innervate the bone or skeletal tissue has not been shown. This information is crucial, since bone pain, including cancer-induced bone pain, is an area of high importance in pain biology. In this study, we found that AAVrh10 transduces neurons in the spinal cord and dorsal root ganglia of immunodeficient mice with higher efficacy than AAV2, 5, 6, 8, and 9 when injected intrathecally. Additionally, AAVrh10 has tropism towards sensory neurons in skeletal tissue, such as bone marrow and periosteum, while it occasionally reaches the sensory nerve fibers in the mouse footpad. Moreover, AAVrh10 has higher tropic affinity to large myelinated and small peptidergic sensory neurons that innervate bone, compared to small non-peptidergic sensory neurons that rarely innervate bone. Taken together, these results suggest that AAVrh10 is a useful gene delivery vector to target the sensory nerves innervating bone. This finding may lead to a greater understanding of the molecular mechanisms of chronic bone pain and cancer-induced bone pain.
Modelling of the impact of universal added sugar reduction through food reformulation
Authors: Yeung Chris Ho Ching , Gohil Paayal , Rangan Anna M. , Flood Victoria M. , Arcot Jayashree , Gill Timothy P. , Louie Jimmy Chun Yu
Published: December 2017

Food reformulation has been suggested to be one of the strategies to reduce population added sugar (AS) intake. This study aims to investigate the untested assumption that a reduction in AS through reformulation will result in a reduction in population intakes of AS and energy. Plausible dietary data from 4,140 respondents of an Australian national nutrition survey were used. Dietary modelling was performed at AS reductions of 10%, 15%, and 25% using four strategies: simple removal of AS or replacement with non-nutritive sweeteners (NNS), and replacement of AS with NNS and either: polyols, 50% fibres or 50% maltodextrin. Paired t-tests were conducted to compare the intake of energy, fat, and AS pre- and post-reformulation. The chosen reformulation strategies resulted in a projected reduction in AS and energy, with the greatest reduction found in 25% reformulation which was the highest level modelled. The overall projected mean (SD) reduction in energy and AS after 25% reformulation was 114 (92) kJ/day and 11.73 (7.52) g/day, p < 0.001. To conclude, product reformulation may be a potentially useful strategy for reducing AS intake. Although the magnitude of projected reduction was small at the individual level, the impact may be meaningful at a population level.