bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells
Authors: Cheng Chieh-Yang , Zhou Zongxiang , Stone Meredith , Lu Bao , Flesken-Nikitin Andrea , Nanus David M. , Nikitin Alexander Yu. 
Published: December 2019

SummaryAberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.
Design to Data for mutants of β-glucosidase B fromPaenibacillus polymyxa: Q22T, W123R, F155G, Y169M, W438D, V401A
Authors: Hou Chengrui , Smith Paul , Huang Joyce , Fell Jason , Huang Peishan , Vater Ashley , Siegel Justin B. 
Published: December 2019

AbstractA key goal of protein engineering is to accurately model the stability and catalytic activity of enzymes. However, the limitations of functional predictive abilities pose a major challenge for modeling algorithm design, and can be attributed to the lack of large data sets quantifying the functional properties of enzymes. Here, the thermal stability (TM) and Michaelis-Menten constants (kcat, KM, andkcat/KM) of six new variants of the β-glucosidase B (BglB) protein are quantitatively characterized. Molecular stability of the enzyme variants were hypothesized using the Foldit software and BglB was synthesized inE. colicells. Testing was done through a colorimetric kinetic assay and thermal stability fluorescence-based protein unfolding assay. Results from the assays suggest that all mutations, with the exception of variant Y169M, all experienced reduced catalytic efficiency compared to the wildtype. Assay results indicate that variant W123R is more thermally stable compared to the wildtype, while the differences in thermal stability between the other variants, and the wildtype are negligible. The collected thermal stability and catalytic efficiency data has been added to a data set with the aim of improving Rosetta algorithms for modeling and predicting the functional interactions between biomolecules through a machine learning algorithm and facilitate the precise engineering of protein catalysts.
Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia
Authors: Popovics Petra , Awadallah Wisam N. , Kohrt Sarah , Case Thomas C. , Miller Nicole L. , Ricke Emily , Huang Wei , Ramirez-Solano Marisol , Liu Qi , Vezina Chad M. , Matusik Robert J. , Ricke William A. , Grabowska Magdalena M. 
Published: December 2019

AbstractBackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression ofCXCL1,CXCL2,CXCL8,PTGS2andIL6in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.
Overcoming the design, build, test (DBT) bottleneck for synthesis of nonrepetitive protein-RNA binding cassettes for RNA applications
Authors: Katz Noa , Tripto Eitamar , Goldberg Sarah , Atar Orna , Yakhini Zohar , Orenstein Yaron , Amit Roee 
Published: December 2019

AbstractThe design-build-test (DBT) cycle in synthetic biology is considered to be a major bottleneck for progress in the field. The emergence of high-throughput experimental techniques, such as oligo libraries (OLs), combined with machine learning (ML) algorithms, provide the ingredients for a potential “big-data” solution that can generate a sufficient predictive capability to overcome the DBT bottleneck. In this work, we apply the OL-ML approach to the design of RNA cassettes used in gene editing and RNA tracking systems. RNA cassettes are typically made of repetitive hairpins, therefore hindering their retention, synthesis, and functionality. Here, we carried out a high-throughput OL-based experiment to generate thousands of new binding sites for the phage coat proteins of bacteriophages MS2 (MCP), PP7 (PCP), and Qβ (QCP). We then applied a neural network to vastly expand this space of binding sites to millions of additional predicted sites, which allowed us to identify the structural and sequence features that are critical for the binding of each RBP. To verify our approach, we designed new non-repetitive binding site cassettes and tested their functionality in U2OS mammalian cells. We found that all our cassettes exhibited multiple trackable puncta. Additionally, we designed and verified two additional cassettes, the first containing sites that can bind both PCP and QCP, and the second with sites that can bind either MCP or QCP, allowing for an additional orthogonal channel. Consequently, we provide the scientific community with a novel resource for rapidly creating functional non-repetitive binding site cassettes using one or more of three phage coat proteins with a variety of binding affinities for any application spanning bacteria to mammalian cells.
Cortical neuron response selectivity derives from strength in numbers of synapses
Authors: Scholl Benjamin , Thomas Connon I. , Ryan Melissa A. , Kamasawa Naomi , Fitzpatrick David 
Published: December 2019

AbstractSingle neocortical neurons are driven by populations of excitatory inputs, forming the basis of neural selectivity to features of sensory input. Excitatory connections are thought to mature during development through activity-dependent Hebbian plasticity1, whereby similarity between presynaptic and postsynaptic activity selectively strengthens some synapses and weakens others2. Evidence in support of this process ranges from measurements of synaptic ultrastructure to slice andin vivophysiology and imaging studies3,4,5,6,7,8. These corroborating lines of evidence lead to the prediction that a small number of strong synaptic inputs drive neural selectivity, while weak synaptic inputs are less correlated with the functional properties of somatic output and act to modulate activity overall6,7. Supporting evidence from cortical circuits, however, has been limited to measurements of neighboring, connected cell pairs, raising the question of whether this prediction holds for the full profile of synapses converging onto cortical neurons. Here we measure the strengths of functionally characterized excitatory inputs contacting single pyramidal neurons in ferret primary visual cortex (V1) by combiningin vivotwo-photon synaptic imaging andpost hocelectron microscopy (EM). Using EM reconstruction of individual synapses as a metric of strength, we find no evidence that strong synapses play a predominant role in the selectivity of cortical neuron responses to visual stimuli. Instead, selectivity appears to arise from the total number of synapses activated by different stimuli. Moreover, spatial clustering of co-active inputs, thought to amplify synaptic drive, appears reserved for weaker synapses, further enhancing the contribution of the large number of weak synapses to somatic response. Our results challenge the role of Hebbian mechanisms in shaping neuronal selectivity in cortical circuits, and suggest that selectivity reflects the co-activation of large populations of presynaptic neurons with similar properties and a mixture of strengths.
Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression
Authors: Aiderus Aziz , Newberg Justin Y. , Guzman-Rojas Liliana , Contreras-Sandoval Ana M. , Meshey Amanda L. , Jones Devin J. , Amaya-Manzanares Felipe , Rangel Roberto , Ward Jerrold M. , Lee Song-Choon , Ban Kenneth Hon-Kim , Rogers Keith , Rogers Susan M. , Selvanesan Luxmanan , McNoe Leslie A. , Copeland Neal G. , Jenkins Nancy A. , Tsai Kenneth Y. , Black Michael A. , Mann Karen M. , Mann Michael B. 
Published: December 2019

AbstractThe systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized theSleeping Beautytransposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progressionin vivoin the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for theZMIZgenes, and tumor suppressive roles forKMT2C, CREBBPandNCOA2, in the initiation or progression of human cuSCC. Taken together, ourin vivoscreen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.
HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137
Authors: Zhang Fengwen , Bieniasz Paul D. 
Published: December 2019

SummaryThe HIV-1 Vpr accessory protein induces ubiquitin/proteasome-dependent degradation of many cellular proteins by recruiting them to a cullin4A-DDB1-DCAF1 complex. In so doing, Vpr enhances HIV-1 gene expression and induces (G2/M) cell cycle arrest. However, the identities of Vpr target proteins through which these biological effects are exerted are unknown. We show that a chromosome periphery protein, CCDC137/cPERP-B, is targeted for depletion by HIV-1 Vpr, in a cullin4A-DDB1-DCAF1 dependent manner. CCDC137 depletion caused G2/M cell-cycle arrest, while Vpr-resistant CCDC137 mutants conferred resistance to Vpr-induced G2/M arrest. CCDC137 depletion also recapitulated the ability of Vpr to enhance HIV-1 gene expression, particularly in macrophages. Our findings indicate that Vpr promotes cell-cycle arrest and HIV-1 gene expression through depletion of CCDC137.
The String Decomposition Problem and its Applications to Centromere Assembly
Authors: Dvorkina Tatiana , Bzikadze Andrey V. , Pevzner Pavel A. 
Published: December 2019

AbstractRecent attempts to assemble long tandem repeats (such as multi-megabase long centromeres) faced the challenge of accurate translation of long error-prone reads from the nucleotide alphabet into the alphabet of repeatunits. Centromeres represent a particularly complex type ofnested tandem repeats, where each unit is itself a repeat formed by chromosome-specificmonomers(a repeat within repeat). Given a set of monomers forming a specific centromere, translation of a read into monomers is modeled as the String Decomposition Problem, finding a concatenate of monomers with the highest-scoring sequence alignment to a given read. We developed a StringDecomposer algorithm for solving this problem, benchmarked it on the set of reads generated by the Telomere-to-Telomere consortium, and identified a novel (rare) monomer that extends the set of twelve X-chromosome specific monomers identified more than three decades ago. The accurate translation of each read into a monomer alphabet turns centromere assembly into a more tractable problem than the notoriously difficult problem of assembling centromeres in the nucleotide alphabet. Our identification of a novel monomer emphasizes the importance of careful identification of all (even rare) monomers for follow-up centromere assembly efforts.
Colonies of the fungus Aspergillus niger are highly differentiated to adapt to local carbon source variation
Authors: Daly Paul , Peng Mao , Mitchell Hugh D. , Kim Young‐Mo , Ansong Charles , Brewer Heather , de Gijsel Peter , Lipton Mary S. , Markillie Lye Meng , Nicora Carrie D. , Orr Galya , Wiebenga Ad , Hildén Kristiina S. , Kabel Mirjam A. , Baker Scott E. , Mäkelä Miia R. , de Vries Ronald P. 
Published: December 2019

SummarySaprobic fungi, such as Aspergillus niger, grow as colonies consisting of a network of branching and fusing hyphae that are often considered to be relatively uniform entities in which nutrients can freely move through the hyphae. In nature, different parts of a colony are often exposed to different nutrients. We have investigated, using a multi‐omics approach, adaptation of A. niger colonies to spatially separated and compositionally different plant biomass substrates. This demonstrated a high level of intra‐colony differentiation, which closely matched the locally available substrate. The part of the colony exposed to pectin‐rich sugar beet pulp and to xylan‐rich wheat bran showed high pectinolytic and high xylanolytic transcript and protein levels respectively. This study therefore exemplifies the high ability of fungal colonies to differentiate and adapt to local conditions, ensuring efficient use of the available nutrients, rather than maintaining a uniform physiology throughout the colony.
Redox cycling of Fe(II) and Fe(III) in magnetite accelerates aceticlastic methanogenesis by Methanosarcina mazei
Authors: Wang Hui , Byrne James M. , Liu Pengfei , Liu Juan , Dong Xiuzhu , Lu Yahai 
Published: December 2019

SummaryIt has been recently shown that magnetite nanoparticles (nanoFe3O4) can facilitate methanogenic syntrophy but the effect of magnetite on methanogenesis alone remains elusive. Here we show that aceticlastic methanogenesis by Methanosarcina mazei is accelerated by magnetite and is correlated with the redox cycling of structural Fe(II) and Fe(III) in the mineral. An enrichment and its closest pure culture relative, Ms. mazei zm‐15, both obtained from a natural wetland of the Tibetan plateau were tested in this experiment. The Fe(II) to Fe(III) ratios in magnetite, as measured by multiple approaches, show an initial increase in both the methanogenic cultures and the blank preparations containing no microbes. The Fe(II)/Fe(III) ratio then displays a distinct decline followed by an increase towards the end of incubation only in the enrichment and pure culture cultivations. This redox cycling of magnetite is in accordance with the stimulation of aceticlastic methanogenesis. Microscopic observation reveals the precipitation of nanoFe3O4 on methanogen cell surface. The genomic analysis predicts that in addition to electron transfer components essential for aceticlastic methanogenesis, Ms. mazei zm‐15 contains an outer‐surface multiheme c‐type cytochrome (MHC) and a few function‐unknown surface proteins that harbour monoheme motif. We hypothesize that the redox cycling of nanoFe3O4 delivers a positive influence via the MHC to the membrane electron transfer chain and hence promote the aceticlastic methanogenesis.
Joint species distribution modelling with ther‐package Hmsc
Authors: Tikhonov Gleb , Opedal Øystein H. , Abrego Nerea , Lehikoinen Aleksi , de Jonge Melinda M. J. , Oksanen Jari , Ovaskainen Otso 
Published: December 2019

AbstractJoint Species Distribution Modelling (JSDM) is becoming an increasingly popular statistical method for analysing data in community ecology. Hierarchical Modelling of Species Communities (HMSC) is a general and flexible framework for fitting JSDMs. HMSC allows the integration of community ecology data with data on environmental covariates, species traits, phylogenetic relationships and the spatio‐temporal context of the study, providing predictive insights into community assembly processes from non‐manipulative observational data of species communities.The full range of functionality of HMSC has remained restricted to Matlab users only. To make HMSC accessible to the wider community of ecologists, we introduce Hmsc3.0, a user‐friendlyrimplementation.We illustrate the use of the package by applying Hmsc3.0 to a range of case studies on real and simulated data. The real data consist of bird counts in a spatio‐temporally structured dataset, environmental covariates, species traits and phylogenetic relationships. Vignettes on simulated data involve single‐species models, models of small communities, models of large species communities and models for large spatial data. We demonstrate the estimation of species responses to environmental covariates and how these depend on species traits, as well as the estimation of residual species associations. We demonstrate how to construct and fit models with different types of random effects, how to examine MCMC convergence, how to examine the explanatory and predictive powers of the models, how to assess parameter estimates and how to make predictions. We further demonstrate how Hmsc3.0 can be applied to normally distributed data, count data and presence–absence data.The package, along with the extended vignettes, makes JSDM fitting and post‐processing easily accessible to ecologists familiar withr.
Preparation, structural, microstructural, mechanical, and cytotoxic characterization of Ti‐15Nb alloy for biomedical applications
Authors: Kuroda Pedro Akira Bazaglia , da Silva Luciano Monteiro , Sousa Karolyne dos Santos Jorge , Donato Tatiani Ayako Goto , Grandini Carlos Roberto 
Published: December 2019

AbstractTitanium alloys are widely used in the biomedical field due to their excellent resistance to corrosion, high mechanical strength/density ratio, low elastic modulus, and good biocompatibility. Niobium is a β‐stabilizer element that has the potential to decrease elastic modulus and possesses excellent corrosion resistance. In this article, Ti‐15Nb alloy was prepared via arc‐melting, with the aim of using it in biomedical applications to replace implants that fail due to mechanical incompatibility with human bone. This Ti‐15Nb alloy was structurally, chemically, and microstructurally characterized. Its mechanical properties were analyzed via Vickers microhardness and elastic modulus measurements. The cytotoxicity of the alloy was evaluated via direct and indirect MTT tests. In the direct MTT test, the cells were grown on alloy and in the indirect test, Ti‐15Nb alloy extracts were prepared (1 g/1 mL at 310 K for 48 hours). The results of chemical composition showed that the alloy produced has good quality and low content of gaseous impurities, such as oxygen and nitrogen. The obtained results for structure and microstructure indicated the presence of the martensite α’ phase. The microhardness of the Ti‐15Nb alloy is superior to that of cp‐Ti due to solid solution hardening, and the alloy has a better elastic modulus as compared to pure titanium. Cytotoxic effects were not observed. The Ti‐15Nb alloy shows good results of mechanical properties and does not show cytotoxic effects. In addition, morphological variations were not found in the cells and good cell adhesion in all the studied conditions was observed. In general, the alloy proposed in this article has satisfactory characteristics as a biomedical material.
Clinical outcomes of venoarterial extracorporeal life support in 462 patients: Single‐center experience
Authors: Zhigalov Konstantin , Sá Michel Pompeu Barros Oliveira , Safonov Dmitrii , Zagitov Ilgiz , Alofesh Ahmad , Pavlova Varvara , Easo Jerry , Eichstaedt Harald C. , Ennker Juergen , Ruhparwar Arjang , Weymann Alexander ,   ITCVR
Published: December 2019

AbstractThis study aims to investigate the outcomes of venoarterial extracorporeal life support (VA‐ECLS) in a large single‐center patient cohort regarding survival and adverse events. Between June 2009 and March 2019, 462 consecutive patients received VA‐ECLS. The mean age was 66.2 ± 11.9 years. Two patient groups were identified: Group 1—patients with ECLS due to postcardiotomy shock (PCS) after cardiac surgery (PCS, n = 357); Group 2—patients with ECLS due to cardiogenic shock (CS) without previous surgery (nonPCS, n = 105). The primary end point was overall in‐hospital survival, while secondary end points were adverse events during the study period. Overall, the in‐hospital survival rate was 26%. There was no statistically significant difference between the groups: 26.3% for PCS and 24.8% for nonPCS, respectively (P > .05). Weaning from VA‐ECLS was possible in 44.3% for PCS and in 29.5% for nonPCS (P = .004). The strong predictors of overall mortality were postoperative hepatic dysfunction (OR = 14.362, 95%CI = 1.948‐105.858), cardiopulmonary resuscitation > 30 minutes (OR = 6.301, 95%CI = 1.488‐26.673), bleeding with a need for revision (OR = 2.123, 95%CI = 1.343‐3.355), and previous sternotomy (OR = 2.077, 95%CI = 1.021‐4.223). Despite its low survival rates, VA‐ECLS therapy is the last resort and the only lifesaving option for patients in refractory CS. In contrast, there is still a lack of evidence for VA‐ECLS in PCS patients. Future studies are warranted to evaluate the outcomes of VA‐ECLS therapy after cardiac surgery.