bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Co-Evolution Strategies Detect Predicted Functional Interaction Between the Serotonin 5-HT2A and 5-HT2C Receptors
Authors: Fongang Bernard , Cunningham Kathryn A. , Rowicka Maga , Kudlicki Andrzej 
Published: January 2019

ABSTRACTSerotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT2AR and 5-HT2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT2AR and 5-HT2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT2AR and 5-HT2CR to identify potential interactions between residues in both proteins. Coevolution studies can detect protein interactions, and since the thus uncovered interactions are subject to evolutionary pressure, they are likely functional. We assessed the significance of the 5-HT2AR/5-HT2CR interactions using randomized phylogenetic trees and found the interaction significant (p-value = 0.01). We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT2AR and 5-HT2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT2AR/5-HT2CR and indicate a correlation between this interface and location of SNPs in both proteins.
The gut microbiota is associated with clearance of Clostridium difficile infection independent of adaptive immunity
Authors: Leslie Jhansi L. , Vendrov Kimberly C. , Jenior Matthew L. , Young Vincent B. 
Published: January 2019

AbstractClostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium is the leading single cause of nosocomial infections in the United States. A major risk factor for C. difficile infection (CDI) is prior exposure to antibiotics as they increase susceptibility to CDI by altering the membership of the microbial community enabling colonization. The importance of the gut microbiota in providing protection from CDI is underscored by the reported 80-90% success rate of fecal microbial transplants in treating recurrent infection. Adaptive immunity, specifically humoral immunity, is also sufficient to protect from both acute and recurrent CDI. However, the role of the adaptive immune system in mediating clearance of C. difficile has yet to be resolved. Using murine models of CDI, we found that adaptive immunity is dispensable for clearance of C. difficile. However, Random Forest analysis using only 2 members of the resident bacterial community correctly identified animals that would go on to clear the infection with 66.7% accuracy. These findings indicate that the indigenous gut microbiota independent of adaptive immunity facilitates clearance of C. difficile from the murine gastrointestinal tract.ImportanceC. difficile infection is a major cause of morbidity and mortality in hospitalized patients in the United States. Currently the role of the adaptive immune response in modulating levels of C. difficile colonization is unresolved. This work suggests that the indigenous gut microbiota is a main factor that promotes clearance of C. difficile from the GI tract. Our results show that clearance of C. difficile can occur without contributions from the adaptive immune response. This study also has implications for the design of preclinical studies testing the efficacy of vaccines on clearance of bacterial pathogens as inherent differences in the baseline community structure of animals may bias findings.
Multilocus sequence analysis, a rapid and accurate identification tool for taxonomic classification, evolutionary relationship and population biology of the genus Shewanella
Authors: Fang Yujie , Wang Yonglu , Liu Zongdong , Dai Hang , Cai Hongyan , Li Zhenpeng , Du Zongjun , Wang Xin , Jing Huaiqi , Wei Qiang , Kan Biao , Wang Duochun 
Published: January 2019

ABSTRACTThe genus Shewanella comprises a group of marine-dwelling species with worldwide distribution. Several species are regarded as causative agents of food spoilage and opportunistic pathogens of human diseases. In this study, a standard multilocus sequence analysis (MLSA) based on six protein-coding genes (gyrA, gyrB, infB, recN, rpoA and topA) was established as a rapid and accurate identification tool in fifty-nine type Shewanella strains. This method yielded sufficient resolving power in regard to enough informative sites, adequate sequence divergences and distinct interspecies branches. The stability of phylogenetic topology was supported by high bootstrap values and concordance with different methods. The reliability of the MLSA scheme was further validated by identical phylogenies and high correlations of genomes. The MLSA approach provided a robust system to exhibit evolutionary relationships in the Shewanella genus. The split network tree proposed twelve distinct monophyletic clades with identical G+C contents and high genetic similarities. Eighty-six tested strains were investigated to explore the population biology of the Shewanella genus in China. The most prevalent Shewanella species were Shewanella algae, Shewanella xiamenensis, Shewanella chilikensis, Shewanella indica, Shewanella seohaensis and Shewanella carassii. The strains frequently isolated from clinical and food samples highlighted the importance of increasing the surveillance of Shewanella species. Combined with the genetic, genomic and phenotypic analyses, Shewanella upenei should be considered a synonym of S. algae, and Shewanella pacifica should be reclassified as a synonym of Shewanella japonica.IMPORTANCEThe MLSA scheme based on six HKGs (gyrA, gyrB, infB, recN, rpoA and topA) is well established as a reliable tool for taxonomic, evolutionary and epidemiological analyses of the genus Shewanella in this study. The standard MLSA method allows researchers to make rapid, economical and precise identification of Shewanella strains. The robust phylogenetic network of MLSA provides profound insight into the evolutionary structure of the genus Shewanella. The population genetics of Shewanella species determined by the MLSA approach plays a pivotal role in clinical diagnosis and routine monitoring. Further studies on remaining species and genomic analysis will enhance a more comprehensive understanding of the microbial systematics, phylogenetic relationships and ecological status of the genus Shewanella.
Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome
Authors: Pierson Alison , Darrigrand Romain , Rouillon Marine , Boulpicante Mathilde , Renko Zafiarisoa Dolor , Garcia Camille , Ghosh Michael , Laiguillon Marie-Charlotte , Lobry Camille , Alami Mouad , Apcher Sébastien 
Published: January 2019

AbstractThe success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented by tumor cells on MHC class I molecules. Alternative translation events emerged as a rich source of TAs and generate the so-called Pioneer Translation Products (PTPs), which are peptides generated from unspliced mRNA. We demonstrated in vitro and in vivo that the splicing inhibitor isoginkgetin and a derived water-soluble and less toxic molecule, IP2, act at the production stage of the PTPs. We showed that IP2 increases PTP-derived antigen presentation in cancer cellsin vitroand decreases tumor growthin vivoin an immune-dependent manner. Furthermore, IP2 treatment induces a long-lasting antitumor response. Finally, we observed that the epitope repertoire displayed on MHC-I molecules is altered upon treatment with IP2 with the modulation of pre-existing peptides and the emergence of novel antigens derived from both coding and allegedly non-coding sequences.SignificanceIP2 is a new efficient “first in class” immunomodulator of the MHC I presentation pathway. IP2 reduces the growth of sarcoma MCA205 and melanoma B16F10 tumors bearing the PTP-derived SL8 epitope and significantly extends mice survival. IP2 treatment reshape the cancer cell MHC-I immunopeptidome. These findings add to the understanding of the role of the splicing machinery in antigen production and presentation and identify the spliceosome as a druggable target to enhance cancer immunosurveillance.
Inhibition of miR-22-3p reduces kidney disease associated with systemic lupus erythematosus
Authors: Michell Danielle L. , Faust Ashley , Moore Jared L. , Appleton Brenna D. , Ormseth Michelle , Ramirez-Solano Marisol , Sheng Quanhu , Solus Joseph F. , Stein C. Michael , Vickers Kasey C. , Major Amy S. 
Published: January 2019

AbstractCellular microRNAs (miRNA) have proven to be critical regulators of inflammatory gene expression across many pathways within autoimmunity. Circulating miRNAs serve as a new class of disease biomarkers. Nevertheless, the functional roles of miRNAs, particularly extracellular miRNAs, in systemic lupus erythematosus (SLE) remain poorly understood. Therefore, we aimed to link changes in extracellular miRNAs to lymphocyte gene regulation and the pathophysiology of SLE. Here, we demonstrate that circulating miR-22-3p levels are associated with SLE, and miR-22-3p regulates T and B cell function and SLE-associated kidney disease. Based on high-throughput small RNA sequencing and real-time PCR, extracellular miR-22-3p levels were found to be significantly increased in whole plasma in human SLE subjects. To determine the functional impact of miR-22-3p in SLE, miR-22-3p loss-of-function studies were performed in a mouse model of SLE (B6.SLE1.2.3). We found thatin vivoadministration of locked-nucleic acid inhibitors of miR-22-3p (LNA-22) reduced lymphocyte accumulation in both the spleen and lymph nodes compared to LNA scramble (LNA-Scr) control-treated mice. Strikingly, LNA-22-3p treatments reduced kidney disease pathology and glomerular IgG deposition compared to LNA-Scr treatments in SLE mice. Moreover, miR-22-3p inhibition reduced the proportion of T effector memory IFN-γ producing CD4+T cells, suggesting that miR-22-3p regulates Th1 T cell differentiation. We also found that miR-22 inhibition in mice reduced STAT1 phosphorylation in the kidney which was correlated with loss of IFN-γ production by splenic CD4+T cells. In conclusion, our findings suggest that miR-22-3p is a critical regulator of SLE-associated CD4+T cell immunity and kidney disease. These results provide therapeutic potential for limiting splenic Th1 signaling and preventing the progression of lupus nephritis.Key FindingsExtracellular miR-22-3p levels are significantly increased in plasma from human SLE subjects.Inhibition of miR-22-3pin vivosignificantly reduced lymphocyte accumulation in both the spleen and lymph nodes in a mouse model of SLE, thus reducing splenomegaly and lymphadenopathy.miR-22-3p inhibition significantly reduced IFN-γ expression and secretion from splenic T cell subsets.Inhibition of miR-22-3pin vivoresulted in decreased IgG deposition in the kidney, decreased STAT1 phosphorylation, and decreased kidney disease in a mouse model of SLE.
Active cargo positioning in antiparallel transport networks
Authors: Richard Mathieu , Blanch-Mercader Carles , Ennomani Hajer , Cao Wenxiang , De La Cruz Enrique M. , Joanny Jean-François , Jülicher Frank , Blanchoin Laurent , Martin Pascal 
Published: January 2019

ABSTRACTCytoskeletal filaments assemble into dense parallel, antiparallel or disordered networks, providing a complex environment for active cargo transport and positioning by molecular motors. The interplay between the network architecture and intrinsic motor properties clearly affects transport properties but remains poorly understood. Here, by using surface micro-patterns of actin polymerization, we investigate stochastic transport properties of colloidal beads in antiparallel networks of overlapping actin filaments. We found that 200-nm beads coated with myosin-Va motors displayed directed movements towards positions where the net polarity of the actin network vanished, accumulating there. The bead distribution was dictated by the spatial profiles of local bead velocity and diffusion coefficient, indicating that a diffusion-drift process was at work. Remarkably, beads coated with heavy mero-myosin-II motors showed a similar behavior. However, although velocity gradients were steeper with myosin II, the much larger bead diffusion observed with this motor resulted in less precise positioning. Our observations are well described by a three-state model, in which active beads locally sense the net polarity of the network by frequently detaching from and reattaching to the filaments. A stochastic sequence of processive runs and diffusive searches results in a biased random walk. The precision of bead positioning is set by the gradient of net actin polarity in the network and by the run length of the cargo in an attached state. Our results unveiled physical rules for cargo transport and positioning in networks of mixed polarity.Significance statementCellular functions rely on small groups of molecular motors to transport their cargoes throughout the cell along polar filaments of the cytoskeleton. Cytoskeletal filaments self-assemble into dense networks comprising intersections and filaments of mixed polarity, challenging directed motor-based transport. Using micro-patterns of actin polymerization in-vitro, we investigated stochastic transport of colloidal beads in antiparallel networks of overlapping actin filaments. We found that beads coated with myosin motors sensed the net polarity of the actin network, resulting in active bead positioning to regions of neutral polarity with a precision depending on the motor type. A theoretical description of our experimental results provides the key physical rules for cargo transport and positioning in filament networks of mixed polarity.
The Largest Subunit of Human TFIIIC Complex, TFIIIC220, a Lysine Acetyltransferase Targets Histone H3K18
Authors: Basu Moumita , Boopathi Ramachandran , Das Sadhan , Kundu Tapas K 
Published: January 2019

ABSTRACTTFIIIC is a multisubunit complex that recognizes promoter elements and recruits TFIIIB and RNA polymerase III. Human TFIIIC complex possess lysine acetyltransferase activity which is critical in relieving chromatin mediated repression for RNA polymerase III-mediated transcription; two subunits of the TFIIIC complex, TFIIIC110 and TFIIIC90, were shown to acetylate H3 in vitro. Here we show that the largest and DNA binding subunit of TFIIIC complex, TFIIIC220, possesses intrinsic lysine acetyltransferase activity and acetylates histone H3K18 residue. By employing homology search we have identified the potential catalytic domain of TFIIIC220 which efficiently acetylate core histones in vitro. Point mutations at the critical residues of the identified acetyltransferase domain drastically reduces the acetyltransferase activity. Significantly, knockdown of TFIIIC220 in HepG2 cell line dramatically reduces global H3K18 acetylation level suggesting that TFIIIC220 is a crucial KAT to maintain acetylation homeostasis in the cell.
High concentration and yield production of mannose from açaí (Euterpe oleracea) seeds via diluted-acid and mannanase-catalyzed hydrolysis
Authors: Monteiro Alvaro Ferreira , Miguez Ingrid Santos , Barros Silva João Pedro R. , Silva Ayla Santana 
Published: January 2019

AbstractThe açaí berry’s seed corresponds to 85–95% of the fruit’s weight and represents ~1.1 million tons of residue yearly accumulated in the Amazon region. This study confirmed that mannan is the major component of mature seeds, corresponding to 80% of the seed’s total carbohydrates and about 50% of its dry weight. To convert this high mannan content into mannose, a sequential process of diluted acid and enzymatic hydrolysis was evaluated. Diluted-H2SO4 hydrolysis (3%-acid, 60-min, 121°C) resulted in a 30% mannan hydrolysis yield and 41.7 g/L of mannose. Because ~70% mannan remained in the seed, a mannanase-catalyzed hydrolysis was sequentially performed with 2–20% seed concentration, reaching 146.3 g/L of mannose and a 96.8% yield with 20% solids. As far as we know, this is the highest reported concentration of mannose produced from a residue. Thus, this work provides fundamental data for achieving high concentrations and yields of mannose from açaí seeds.HighlightsMannan was confirmed as the major component (~50%) of açaí seeds.Diluted-H2SO4 hydrolysis had a limited effect on mannan conversion into mannose.Enzymatic hydrolysis was sequentially performed with a high seed concentration.Mannan was efficiently hydrolyzed by mannanases, producing a 96.8% yield.Mannose production of 146.3 g/L was obtained with mannanase-catalyzed hydrolysis.Graphical abstract
Estimating residence times of lymphocytes in ovine lymph nodes
Authors: McDaniel Margaret M. , Ganusov Vitaly V. 
Published: January 2019

AbstractThe ability of lymphocytes to recirculate between blood and secondary lymphoid tissues such as lymph nodes (LNs) and spleen is well established. Sheep have been used as an experimental system to study lymphocyte recirculation for decades and multiple studies exist documenting accumulation and loss of intravenously (i.v.) transferred lymphocytes in efferent lymph of various ovine LNs. Yet, surprisingly little work has been done to accurately quantify the dynamics of lymphocyte exit from the LNs and to estimate the average residence times of lymphocytes in ovine LNs. In this work we developed a series of mathematical models based on fundamental principles of lymphocyte recirculation in the body and specifically, on how lymphocytes enter and exit lymph nodes in non-inflammatory (resting) conditions. We fitted these models to data from several independent experiments. Our analysis suggested that in sheep, recirculating lymphocytes spend on average 3 hours in the spleen and 20 hours in skin or gut-draining LNs with a distribution of residence times in LNs following a skewed gamma (lognormal-like) distribution. The latter result is in contrast which recent suggestions that the distribution of residence times of naive T cells in murine LNs is exponential and that lymphocyte residence times depend on the LN type (e.g., gut- vs. skin-draining). Our mathematical models also suggested an explanation for a puzzling observation of the long-term persistence of i.v. transferred lymphocytes in the efferent lymph of the prescapular LN (pLN); the model predicted that this is a natural consequence of long-term persistence of the transferred lymphocytes in circulation. We also found that lymphocytes isolated from the skin-draining pLN have a two-fold increased entry rate into the pLN as opposed to the mesenteric (gut-draining) LN (mLN). Likewise, lymphocytes from mLN had a three-fold increased entry rate into the mLN as opposed to entry rate into pLN. Importantly, these cannulation data could not be explained by preferential retention of cells in LNs of origin. Taken together, our work illustrates the power of mathematical modeling in describing the kinetics of lymphocyte migration in sheep and provides quantitative estimates of lymphocyte residence times in ovine LNs.
Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution
Authors: López Saioa , Lim Emilia , Huebner Ariana , Dietzen Michelle , Mourikis Thanos , Watkins Thomas B.K. , Rowan Andrew , Dewhurst Sally M. , Birkbak Nicolai J. , Wilson Gareth A. , Jamal-Hanjani Mariam , Swanton Charles ,   on behalf of TRACERx Consortium, McGranahan Nicholas 
Published: January 2019

AbstractWhole genome doubling (WGD) is a prevalent macro-evolutionary event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and clinical prognostic relevance, the evolutionary selection pressures for WGD have not been investigated. Here, we explored whether WGD may act to mitigate the irreversible, inexorable ratchet-like, accumulation of deleterious mutations in essential genes. Utilizing 1050 tumor regions from 816 non-small cell lung cancers (NSCLC), we temporally dissect mutations to determine their temporal acquisition in relation to WGD. We find evidence for strong negative selection against homozygous loss of essential cancer genes prior to WGD. However, mutations in essential genes occurring after duplication were not subject to significant negative selection, consistent with WGD providing a buffering effect, decreasing the likelihood of homozygous loss. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify signals of positive selection in lung, breast, colorectal cancer and other cancer types, enabling the elucidation of novel tumour suppressor genes and a deeper characterization of known cancer genes.
The corrosion behavior of compositional modified AISI type 304L stainless steel for nitric acid application
Authors: Shit Gopinath , Ningshen S. 
Published: January 2019

Purpose
High corrosion resistance in different concentrations of nitric acid is essential for structural steels to be used for the aqueous reprocessing of spent nuclear fuels with high plutonium content.

Design/methodology/approach
In the present study, the corrosion resistance of type 304L stainless steel (SS) with modified composition was evaluated in different concentrations of nitric acid using surface analytical techniques, weight loss method and electrochemical measurements.

Findings
Weight loss measurement in boiling 65 per cent nitric acid showed a low corrosion rate value of about 0.2 mm/y (8 mpy) after 240 h exposure. Electrochemical measurements revealed the shift in open circuit potentials as well as corrosion potential toward more noble direction, and the results of electrochemical impedance spectroscopy studies indicated the reduction in the thickness and stability of the passive film with increasing concentration from 6 to 11.5 M nitric acid.

Research limitations/implications
The low corrosion rate observed for this steel is attributed to the higher content of Cr (19 per cent), Ni (10 per cent) and Si (0.3 per cent) and controlled minor alloying elements (S, P, B, C, etc.) in the alloy that contributed to improving the transpassive corrosion resistance and minimizing the intergranular corrosion attack. The X-ray photoelectron spectroscopic analysis revealed the composition of the passive films to be mainly of iron and chromium oxides.

Practical implications
Materials with lower corrosion rates are desirable for applications in nitric acid.

Social implications
The used of nitric acid creates a severe corrosive environment in chemical or aqueous nuclear reprocessing plants, and hence with a modified composition of type 304L SS resulting in minimizing failure of components are desirable for reducing cost and maintenance.

Originality/value
The present paper is an original work carried out by the authors on the corrosion resistance behaviors of composition modified AISI type 304L SS for nitric acid application. The effects of different nitric acid concentrations were compared to provide understanding on in applicability in boiling and high nitric acid concentrations.