bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence, risk factors and antimicrobial resistance ofSalmonelladiarrhoeal infection among children in Thi-Qar Governorate, Iraq
Authors: HARB A. , O'DEA M. , HANAN Z. K. , ABRAHAM S. , HABIB I.
Published: November 2017

We conducted a hospital-based cross-sectional study among children aged <5 years in Thi-Qar Governorate, south-eastern Iraq, in order to examine the prevalence, risk factors and antimicrobial resistance associated with gastroenteritis caused bySalmonellainfection. From 320 diarrhoea cases enrolled between March and August 2016, 33 (10·3%, 95% confidence interval (CI) 8·4–12·4) cases were stool culture-positive for non-typhoidalSalmonella enterica. The most commonly identified serovar was Typhimurium (54%). Multivariable logistic regression analysis indicated that the odds ofSalmonellainfection in children from households supplied by pipe water was 4·7 (95% CI 1·6–13·9) times higher compared with those supplied with reverse osmosis treated water. Similarly, children from households with domestic animals were found to have a higher odds (OR 10·5; 95% CI 3·8–28·4) of beingSalmonellastool culture-positive. The likelihood ofSalmonellainfection was higher (OR 3·9; 95% CI 1·0–6·4) among children belonging to caregiver with primaryvs. tertiary education levels. Lower odds (OR 0·4; 95% CI 0·1–0·9) ofSalmonellainfection were associated with children exclusively breast fed as compared with those exclusively bottle fed.Salmonellainfection was three times lower (95% CI 0·1–0·7) in children belonging to caregiver who reported always washing hands after cleaning children following defecation,vs.those belonging to caregivers who did not wash hands. The antimicrobial resistance profile by disc diffusion revealed that non-susceptibility to tetracycline (78·8%), azithromycin (66·7%) and ciprofloxacin (57·6%) were the most commonly seen, and 84·9% ofSalmonellaisolates were classified as multi-drug resistant. This is the first study on prevalence and antimicrobial resistance ofSalmonellainfection among children in this setting. This work provides specific epidemiological data which are crucial to understand and combat paediatric diarrhoea in Iraq.
Anaplasmataceae agents among wild mammals and ectoparasites in Brazil
Authors: DE SOUSA K. C. M. , CALCHI A. C. , HERRERA H. M. , DUMLER J. S. , BARROS-BATTESTI D. M. , MACHADO R. Z. , ANDRÉ M. R.
Published: November 2017

Anaplasmataceae agents comprise obligate intracellular bacteria that can cause disease in humans and animals. Between August 2013 and March 2015, 31Nasua nasua(coati), 78Cerdocyon thous(crab-eating fox), sevenLeopardus pardalis(ocelot), 110 wild rodents, 30 marsupials, and 42 dogs were sampled in the Pantanal wetland, Brazil. In addition, ectoparasites found parasitizing the animals were collected and identified. The present work aimed to investigate the occurrence of Anaplasmataceae agents in wild mammals, domestic dogs and ectoparasites, by molecular and serological techniques. Overall, 14 (17·9%)C. thous, seven (16·6%) dogs and one (3·2%)N. nasuawere seroreactive toEhrlichia canis. Nine dogs, twoC. thous,oneN. nasua, eight wild rodents, five marsupials, eightAmblyomma sculptum,fourAmblyomma parvum,13A. sculptumnymphal pools, twoAmblyommalarvae pools and onePolygenis (Polygenis) bohlsi bohlsiflea pool were positive forEhrlichiaspp. closely related toE. canis. SevenN. nasua, two dogs, oneC. thous,oneL. pardalis, four wild rodents, three marsupials, 15A. sculptum, twoAmblyomma ovale,twoA. parvumand oneAmblyommaspp. larval pools were positive forAnaplasmaspp. closely related toA. phagocytophilumorA. bovis. The present study provided evidence that wild animals from Brazilian Pantanal are exposed to Anaplasmataceae agents.
The electoral advantage of the left in times of fiscal adjustment
Authors: Bojar Abel
Published: November 2017

Despite widely held views on fiscal adjustment as a political minefield for government parties, the empirical literature on the issue has been surprisingly inconclusive. A crucial variable that has been often overlooked in the debate is partisan politics. Building on the micro-logic of Albert Hirschman’s ‘exit, voice, and loyalty’ framework, this article offers a novel theoretical perspective on the conditioning impact of partisan government in the electoral arena. Due to their more limited exit options at their disposal, left-wing voters are less likely to inflict electoral punishment on their parties, offering the latter an electoral advantage over their right-wing rivals. Relying on the largest cross-national data set to date on the evolution of close to 100 parties’ popularity ratings in 21 democracies, time-series–cross-section results confirm this electoral advantage. Somewhat paradoxically, while center-right government parties systematically lose popularity in years of fiscal adjustment, no such regularity is found for left-leaning incumbents.
Glucose-regulated protein 75 determines ER–mitochondrial coupling and sensitivity to oxidative stress in neuronal cells
Authors: Honrath Birgit , Metz Isabell , Bendridi Nadia , Rieusset Jennifer , Culmsee Carsten , Dolga Amalia M
Published: November 2017

The crosstalk between different organelles allows for the exchange of proteins, lipids and ions. Endoplasmic reticulum (ER) and mitochondria are physically linked and signal through the mitochondria-associated membrane (MAM) to regulate the transfer of Ca2+from ER stores into the mitochondrial matrix, thereby affecting mitochondrial function and intracellular Ca2+homeostasis. The chaperone glucose-regulated protein 75 (GRP75) is a key protein expressed at the MAM interface which regulates ER–mitochondrial Ca2+transfer. Previous studies revealed that modulation of GRP75 expression largely affected mitochondrial integrity and vulnerability to cell death. In the present study, we show that genetic ablation of GRP75, by weakening ER–mitochondrial junctions, provided protection against mitochondrial dysfunction and cell death in a model of glutamate-induced oxidative stress. Interestingly, GRP75 silencing attenuated both cytosolic and mitochondrial Ca2+overload in conditions of oxidative stress, blocked the formation of reactive oxygen species and preserved mitochondrial respiration. These data revealed a major role for GRP75 in regulating mitochondrial function, Ca2+and redox homeostasis. In line, GRP75 overexpression enhanced oxidative cell death induced by glutamate. Overall, our findings suggest weakening ER–mitochondrial connectivity by GRP75 inhibition as a novel protective approach in paradigms of oxidative stress in neuronal cells.
Supramammillary glutamate neurons are a key node of the arousal system
Authors: Pedersen Nigel P. , Ferrari Loris , Venner Anne , Wang Joshua L. , Abbott Stephen B. G. , Vujovic Nina , Arrigoni Elda , Saper Clifford B. , Fuller Patrick M.
Published: November 2017

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system.
The emergence of piRNAs against transposon invasion to preserve mammalian genome integrity
Authors: Ernst Christina , Odom Duncan T. , Kutter Claudia
Published: November 2017

Transposable elements (TEs) contribute to the large amount of repetitive sequences in mammalian genomes and have been linked to species-specific genome innovations by rewiring regulatory circuitries. However, organisms need to restrict TE activity to ensure genome integrity, especially in germline cells to protect the transmission of genetic information to the next generation. This review features our current understandings of mammalian PIWI-interacting RNAs (piRNAs) and their role in TE regulation in spermatogenesis. Here we discuss functional implication and explore additional molecular mechanisms that inhibit transposon activity and altogether illustrate the paradoxical arms race between genome evolution and stability.
Probing dopant segregation in distinct cation sites at perovskite oxide polycrystal interfaces
Authors: Yoon Hye-In , Lee Dong-Kyu , Bae Hyung Bin , Jo Gi-Young , Chung Hee-Suk , Kim Jin-Gyu , Kang Suk-Joong L. , Chung Sung-Yoon
Published: November 2017

Although theoretical studies and experimental investigations have demonstrated the presence of space-charge-induced dopant segregation, most work has been confined largely to the crystal-free surface and some special grain boundaries, and to the best of our knowledge there has been no systematic comparison to understand how the segregation varies at different types of interfaces in polycrystals. Here, through atomic-column resolved scanning transmission electron microscopy in real polycrystalline samples, we directly elucidate the space-charge segregation features at five distinct types of interfaces in an ABO3 perovskite oxide doped with A- and B-site donors. A series of observations reveals that both the interfacial atomic structure and the subsequent segregation behaviour are invariant regardless of the interface type. The findings in this study thus suggest that the electrostatic potential variation by the interface excess charge and compensating space charge provides a crucial contribution to determining not only the distribution of dopants but also the interfacial structure in oxides.
Structural basis of arrestin-3 activation and signaling
Authors: Chen Qiuyan , Perry Nicole A. , Vishnivetskiy Sergey A. , Berndt Sandra , Gilbert Nathaniel C. , Zhuo Ya , Singh Prashant K. , Tholen Jonas , Ohi Melanie D. , Gurevich Eugenia V. , Brautigam Chad A. , Klug Candice S. , Gurevich Vsevolod V. , Iverson T. M.
Published: November 2017

A unique aspect of arrestin-3 is its ability to support both receptor-dependent and receptor-independent signaling. Here, we show that inositol hexakisphosphate (IP6) is a non-receptor activator of arrestin-3 and report the structure of IP6-activated arrestin-3 at 2.4-Å resolution. IP6-activated arrestin-3 exhibits an inter-domain twist and a displaced C-tail, hallmarks of active arrestin. IP6 binds to the arrestin phosphate sensor, and is stabilized by trimerization. Analysis of the trimerization surface, which is also the receptor-binding surface, suggests a feature called the finger loop as a key region of the activation sensor. We show that finger loop helicity and flexibility may underlie coupling to hundreds of diverse receptors and also promote arrestin-3 activation by IP6. Importantly, we show that effector-binding sites on arrestins have distinct conformations in the basal and activated states, acting as switch regions. These switch regions may work with the inter-domain twist to initiate and direct arrestin-mediated signaling.
Global patterns of nitrate storage in the vadose zone
Authors: Ascott M. J. , Gooddy D. C. , Wang L. , Stuart M. E. , Lewis M. A. , Ward R. S. , Binley A. M.
Published: November 2017

Global-scale nitrogen budgets developed to quantify anthropogenic impacts on the nitrogen cycle do not explicitly consider nitrate stored in the vadose zone. Here we show that the vadose zone is an important store of nitrate that should be considered in future budgets for effective policymaking. Using estimates of groundwater depth and nitrate leaching for 1900–2000, we quantify the peak global storage of nitrate in the vadose zone as 605–1814 Teragrams (Tg). Estimates of nitrate storage are validated using basin-scale and national-scale estimates and observed groundwater nitrate data. Nitrate storage per unit area is greatest in North America, China and Europe where there are thick vadose zones and extensive historical agriculture. In these areas, long travel times in the vadose zone may delay the impact of changes in agricultural practices on groundwater quality. We argue that in these areas use of conventional nitrogen budget approaches is inappropriate.
Live imaging molecular changes in junctional tension upon VE-cadherin in zebrafish
Authors: Lagendijk Anne Karine , Gomez Guillermo A. , Baek Sungmin , Hesselson Daniel , Hughes William E. , Paterson Scott , Conway Daniel E. , Belting Heinz-Georg , Affolter Markus , Smith Kelly A. , Schwartz Martin A. , Yap Alpha S. , Hogan Benjamin M.
Published: November 2017

Forces play diverse roles in vascular development, homeostasis and disease. VE-cadherin at endothelial cell-cell junctions links the contractile acto-myosin cytoskeletons of adjacent cells, serving as a tension-transducer. To explore tensile changes across VE-cadherin in live zebrafish, we tailored an optical biosensor approach, originally established in vitro. We validate localization and function of a VE-cadherin tension sensor (TS) in vivo. Changes in tension across VE-cadherin observed using ratio-metric or lifetime FRET measurements reflect acto-myosin contractility within endothelial cells. Furthermore, we apply the TS to reveal biologically relevant changes in VE-cadherin tension that occur as the dorsal aorta matures and upon genetic and chemical perturbations during embryonic development.
Real-space and real-time dynamics of CRISPR-Cas9 visualized by high-speed atomic force microscopy
Authors: Shibata Mikihiro , Nishimasu Hiroshi , Kodera Noriyuki , Hirano Seiichi , Ando Toshio , Uchihashi Takayuki , Nureki Osamu
Published: November 2017

The CRISPR-associated endonuclease Cas9 binds to a guide RNA and cleaves double-stranded DNA with a sequence complementary to the RNA guide. The Cas9–RNA system has been harnessed for numerous applications, such as genome editing. Here we use high-speed atomic force microscopy (HS-AFM) to visualize the real-space and real-time dynamics of CRISPR-Cas9 in action. HS-AFM movies indicate that, whereas apo-Cas9 adopts unexpected flexible conformations, Cas9–RNA forms a stable bilobed structure and interrogates target sites on the DNA by three-dimensional diffusion. These movies also provide real-time visualization of the Cas9-mediated DNA cleavage process. Notably, the Cas9 HNH nuclease domain fluctuates upon DNA binding, and subsequently adopts an active conformation, where the HNH active site is docked at the cleavage site in the target DNA. Collectively, our HS-AFM data extend our understanding of the action mechanism of CRISPR-Cas9.
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice
Authors: Ma Qiaoli , Ineichen Benjamin V. , Detmar Michael , Proulx Steven T.
Published: November 2017

Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions.
Electrostrictive microelectromechanical fibres and textiles
Authors: Khudiyev Tural , Clayton Jefferson , Levy Etgar , Chocat Noémie , Gumennik Alexander , Stolyarov Alexander M. , Joannopoulos John , Fink Yoel
Published: November 2017

Microelectromechanical systems (MEMS) enable many modern-day technologies, including actuators, motion sensors, drug delivery systems, projection displays, etc. Currently, MEMS fabrication techniques are primarily based on silicon micromachining processes, resulting in rigid and low aspect ratio structures. In this study, we report on the discovery of MEMS functionality in fibres, thereby opening a path towards flexible, high-aspect ratio, and textile MEMS. The method used for generating these MEMS fibres leverages a preform-to-fibre thermal drawing process, in which the MEMS architecture and materials are embedded into a preform and drawn into kilometers of microstructured multimaterial fibre devices. The fibre MEMS functionality is enabled by an electrostrictive P(VDF-TrFE-CFE) ferrorelaxor terpolymer layer running the entire length of the fibre. Several modes of operation are investigated, including thickness-mode actuation with over 8% strain at 25 MV m−1, bending-mode actuation due to asymmetric positioning of the electrostrictive layer, and resonant fibre vibration modes tunable under AC-driving conditions.
Natural variation of YELLOW SEEDLING1 affects photosynthetic acclimation of Arabidopsis thaliana
Authors: van Rooijen Roxanne , Kruijer Willem , Boesten René , van Eeuwijk Fred A. , Harbinson Jeremy , Aarts Mark G. M.
Published: November 2017

Exploiting genetic variation for more efficient photosynthesis is an underexplored route towards new crop varieties. This study demonstrates the genetic dissection of higher plant photosynthesis efficiency down to the genomic DNA level, by confirming that allelic sequence variation at the Arabidopsis thaliana YELLOW SEEDLING1 (YS1) gene explains natural diversity in photosynthesis acclimation to high irradiance. We use a genome-wide association study to identify quantitative trait loci (QTLs) involved in the Arabidopsis photosynthetic acclimation response. Candidate genes underlying the QTLs are prioritized according to functional clues regarding gene ontology, expression and function. Reverse genetics and quantitative complementation confirm the candidacy of YS1, which encodes a pentatrico-peptide-repeat (PPR) protein involved in RNA editing of plastid-encoded genes (anterograde signalling). Gene expression analysis and allele sequence comparisons reveal polymorphisms in a light-responsive element in the YS1 promoter that affect its expression, and that of its downstream targets, resulting in the variation in photosynthetic acclimation.
Nanoscale design of polarization in ultrathin ferroelectric heterostructures
Authors: De Luca Gabriele , Strkalj Nives , Manz Sebastian , Bouillet Corinne , Fiebig Manfred , Trassin Morgan
Published: November 2017

The success of oxide electronics depends on the ability to design functional properties such as ferroelectricity with atomic accuracy. However, despite tremendous advances in ferroelectric heterostructures, the development towards multilevel architectures with precise layer-by-layer command over the polarization is impeded by the lack of continuous control over the balance of electrostatics, strain, chemistry and film thickness during growth. Moreover, the polarization in the deeper layers becomes inaccessible when these are buried by the ongoing deposition. Taking ferroelectric BaTiO3 and multiferroic BiFeO3 as model systems, we observe and engineer the emergence, orientation and interaction of ferroelectric polarization in ultrathin heterostructures with monolayer accuracy. We achieve this by optical second harmonic generation which tracks the evolution of spontaneous polarization in real time throughout the deposition process. Such direct and in situ access to the polarization during growth leads us to heterostructures with user-defined polarization sequences—towards a new class of functional ferroic materials.
Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes
Authors: Burwitz Benjamin J. , Wu Helen L. , Abdulhaqq Shaheed , Shriver-Munsch Christine , Swanson Tonya , Legasse Alfred W. , Hammond Katherine B. , Junell Stephanie L. , Reed Jason S. , Bimber Benjamin N. , Greene Justin M. , Webb Gabriela M. , Northrup Mina , Laub Wolfram , Kievit Paul , MacAllister Rhonda , Axthelm Michael K. , Ducore Rebecca , Lewis Anne , Colgin Lois M. A. , Hobbs Theodore , Martin Lauren D. , Ferguson Betsy , Thomas Charles R. , Panoskaltsis-Mortari Angela , Meyers Gabrielle , Stanton Jeffrey J. , Maziarz Richard T. , Sacha Jonah B.
Published: November 2017

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.
Unique architecture of thermophilic archaeal virus APBV1 and its genome packaging
Authors: Ptchelkine Denis , Gillum Ashley , Mochizuki Tomohiro , Lucas-Staat Soizick , Liu Ying , Krupovic Mart , Phillips Simon E. V. , Prangishvili David , Huiskonen Juha T.
Published: November 2017

Archaeal viruses have evolved to infect hosts often thriving in extreme conditions such as high temperatures. However, there is a paucity of information on archaeal virion structures, genome packaging, and determinants of temperature resistance. The rod-shaped virus APBV1 (Aeropyrum pernix bacilliform virus 1) is among the most thermostable viruses known; it infects a hyperthermophile Aeropyrum pernix, which grows optimally at 90 °C. Here we report the structure of APBV1, determined by cryo-electron microscopy at near-atomic resolution. Tight packing of the major virion glycoprotein (VP1) is ensured by extended hydrophobic interfaces, and likely contributes to the extreme thermostability of the helical capsid. The double-stranded DNA is tightly packed in the capsid as a left-handed superhelix and held in place by the interactions with positively charged residues of VP1. The assembly is closed by specific capping structures at either end, which we propose to play a role in DNA packing and delivery.
Origin of the omnipotence of eukaryotic release factor 1
Authors: Lind Christoffer , Oliveira Ana , Åqvist Johan
Published: November 2017

Termination of protein synthesis on the ribosome requires that mRNA stop codons are recognized with high fidelity. This is achieved by specific release factor proteins that are very different in bacteria and eukaryotes. Hence, while there are two release factors with overlapping specificity in bacteria, the single omnipotent eRF1 release factor in eukaryotes is able to read all three stop codons. This is particularly remarkable as it is able to select three out of four combinations of purine bases in the last two codon positions. With recently determined 3D structures of eukaryotic termination complexes, it has become possible to explore the origin of eRF1 specificity by computer simulations. Here, we report molecular dynamics free energy calculations on these termination complexes, where relative eRF1 binding free energies to different cognate and near-cognate codons are evaluated. The simulations show a high and uniform discrimination against the near-cognate codons, that differ from the cognate ones by a single nucleotide, and reveal the structural mechanisms behind the precise decoding by eRF1.
Author Correction: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk
Authors: Slavin Thomas P. , Maxwell Kara N. , Lilyquist Jenna , Vijai Joseph , Neuhausen Susan L. , Hart Steve N. , Ravichandran Vignesh , Thomas Tinu , Maria Ann , Villano Danylo , Schrader Kasmintan A. , Moore Raymond , Hu Chunling , Wubbenhorst Bradley , Wenz Brandon M. , D’Andrea Kurt , Robson Mark E. , Peterlongo Paolo , Bonanni Bernardo , Ford James M. , Garber Judy E. , Domchek Susan M. , Szabo Csilla , Offit Kenneth , Nathanson Katherine L. , Weitzel Jeffrey N. , Couch Fergus J.
Published: November 2017

A correction to this article has been published and is linked from the HTML version of this article.
Thermostability improvement of a Talaromyces leycettanus xylanase by rational protein engineering
Authors: Wang Xiaoyu , Ma Rui , Xie Xiangming , Liu Weina , Tu Tao , Zheng Fei , You Shuai , Ge Jianzhong , Xie Huifang , Yao Bin , Luo Huiying
Published: November 2017

Thermophilic xylanases with high catalytic efficiency are of great interest in the biofuel, food and feed industries. This study identified a GH11 xylanase gene, Tlxyn11B, in Talaromyces leycettanus JCM12802. Recombinant TlXyn11B produced in Pichia pastoris is distinguished by high specific activity (8259 ± 32 U/mg with beechwood xylan as substrate) and excellent pH stability (from 1.0 to 10.5). The beechwood xylan hydrolysates consisted mainly of xylobiose, xylotriose and xylotetraose, thus TlXyn11B could be used for the production of prebiotic xylooligosaccharide. By using the structure-based rational approach, the N-terminal sequence of TlXyn11B was modified for thermostability improvement. Mutants S3F and S3F/D35V/I/Q/M had elevated Tm values of 60.01 to 67.84 °C, with S3F/D35I the greatest. Homology modeling and molecular dynamics (MD) simulation analysis revealed that the substituted F3 and I35 formed a sandwich structure with S45 and T47, which may enhance the overall structure rigidity with lowered RMSD values. This study verifies the efficiency of rational approach in thermostability improvement and provides a xylanase candidate of GH11 with great commercialization potential.
Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease
Authors: Sun Kaiqi , D’Alessandro Angelo , Ahmed Mostafa H. , Zhang Yujin , Song Anren , Ko Tzu-Ping , Nemkov Travis , Reisz Julie A. , Wu Hongyu , Adebiyi Morayo , Peng Zhangzhe , Gong Jing , Liu Hong , Huang Aji , Wen Yuan Edward , Wen Alexander Q. , Berka Vladimir , Bogdanov Mikhail V. , Abdulmalik Osheiza , Han Leng , Tsai Ah-lim , Idowu Modupe , Juneja Harinder S. , Kellems Rodney E. , Dowhan William , Hansen Kirk C. , Safo Martin K. , Xia Yang
Published: November 2017

Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression. Functional studies revealed that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure at 1.9 Å resolution deciphered that S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to α1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the “switch region”, as well as with α2-heme like a molecular “sticky tape” with the last 3–4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying S1P-mediated pathogenic metabolic reprogramming in SCD and novel therapeutic avenues.
Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance
Authors: Du Peina , Huang Peide , Huang Xuanlin , Li Xiangchun , Feng Zhimin , Li Fengyu , Liang Shaoguang , Song Yongmei , Stenvang Jan , Brünner Nils , Yang Huanming , Ou Yunwei , Gao Qiang , Li Lin
Published: November 2017

Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.
Crystal Structure of Borrelia turicatae protein, BTA121, a differentially regulated gene in the tick-mammalian transmission cycle of relapsing fever spirochetes
Authors: Luo Zhipu , Kelleher Alan J. , Darwiche Rabih , Hudspeth Elissa M. , Shittu Oluwatosin K. , Krishnavajhala Aparna , Schneiter Roger , Lopez Job E. , Asojo Oluwatoyin A.
Published: November 2017

Tick-borne relapsing fever (RF) borreliosis is a neglected disease that is often misdiagnosed. RF species circulating in the United States include Borrelia turicatae, which is transmitted by argasid ticks. Environmental adaptation by RF Borrelia is poorly understood, however our previous studies indicated differential regulation of B. turicatae genes localized on the 150 kb linear megaplasmid during the tick-mammalian transmission cycle, including bta121. This gene is up-regulated by B. turicatae in the tick versus the mammal, and the encoded protein (BTA121) is predicted to be surface localized. The structure of BTA121 was solved by single-wavelength anomalous dispersion (SAD) using selenomethionine-derivative protein. The topology of BTA121 is unique with four helical domains organized into two helical bundles. Due to the sequence similarity of several genes on the megaplasmid, BTA121 can serve as a model for their tertiary  structures. BTA121 has large interconnected tunnels and cavities that can accommodate ligands, notably long parallel helices, which have a large hydrophobic central pocket. Preliminary in-vitro studies suggest that BTA121 binds lipids, notably palmitate with a similar order of binding affinity as tablysin-15, a known palmitate-binding protein. The reported data will guide mechanistic studies to determine the role of BTA121 in the tick-mammalian transmission cycle of B. turicatae.
Human Gingiva-Derived Mesenchymal Stem Cells Ameliorate Streptozoticin-induced T1DM in mice via Suppression of T effector cells and Up-regulating Treg Subsets
Authors: Zhang Wei , Zhou Li , Dang Junlong , Zhang Ximei , Wang Julie , Chen Yanming , Liang Jichao , Li Dongqing , Ma Jilin , Yuan Jia , Chen Weiwen , Zadeh Homayoun H. , Olsen Nancy , Zheng Song Guo
Published: November 2017

There is yet no cure for type 1 diabetes (T1DM) so far. A significant body of evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) showed great potential in controlling T1DM. But there exists much difficulty in using BMSCs as a clinical therapy. We here test whether a new population of mesenchymal stem cells from human gingiva (GMSCs), which has many advantages over BMSCs, can delay or prevent progress of T1DM. GMSCs were adoptively transferred to multiple low-dose streptozotocin (STZ)-induced T1DM. Blood glucose levels and disease severities were analyzed. T cells subsets in blood, spleen and lymph nodes were detected dynamically by flow cytometry. GMSC distribution was dynamically analyzed. We found that infusion of GMSCs but not fibroblast cells significantly controlled blood glucose levels, delayed diabetes onset, ameliorated pathology scores in pancreas, and down-regulated production of IL-17 and IFN-γ in CD4+ and CD8+ T cells in spleens, pancreatic lymph nodes (pLN) and other lymph nodes. GMSCs also up-regulated the levels of CD4+ Treg induced in the periphery. Mechanismly, GMSCs could migrate to pancreas and local lymph node and function through CD39/CD73 pathway to regulate effector T cells. Thus, GMSCs show a potential promise in treating T1DM in the clinic.
PDGF Family Expression in Glioblastoma Multiforme: Data Compilation from Ivy Glioblastoma Atlas Project Database
Authors: Cantanhede Isabella Gomes , de Oliveira João Ricardo Mendes
Published: November 2017

Glioblastoma Multiforme (GBM) is the most frequent and lethal primary brain cancer. Due to its therapeutic resistance and aggressiveness, its clinical management is challenging. Platelet-derived Growth Factor (PDGF) genes have been enrolled as drivers of this tumour progression as well as potential therapeutic targets. As detailed understanding of the expression pattern of PDGF system in the context of GBM intra- and intertumoral heterogeneity is lacking in the literature, this study aims at characterising PDGF expression in different histologically-defined GBM regions as well as investigating correlation of these genes expression with parameters related to poor prognosis. Z-score normalised expression values of PDGF subunits from multiple slices of 36 GBMs, alongside with clinical and genomic data on those GBMs patients, were compiled from Ivy Glioblastoma Atlas Project – Allen Institute for Brain Science data sets. PDGF subunits show differential expression over distinct regions of GBM and PDGF family is heterogeneously expressed among different brain lobes affected by GBM. Further, PDGF family expression correlates with bad prognosis factors: age at GBM diagnosis, Phosphatase and Tensin Homolog deletion and Isocitrate Dehydrogenase 1 mutation. These findings may aid on clinical management of GBM and development of targeted curative therapies against this devastating tumour.
Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein
Authors: Mariani L. L. , Rivaud-Péchoux S. , Charles P. , Ewenczyk C. , Meneret A. , Monga B. B. , Fleury M.-C. , Hainque E. , Maisonobe T. , Degos B. , Echaniz-Laguna A. , Renaud M. , Wirth T. , Grabli D. , Brice A. , Vidailhet M. , Stoppa-Lyonnet D. , Dubois-d’Enghien C. , Le Ber I. , Koenig M. , Roze E. , Tranchant C. , Durr A. , Gaymard B. , Anheim M.
Published: November 2017

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7–15 µg/L), AOA2 (15–65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.
DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway
Authors: Mandemaker I. K. , van Cuijk L. , Janssens R. C. , Lans H. , Bezstarosti K. , Hoeijmakers J. H. , Demmers J. A. , Vermeulen W. , Marteijn J. A.
Published: November 2017

The DNA damage response (DDR), comprising distinct repair and signalling pathways, safeguards genomic integrity. Protein ubiquitylation is an important regulatory mechanism of the DDR. To study its role in the UV-induced DDR, we characterized changes in protein ubiquitylation following DNA damage using quantitative di-Gly proteomics. Interestingly, we identified multiple sites of histone H1 that are ubiquitylated upon UV-damage. We show that UV-dependent histone H1 ubiquitylation at multiple lysines is mediated by the E3-ligase HUWE1. Recently, it was shown that poly-ubiquitylated histone H1 is an important signalling intermediate in the double strand break response. This poly-ubiquitylation is dependent on RNF8 and Ubc13 which extend pre-existing ubiquitin modifications to K63-linked chains. Here we demonstrate that HUWE1 depleted cells showed reduced recruitment of RNF168 and 53BP1 to sites of DNA damage, two factors downstream of RNF8 mediated histone H1 poly-ubiquitylation, while recruitment of MDC1, which act upstream of histone H1 ubiquitylation, was not affected. Our data show that histone H1 is a prominent target for ubiquitylation after UV-induced DNA damage. Our data are in line with a model in which HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DDR.
Wavefront aberrations and retinal image quality in different lenticular opacity types and densities
Authors: Wu Cheng-Zhe , Jin Hua , Shen Zhen-Nv , Li Ying-Jun , Cui Xun
Published: November 2017

To investigate wavefront aberrations in the entire eye and in the internal optics (lens) and retinal image qualities according to different lenticular opacity types and densities. Forty-one eyes with nuclear cataract, 33 eyes with cortical cataract, and 29 eyes with posterior subcapsular cataract were examined. In each group, wavefront aberrations in the entire eye and in the internal optics and retinal image quality were measured using a raytracing aberrometer. Eyes with cortical cataracts showed significantly higher coma-like aberrations compared to the other two groups in both entire eye and internal optic aberrations (P = 0.012 and P = 0.007, respectively). Eyes with nuclear cataract had lower spherical-like aberrations than the other two groups in both entire eye and internal optics aberrations (P < 0.001 and P < 0.001, respectively). In the nuclear cataract group, nuclear lens density was negatively correlated with internal spherical aberrations (r = −0.527, P = 0.005). Wavefront technology is useful for objective and quantitative analysis of retinal image quality deterioration in eyes with different early lenticular opacity types and densities. Understanding the wavefront optical properties of different crystalline lens opacities may help ophthalmic surgeons determine the optimal time to perform cataract surgery.
Indoor PM2.5 exposure affects skin aging manifestation in a Chinese population
Authors: Ding Anan , Yang Yajun , Zhao Zhuohui , Hüls Anke , Vierkötter Andrea , Yuan Ziyu , Cai Jing , Zhang Juan , Gao Wenshan , Li Jinxi , Zhang Manfei , Matsui Mary , Krutmann Jean , Kan Haidong , Schikowski Tamara , Jin Li , Wang Sijia
Published: November 2017

Traffic-related air pollution is known to be associated with skin aging manifestations. We previously found that the use of fossil fuels was associated with skin aging, but no direct link between indoor air pollutants and skin aging manifestations has ever been shown. Here we directly measured the indoor PM2.5 exposure in 30 households in Taizhou, China. Based on the directly measured PM2.5 exposure and questionnaire data of indoor pollution sources, we built a regression model to predict the PM2.5 exposure in larger datasets including an initial examination group (N = 874) and a second examination group (N = 1003). We then estimated the association between the PM2.5 exposure and skin aging manifestations by linear regression. In the initial examination group, we showed that the indoor PM2.5 exposure levels were positively associated with skin aging manifestation, including score of pigment spots on forehead (12.5% more spots per increase of IQR, P-value 0.0371), and wrinkle on upper lip (7.7% more wrinkle on upper lip per increase of IQR, P-value 0.0218). The results were replicated in the second examination group as well as in the pooled dataset. Our study provided evidence that the indoor PM2.5 exposure is associated with skin aging manifestation in a Chinese population.
Proteolytic cleavage of transmembrane cell adhesion molecule L1 by extracellular matrix molecule Reelin is important for mouse brain development
Authors: Lutz David , Sharaf Ahmed , Drexler Dagmar , Kataria Hardeep , Wolters-Eisfeld Gerrit , Brunne Bianka , Kleene Ralf , Loers Gabriele , Frotscher Michael , Schachner Melitta
Published: November 2017

The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1-80 coincide in time at early developmental stages of the cerebral cortex. Reelin-mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain development at early developmental stages.
Metabolic Profiling of healthy and cancerous tissues in 2D and 3D
Authors: Russell Shonagh , Wojtkowiak Jonathan , Neilson Andy , Gillies Robert J.
Published: November 2017

Metabolism is a compartmentalized process, and it is apparent in studying cancer that tumors, like normal tissues, demonstrate metabolic cooperation between different cell types. Metabolic profiling of cells in 2D culture systems often fails to reflect the metabolism occurring within tissues in vivo due to lack of other cell types and 3D interaction. We designed a tooling and methodology to metabolically profile and compare 2D cultures with cancer cell spheroids, and microtissue slices from tumors, and normal organs. We observed differences in the basal metabolism of 2D and 3D cell cultures in response to metabolic inhibitors, and chemotherapeutics. The metabolic profiles of microtissues derived from normal organs (heart, kidney) were relatively consistent when comparing microtissues derived from the same organ. Treatment of heart and kidney microtissues with cardio- or nephro-toxins had early and marked effects on tissue metabolism. In contrast, microtissues derived from different regions of the same tumors exhibited significant metabolic heterogeneity, which correlated to histology. Hence, metabolic profiling of complex microtissues is necessary to understand the effects of metabolic co-operation and how this interaction, not only can be targeted for treatment, but this method can be used as a reproducible, early and sensitive measure of drug toxicity.
First insights into the pleiotropic role of vrf (yedF), a newly characterized gene of Salmonella Typhimurium
Authors: Ballesté-Delpierre Clara , Fernandez-Orth Dietmar , Ferrer-Navarro Mario , Díaz-Peña Ramón , Odena-Caballol Antonia , Oliveira Eliandre , Fàbrega Anna , Vila Jordi
Published: November 2017

Salmonella possesses virulence determinants that allow replication under extreme conditions and invasion of host cells, causing disease. Here, we examined four putative genes predicted to encode membrane proteins (ydiY, ybdJ, STM1441 and ynaJ) and a putative transcriptional factor (yedF). These genes were identified in a previous study of a S. Typhimurium clinical isolate and its multidrug-resistant counterpart. For STM1441 and yedF a reduced ability to interact with HeLa cells was observed in the knock-out mutants, but an increase in this ability was absent when these genes were overexpressed, except for yedF which phenotype was rescued when yedF was restored. In the absence of yedF, decreased expression was seen for: i) virulence-related genes involved in motility, chemotaxis, attachment and survival inside the host cell; ii) global regulators of the invasion process (hilA, hilC and hilD); and iii) factors involved in LPS biosynthesis. In contrast, an increased expression was observed for anaerobic metabolism genes. We propose yedF is involved in the regulation of Salmonella pathogenesis and contributes to the activation of the virulence machinery. Moreover, we propose that, when oxygen is available, yedF contributes sustained repression of the anaerobic pathway. Therefore, we recommend this gene be named vrf, for virulence-related factor.