bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional anatomy of the full length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis
Authors: Stephens Bryan S. , Ngo Tony , Kufareva Irina , Handel Tracy M. 
Published: January 2020

AbstractDue to their prominent role in development and infamy in cancer and HIV, the chemokine receptor CXCR4 and its ligand, CXCL12, have been the subject of numerous structural and functional studies. Nevertheless, a high resolution structure of the CXCR4-CXCL12 complex has not been reported. Even with several alternative computational models of the complex at hand, the relative contributions of different interaction epitopes to ligand binding, ligand selectivity and signaling are not readily apparent. Here, building upon our latest structural model, we employed a systematic mutagenesis strategy to dissect the functional anatomy of the of CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments supported pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of the predicted orientation of the chemokine relative to the receptor, while also providing insight into ligand selectivity. Progressive deletion of N-terminal residues revealed an unexpected contribution of the receptor N-terminus to chemokine signaling; this finding challenges a longstanding “two-site” hypothesis about the essential features of the receptor-chemokine interaction where the N-terminus is purported to only contribute to binding affinity. The results suggest that while the interaction of the chemokine N-terminus with the receptor binding pocket is the key driver of signaling, the signaling amplitude depends on the extent to which the receptor N-terminus binds the chemokine. Along with systematic characterization of other epitopes, the current data allow us to propose a comprehensive experimentally-consistent structural model for how the chemokine binds CXCR4 and initiates signal transmission through the receptor TM domain.One sentence summaryA systematic structure-guided mutagenesis study of chemokine receptor CXCR4 reveals novel insights into epitopes regulating ligand recognition, ligand specificity and CXCL12-mediated signaling.
Mechanism of Action of a Prostaglandin E2Receptor Antagonist with antimicrobial activity againstStaphylococcus aureus
Authors: Lilly Elizabeth A. , Ikeh Mélanie A. C. , Fidel Paul L. , Noverr Mairi C. 
Published: January 2020

AbstractOur laboratory recently reported that the EP4receptor antagonist, L-161,982, had direct growth-inhibitory effects onStaphylococcus aureus in vitroand in vivo, reducing microbial burden and providing significant protection against lethality in models ofS. aureusmonomicrobial and polymicrobial intra-abdominal infection. This antimicrobial activity was observed with both methicillin-sensitive and methicillin-resistantS. aureus(MRSA), as well as other Gram-positive bacteria. The antimicrobial activity of L-161,982 was independent of EP4receptor inhibitory activity. In this study, we investigated the mechanism of action (MOA) of L-161,982, which contains a sulfonamide functional group. However, results demonstrate L-161,982 does not affect folate synthesis (sulfonamide MOA), oxidative stress, or membrane permeability. Instead, our results suggest that the inhibitor works via effects on inhibition of the electron transport chain (ETC). Similar to other ETC inhibitors, L-161,982 exposure results in a small colony size variant phenotype and inhibition of pigmentation, as well as significantly reduced hemolytic activity, and ATP production. In addition, L-161,982 potentiated the antimicrobial activity of another ETC inhibitor and inhibition was partially rescued by supplementation with nutrients required for ETC auxotrophs. Taken together, these findings demonstrate that L-161,982 exerts antimicrobial activity against MRSA via inhibition the ETC, representing a new member of a potentially novel antimicrobial drug class.
Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis
Authors: Li Yiding , Wang Zhiming , Lin Huayu , Wang Lisha , Chen Xiangyu , Liu Qiao , Zuo Qianfei , Hu Jianjun , Wang Haoqiang , Guo Junyi , Xie Luoyingzi , Tang Jianfang , Li Zhirong , Hu Li , Ye Lilin , Huang Qizhao , Xu Lifan 
Published: January 2020

AbstractDuring tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.
An enhanced characterization of the human skin microbiome: a new biodiversity of microbial interactions
Authors: Emiola Akintunde , Zhou Wei , Oh Julia 
Published: January 2020

ABSTRACTThe healthy human skin microbiome is shaped by skin site physiology, individual-specific factors, and is largely stable over time despite significant environmental perturbation. Studies identifying these characteristics used shotgun metagenomic sequencing for high resolution reconstruction of the bacteria, fungi, and viruses in the community. However, these conclusions were drawn from a relatively small proportion of the total sequence reads analyzable by mapping to known reference genomes. ‘Reference-free’ approaches, based onde novoassembly of reads into genome fragments, are also limited in their ability to capture low abundance species, small genomes, and to discriminate between more similar genomes. To account for the large fraction of non-human unmapped reads on the skin—referred to as microbial ‘dark matter’—we used a hybridde novoand reference-based approach to annotate a metagenomic dataset of 698 healthy human skin samples. This approach reduced the overall proportion of uncharacterized reads from 42% to 17%. With our refined characterization, we revisited assumptions about the skin microbiome, and demonstrated higher biodiversity and lower stability, particularly in dry and moist skin sites. To investigate hypotheses underlying stability, we examined growth dynamics and interspecies interactions in these communities. Surprisingly, even though most skin sites were relatively stable, many dominant skin microbes, includingCutibacterium acnesand staphylococci, were actively growing in the skin, with poor or no relationship between growth rate and relative abundance, suggesting that host selection or interspecies competition may be important factors maintaining community homeostasis. To investigate other mechanisms facilitating adaptation to a specific skin site, we identifiedStaphylococcus epidermidisgenes that are likely involved in stress response and provide mechanisms essential for growth in oily sites. Finally, horizontal gene transfer—another mechanism of competition by which strains may swap antagonistic or virulent coding regions—was relatively limited in healthy skin, but suggested exchange of different metabolic and environmental tolerance pathways. Altogether, our findings underscore the value of a combined reference-based andde novoapproach to provide significant new insights into microbial composition, physiology, and interspecies interactions to maintain community homeostasis in the healthy human skin microbiome.
Exploiting toxin internalization receptors to enhance delivery of proteins to lysosomes for enzyme replacement therapy
Authors: Sugiman-Marangos Seiji N. , Beilhartz Greg L. , Zhao Xiaochu , Zhou Dongxia , Hua Rong , Kim Peter K. , Rini James M. , Minassian Berge A. , Melnyk Roman A. 
Published: January 2020

AbstractLysosomal storage diseases are a group of over 70 inherited genetic diseases caused by a defect or deficiency in a lysosomal protein. Enzyme replacement therapy, in which a functional copy of the defective enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases; however, the inefficient uptake of recombinant enzymes into cells and tissuesviathe low-affinity mannose-6-phosphate receptor prohibits broader utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endo-lysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that the targeted TPP1 chimera binds with high affinity to target cells and is delivered into lysosomes with much greater efficiency than TPP1 alone. Further, we demonstrate efficient and durable uptake of the chimerain vivofollowing intracerebroventricular injection in mice lacking TPP1. Targeting the highly efficient diphtheria toxin internalization pathway represents a novel approach for improving the efficacy and utility of enzyme replacement therapy for treating lysosomal storage diseases.
Simplified probabilistic seismic assessment of dampers in tall and braced structures in buildings
Authors: Singh Tanuja , Kalra Megha , Misra Anil Kumar 
Published: January 2020

PurposeThe paper aims to focus on adjacent buildings response, equipped with damper, to analyze the vibration reduction in the nearby buildings. The nearby buildings were also equipped with dampers. The occurrence of adjacent buildings with adequate or inadequate space in between is a common phenomenon. However, many a times not much attention is paid to provide or check gap adequacy or to connect the two buildings suitably to avoid pounding of two structures on each other. This study emphasizes the utility of providing a damper in between two adjacent buildings for better performance.Design/methodology/approachThe two steel structures taken for study are prototype of two structures normally found in industrial structure such as power plant, where in one of boiler structure is often tall and braced and short structure of turbine building which is moment resistant, modeled in SAP. There could be similar such structures which are often connected to a platform or a walkway with a sliding end, so as not to transfer horizontal force to other structures. If the advantage of stiffness of tall braced structure is taken into account, shorter structure can be suitably connected to braced structure to transfer forces during seismic cases under nonlinear conditions, thereby avoiding pounding (incase gap is too less), reducing response and thus optimizing the section sizes. The structures were subjected to El Centro earthquake, to simulate MCE (which could be the other site TH scaled up as desired for real site PGA), and damper location and parameters were varied to find optimum value which offers reduced base shear, reduced top floor displacement and minimum inter story drift and highest energy absorption by fluid viscous dampers.FindingsThe findings show that taller structures, which are braced, have more stiffness; the effect of damper is more pronounced in reducing displacement of shorter moment resistant structure to the tune of 60%, with suitably defined Cd value which is found to be 600 KNs/m for the present study. Thus, advantage of stiffener structure is taken to leverage and reduce the displacement of shorter moment resistant structure in reducing its displacement under nonlinear conditions of seismic case.Originality/valueThis work shows the original findings, of the adjacent buildings response, equipped with damper, to analyze the vibration reduction on other buildings which were planned to be constructed nearby.
Long-range dependence in the returns and volatility of the Finnish housing market
Authors: Dufitinema Josephine , Pynnönen Seppo 
Published: January 2020

PurposeThe purpose of this paper is to examine the evidence of long-range dependence behaviour in both house price returns and volatility for fifteen main regions in Finland over the period of 1988:Q1 to 2018:Q4. These regions are divided geographically into 45 cities and sub-areas according to their postcode numbers. The studied type of dwellings is apartments (block of flats) divided into one-room, two-rooms, and more than three rooms apartments types.Design/methodology/approachFor each house price return series, both parametric and semiparametric long memory approaches are used to estimate the fractional differencing parameter d in an autoregressive fractional integrated moving average [ARFIMA (p, d,q)] process. Moreover, for cities and sub-areas with significant clustering effects (autoregressive conditional heteroscedasticity [ARCH] effects), the semiparametric long memory method is used to analyse the degree of persistence in the volatility by estimating the fractional differencing parameter d in both squared and absolute price returns.FindingsA higher degree of predictability was found in all three apartments types price returns with the estimates of the long memory parameter constrained in the stationary and invertible interval, implying that the returns of the studied types of dwellings are long-term dependent. This high level of persistence in the house price indices differs from other assets, such as stocks and commodities. Furthermore, the evidence of long-range dependence was discovered in the house price volatility with more than half of the studied samples exhibiting long memory behaviour.Research limitations/implicationsInvestigating the long memory behaviour in both returns and volatility of the house prices is crucial for investment, risk and portfolio management. One reason is that the evidence of long-range dependence in the housing market returns suggests a high degree of predictability of the asset. The other reason is that the presence of long memory in the housing market volatility aids in the development of appropriate time series volatility forecasting models in this market. The study outcomes will be used in modelling and forecasting the volatility dynamics of the studied types of dwellings. The quality of the data limits the analysis and the results of the study.Originality/valueTo the best of the authors’ knowledge, this is the first research that assesses the long memory behaviour in the Finnish housing market. Also, it is the first study that evaluates the volatility of the Finnish housing market using data on both municipal and geographical level.
Molecular epidemiology of clinically high‐risk Pseudomonas aeruginosa strains: Practical overview
Authors: Sawa Teiji , Momiyama Kyoko , Mihara Toshihito , Kainuma Atsushi , Kinoshita Mao , Moriyama Kiyoshi 
Published: January 2020

AbstractIn recent years, numerous outbreaks of multidrug‐resistant Pseudomonas aeruginosa have been reported across the world. Once an outbreak occurs, besides routinely testing isolates for susceptibility to antimicrobials, it is required to check their virulence genotypes and clonality profiles. Replacing pulsed‐field gel electrophoresis DNA fingerprinting are faster, easier‐to‐use, and less expensive polymerase chain reaction (PCR)‐based methods for characterizing hospital isolates. P. aeruginosa possesses a mosaic genome structure and a highly conserved core genome displaying low sequence diversity and a highly variable accessory genome that communicates with other Pseudomonas species via horizontal gene transfer. Multiple‐locus variable‐number tandem‐repeat analysis and multilocus sequence typing methods allow for phylogenetic analysis of isolates by PCR amplification of target genes with the support of Internet‐based services. The target genes located in the core genome regions usually contain low‐frequency mutations, allowing the resulting phylogenetic trees to infer evolutionary processes. The multiplex PCR‐based open reading frame typing (POT) method, integron PCR, and exoenzyme genotyping can determine a genotype by PCR amplifying a specific insertion gene in the accessory genome region using a single or a multiple primer set. Thus, analyzing P. aeruginosa isolates for their clonality, virulence factors, and resistance characteristics is achievable by combining the clonality evaluation of the core genome based on multiple‐locus targeting methods with other methods that can identify specific virulence and antimicrobial genes. Software packages such as eBURST, R, and Dendroscope, which are powerful tools for phylogenetic analyses, enable researchers and clinicians to visualize clonality associations in clinical isolates.
Long‐term deepened snow cover alters litter layer turnover rate in temperate steppes
Authors: Wang Jing , Liu Weixing , Li Ping , Jia Zhou , Deng Meifeng , Yang Sen , Liu Lingli 
Published: January 2020

Abstract

The turnover of litter layer is a biogeochemical process fundamental to carbon and nutrient cycling, influencing seed germination, species coexisting, and carbon storage. Winter snow depth is undergoing increasing trend in Northern China, which has been shown to alter litter decomposition rate of individual species. However, it remains unknown how changes in snow depth affect the turnover rate of the whole litter layer, and whether the responses vary between different steppes. Most current litter decomposition studies are site‐based or short‐term treated, limiting the exploration of the long‐term response of litter layer turnover in regional pattern.

In this study, we selected six long‐term (11–13 years) snow fence sites in Inner Mongolia, with three in the dry steppe and another three in the wet steppe, and investigated the responses of community‐weighted litter residence time (LRT) to long‐term increased snow treatment.

We found that LRT increased by 0.02 year for every 10 cm increase in snow depth in the wet steppe, but was not affected in the dry steppe. The lack of effect of deepened snow on LRT in the dry steppe was attributed to the offset between the positive effect of the increased plant community‐weighted height possibly via inhibiting photodegradation and the enhanced litter recalcitrance by producing higher proportion of stem litter, and the negative effect of the increased soil moisture via accelerating microbial decomposition. The significantly positive effect of the deepened snow on LRT in the wet steppe was mainly because the deepened snow increased grass biomass but had no effect on forb biomass, which reduced the degradability of the litter layer.

Overall, our findings indicated that deepened snow changed plant community, which altered environmental conditions and enhanced litter recalcitrance, thereby increasing LRT in temperate steppes. However, this effect was diminished by enhancing microbial decomposition in the dry but not wet steppe, resulting in different overall responses of LRT to deep‐snow in the two steppes. The slow litter turnover rate in the wet steppe might result in greater litter accumulation under future increased snow depth, which could be unfavourable for seed germination and alter plant diversity.

A free Plain Language Summary can be found within the Supporting Information of this article.
Phenolic compounds extraction in enzymatic macerations of grape skins identified as low‐level extractable total anthocyanin content
Authors: Nogales‐Bueno Julio , Baca‐Bocanegra Berta , Heredia Francisco José , Hernández‐Hierro José Miguel 
Published: January 2020

AbstractAnthocyanins in wine principally depend on grape skin extractable anthocyanin content, that is, the amount of anthocyanins present in grape skin that are released to wine during the maceration stage. This amount of extractable anthocyanins is closely linked to the cell wall degradation of skin cells. Indeed, among other methodologies, the maceration in presence of different enzymes can be used to increase cell wall degradation, and therefore, the amount of anthocyanins extracted from grape skins to wine. Vitis vinifera L. cv. Tempranillo and Syrah red grapes have been identified as samples with low anthocyanin extraction potential by near infrared hyperspectral imaging. Grape skins have been macerated in the presence of cellulase, glucosidase, and pectinase. Then, color of the supernatants and phenolic compounds extracted from grape skins (total phenols, total flavanols, and total and individual anthocyanins) has been determined. Cellulase and glucosidase have shown a positive effect in the extraction of phenolic compounds from these grapes. Macerations carried out in the presence of cellulase have produced supernatants with a more intense color (lower lightness and higher chroma values), and a higher extraction of flavanols and anthocyanins than the respective control essays. However, pectinase treatments have produced the opposite effect, which could be partially explained by an eventual interaction between the cell wall polysaccharides liberated by pectinase and the phenolic compounds extracted. Synergy effects do not appear between cellulase and glucosidase. Moreover, the negative effect of the addition of pectinase might be due to the interactions between the cell wall material liberated by pectinase and the phenolic compounds extracted.Practical ApplicationIn the present study, grape samples with a low anthocyanin extraction potential have been identified, and these samples have been macerated in the presence of different enzymes. The applied enzymes were three of the most common enzymes that are applied in the wine industry. Individual enzymes and mixtures have been applied to Syrah and Tempranillo grape skin samples and the results have been compared to control macerations. Knowledge in this topic will help the production of quality wines.