bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors
Authors: Malczewska Anna , Frampton Adam E. , Mato Prado Mireia , Ameri Shima , Dabrowska Aleksandra F. , Zagorac Sladjana , Clift Ashley K. , Kos-Kudła Beata , Faiz Omar , Stebbing Justin , Castellano Leandro , Frilling Andrea 
Published: August 2019

Objective:
To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions.

Background:
MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response.

Methods:
This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months).

Results:
Four serum miRNAs (miR-125b-5p, -362–5p, -425–5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362–5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD).

Conclusions:
Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362–5p have potential to be used to detect RSD/RCD.
Mapping RNA-capsid interactions and RNA secondary structure within authentic virus particles using next-generation sequencing
Authors: Zhou Yiyang , Routh Andrew 
Published: August 2019

AbstractTo characterize RNA-capsid binding sites genome-wide within mature RNA virus particles, we have developed a Next-Generation Sequencing (NGS) platform: Photo-Activatable Ribonucleoside Cross-Linking (PAR-CL). In PAR-CL, 4-thiouracil is incorporated into the encapsidated genomes of authentic virus particles and subsequently UV-crosslinked to adjacent capsid proteins. We demonstrate that PAR-CL can readily and reliably identify capsid binding sites in genomic viral RNA by detecting crosslink-specific uridine to cytidine transitions in NGS data. Using Flock House virus (FHV) as a model system, we identified highly consistent and significant PAR-CL signals across virus RNA genome indicating a clear tropism of the encapsidated RNA genome. Certain interaction sites correlate to previously identified FHV RNA motifs. We additionally performed dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) to generate a high-resolution profile of single-stranded genomic RNA inside viral particles. Combining PAR-CL and DMS-MaPseq reveals that the predominant RNA-capsid sites favor double-stranded RNA regions. We disrupted secondary structures associated with PAR-CL sites using synonymous mutations, resulting in varied effects to virus replication, propagation, and packaging. Certain mutations showed substantial deficiency in virus replication, suggesting these RNA-capsid sites are multifunctional. These provide further evidence to support that FHV packaging and replication are highly coordinated and inter-dependent events.ImportanceIcosahedral RNA viruses must package their genetic cargo into the restrictive and tight confines of the protected virions. High resolution structures of RNA viruses have been solved by Cryo-EM and crystallography, but the encapsidated RNA often eluded visualization due to the icosahedral averaging imposed during image reconstruction. Asymmetrical reconstructions of some icosahedral RNA virus particles have revealed that the encapsidated RNAs conform to specific structures, which may be related to programmed assembly pathway or an energy-minima for RNA folding during or after encapsidation. Despite these advances, determining whether encapsidated RNA genomes conform to a single structure and determining what regions of the viral RNA genome interact with the inner surface of the capsid shell remains challenging. Furthermore, it remains to be determined whether there exists a single RNA structure with conserved topology in RNA virus particles or an ensemble of genomic RNA structures. This is important as resolving these features will inform the elusive structures of the asymmetrically encapsidated genomic material and how virus particles are assembled.
Downscaling livestock census data using multivariate predictive models: sensitivity to modifiable areal unit problem
Authors: Da Re Daniele , Gilbert Marius , Chaiban Celia , Bourguignon Pierre , Thanapongtharm Weerapong , Robinson Timothy P. , Vanwambeke Sophie O. 
Published: August 2019

AbstractThe analysis of census data aggregated by administrative units introduces a statistical bias known as the modifiable areal unit problem (MAUP). Previous researches have mostly assessed the effect of MAUP on upscaling models. The present study contributes to clarify the effects of MAUP on the downscaling methodologies, highlighting how a priori scales and shapes choices could influence the results. We aggregated chicken and duck fine-resolution census in Thailand, using three administrative census levels in regular and irregular shapes. We then disaggregated the data within the Gridded Livestock of the World analytical framework, sampling predictors in two different ways. A sensitivity analysis on Pearson’srcorrelation statistics and RMSE were carried out to understand how size and shapes of the response variables affect the goodness-of-fit and downscaling performances. We showed that scale, rather than shapes and sampling methods, affected downscaling precision, suggesting that training the model using the finest administrative level available is preferable. Moreover, datasets showing non-homogeneus distribution but instead spatial clustering seemed less affected by MAUP, yielding higher Pearson’srvalues and lower RMSE compared to a more spatially homogenous dataset. Implementing aggregation sensitivity analysis in spatial studies could help to interpret complex results and disseminate robust products.
Crl activates transcription by stabilizing the active conformation of the master stress factor σS
Authors: Xu Juncao , Cui Kaijie , Shen Liqiang , Shi Jing , Li Lingting , You Linlin , Fang Chengli , Zhao Guoping , Feng Yu , Yang Bei , Zhang Yu 
Published: August 2019

SUMMARYσS is a master transcription initiation factor that protects bacterial cells from various harmful environmental stresses and antibiotic pressure. Although its mechanism remains unclear, it is known that full activation of σS-mediated transcription requires a σS-specific activator, Crl. In this study, we determined a 3.80 Å cryo-EM structure of an E. coli transcription activation complex (E. coli Crl-TAC) comprising E. coli σS-RNAP holoenzyme, Crl, and a nucleic-acid scaffold. The structure reveals that Crl interacts with the domain 2 of σS (σS2), sharing no interaction with promoter DNA. Subsequent hydrogen-deuterium exchange mass spectrometry (HDX-MS) results indicate that Crl stabilizes key structural motifs of σS2 to promote the assembly of σS-RNAP holoenzyme and also to facilitate formation of the RNA polymerase-promoter DNA open complex (RPo). Our study demonstrates a unique DNA contact-independent mechanism of transcription activation, thereby defining a previously unrecognized mode of transcription activation in cells.
Grazer behavior can regulate large-scale patterning of community states
Authors: Karatayev Vadim A. , Baskett Marissa L. , Kushner David J. , Shears Nicholas T. , Caselle Jennifer E. , Boettiger Carl 
Published: August 2019

AbstractEcosystem patterning can arise from environmental heterogeneity, biological feedbacks that produce multiple persistent ecological states, or their interaction. One source of feed-backs is density-dependent changes in behavior that regulates species interactions. By fitting state-space models to large-scale (∼500km) surveys on temperate rocky reefs, we find that behavioral feedbacks best explain why kelp and urchin barrens form either reef-wide patches or local mosaics. Best-supported models in California include feedbacks where starvation intensifies grazing across entire reefs create reef-scale, alternatively stable kelp- and urchin-dominated states (32% of reefs). Best-fitting models in New Zealand include the feedback of urchins avoiding dense kelp stands that can increase abrasion and predation risk, which drives a transition from shallower urchin-dominated to deeper kelp-dominated zones, with patchiness at 3-8m depths with intermediate wave stress. Connecting locally-studied processes with region-wide data, we highlight how behavior can explain community patterning and why some systems exhibit community-wide alternative stable states.
Fungal hyphae colonization byBacillus subtilisrelies on biofilm matrix components
Authors: Kjeldgaard Bodil , Listian Stevanus A. , Ramaswamhi Valliyammai , Richter Anne , Kiesewalter Heiko T. , Kovács Ákos T. 
Published: August 2019

AbstractBacteria interact with their environment including microbes and higher eukaryotes. The ability of bacteria and fungi to affect each other are defined by various chemical, physical and biological factors. During physical association, bacterial cells can directly attach and settle on the hyphae of various fungal species. Such colonization of mycelia was proposed to be dependent on biofilm formation by the bacteria, but the essentiality of the biofilm matrix was not represented before. Here, we demonstrate that secreted biofilm matrix components of the soil-dwelling bacterium,Bacillus subtilisare essential for the establishment of a dense bacterial population on the hyphae of the filamentous black mold fungus,Aspergillus nigerand the basidiomycete mushroom,Agaricus bisporus. We further illustrate that these matrix components can be shared among various mutants highlighting the community shaping impact of biofilm formers on bacteria-fungi interactions.
Pharmaco-genetic screen to uncover actin regulators targeted by prostaglandins duringDrosophilaoogenesis
Authors: Spracklen Andrew J. , Lamb Maureen C. , Groen Christopher M. , Tootle Tina L. 
Published: August 2019

AbstractProstaglandins (PGs) are lipid signaling molecules with numerous physiologic functions, including pain/inflammation, fertility, and cancer. PGs are produced downstream of cyclooxygenase (COX) enzymes, the targets of non-steroidal anti-inflammatory drugs (NSAIDs). In numerous systems, PGs regulate actin cytoskeletal remodeling, however, their mechanisms of action remain largely unknown. To address this deficiency, we undertook a pharmaco-genetic interaction screen during late-stageDrosophilaoogenesis.Drosophilaoogenesis is as an established model for studying both actin dynamics and PGs. Indeed, during Stage 10B, cage-like arrays of actin bundles surround each nurse cell nucleus, and during Stage 11, the cortical actin contracts, squeezing the cytoplasmic contents into the oocyte. Both of these cytoskeletal properties are required for follicle development and fertility, and are regulated by PGs. Here we describe a pharmaco-genetic interaction screen that takes advantage of the facts that Stage 10B follicles will mature in culture and COX inhibitors, such as aspirin, block thisin vitrofollicle maturation. In the screen, aspirin was used at a concentration that blocks 50% of the wild-type follicles from maturing in culture. By combining this aspirin treatment with heterozygosity for mutations in actin regulators, we quantitatively identified enhancers and suppressors of COX inhibition. Here we present the screen results and initial follow-up studies on three strong enhancers – Enabled, Capping protein, and non-muscle Myosin II Regulatory Light Chain. Overall, these studies provide new insight into how PGs regulate both actin bundle formation and cellular contraction, properties that are not only essential for development, but are misregulated in diseases.
Dopamine modulates the integrity of the perisynaptic extracellular matrix at excitatory synapses
Authors: Mitlöhner Jessica , Kaushik Rahul , Niekisch Hartmut , Blondiaux Armand , Gee Christine E. , Happel Max F.K. , Gundelfinger Eckart , Dityatev Alexander , Frischknecht Renato , Seidenbecher Constanze 
Published: August 2019

SummaryIn the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM,in vivoandin vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.
Spatial simulation of co-designed land-cover change scenarios in New England: Alternative futures and their consequences for conservation priorities
Authors: Thompson Jonathan R. , Plisinski Joshua , Lambert Kathy Fallon , Duveneck Matthew J. , Morreale Luca , McBride Marissa , MacLean Meghan Graham , Weis Marissa , Lee Lucy 
Published: August 2019

ABSTRACTTo help prepare for an uncertain future, planners and scientists often engage with stakeholders to co-design alternative scenarios of land-use change. Methods to translate the resulting qualitative scenarios into quantitative simulations that characterize the future landscape condition are needed to understand consequences of the scenarios while maintaining the legitimacy of the process. We use the New England Landscape Futures (NELF) project as a case study to demonstrate a transparent method for translating participatory scenarios to simulations of Land-Use and Land-Cover (LULC) change and for understanding the major drivers of land-use change and diversity of plausible scenarios and the consequences of alternative land-use pathways for conservation priorities. The NELF project co-designed four narrative scenarios that contrast with a Recent Trends scenario that projects a continuation of observed changes across the 18-million-hectare region during the past 20 years. Here, we (1) describe the process and utility of translating qualitative scenarios into spatial simulations using a dynamic cellular land change model; (2) evaluate the outcomes of the scenarios in terms of the differences in the LULC configuration relative to the Recent Trends scenario and to each other; (3) compare the fate of forests within key areas of concern to the stakeholders; and (4) describe how a user-inspired outreach tool was developed to make the simulations and analyses accessible to diverse users. The four alternative scenarios populate a quadrant of future conditions that crosses high to low natural resource planning and innovation with local to global socio-economic connectedness. The associated simulations are strongly divergent in terms of the amount of LULC change and the spatial pattern of change. Features of the simulations can be linked back to the original storylines. Among the scenarios there is a fivefold difference in the amount of high-density development, and a twofold difference in the amount of protected land. Overall, the rate of LULC change has a greater influence on forestlands of concern to the stakeholders than does the spatial configuration. The simulated scenarios have been integrated into an online mapping tool that was designed via a user-engagement process to meet the needs of diverse stakeholders who are interested the future of the land and in using future scenarios to guide land use planning and conservation priorities.
Cross-feeding modulates the rate and mechanism of antibiotic resistance evolution in a model microbial community of Escherichia coli and Salmonella enterica
Authors: Adamowicz Elizabeth M. , Muza Michaela A. , Chacón Jeremey M. , Harcombe William R. 
Published: August 2019

AbstractWith antibiotic resistance rates on the rise, it is critical to understand how microbial species interactions influence the evolution of resistance. We have previously shown that in obligate mutualisms the survival of any one species (regardless of its intrinsic resistance) is contingent on the resistance of its cross-feeding partners, setting the community antibiotic tolerance at that of the ‘weakest link’ species. In this study, we extended that hypothesis to test whether obligate cross-feeding would limit the extent and mechanisms of antibiotic resistance evolution. In both rifampicin and ampicillin treatments, we observed that resistance evolved more slowly in obligate co-cultures of E. coli and S. enterica than in monocultures. While we observed similar mechanisms of resistance arising under rifampicin selection, under ampicillin selection different resistance mechanisms arose in co-cultures and monocultures. In particular, mutations in an essential cell division protein, ftsI, arose in S. enterica only in co-culture. A simple mathematical model demonstrated that reliance on a partner is sufficient to slow the rate of adaptation, and can change the distribution of adaptive mutations that are acquired. Our results demonstrate that cooperative metabolic interactions can be an important modulator of resistance evolution in microbial communities.Significance statementLittle is known about how ecological interactions between bacteria influence the evolution of antibiotic resistance. We tested the impact of metabolic interactions on resistance evolution in an engineered two-species bacterial community. Through experimental and modeling work, we found that obligate metabolic interdependency slows the rate of resistance acquisition, and can change the type and magnitude of resistance mutations that evolve. This work suggests that resistance evolution may be slowed by targeting both a pathogen and its metabolic partners with antibiotics. Additionally, we showed that community context can generate novel trajectories through which antibiotic resistance evolves.
Combining case-control status and family history of disease increases association power
Authors: Hujoel Margaux L.A. , Gazal Steven , Loh Po-Ru , Patterson Nick , Price Alkes L. 
Published: August 2019

AbstractFamily history of disease can provide valuable information about an individual’s genetic liability for disease in case-control association studies, but it is currently unclear how to best combine case-control status and family history of disease. We developed a new association method based on posterior mean genetic liabilities under a liability threshold model, conditional on both case-control status and family history (LT-FH); association statistics are computed via linear regression of genotypes and posterior mean genetic liabilities, equivalent to a score test. We applied LT-FH to 12 diseases from the UK Biobank (average N=350K). We compared LT-FH to genome-wide association without using family history (GWAS) and a previous proxy-based method for incorporating family history (GWAX). LT-FH was +63% (s.e. 6%) more powerful than GWAS and +36% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX, based on the number of independent genome-wide significant loci detected across all diseases (e.g. 690 independent loci for LT-FH vs. 423 for GWAS); the second best method was GWAX for lower-prevalence diseases and GWAS for higher-prevalence diseases, consistent with simulations. We also confirmed that LT-FH was well-calibrated (assessed via stratified LD score regression attenuation ratio), consistent with simulations. When using BOLT-LMM (instead of linear regression) to compute association statistics for all three methods (increasing the power of each method), LT-FH was +67% (s.e. 6%) more powerful than GWAS and +39% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX. In summary, LT-FH greatly increases association power in case-control association studies when family history of disease is available.
Fission yeast Pak1 phosphorylates anillin-like Mid1 for spatial control of cytokinesis
Authors: Magliozzi Joseph O. , Sears Jack , Cressey Lauren , Brady Marielle , Opalko Hannah E. , Kettenbach Arminja N. , Moseley James B. 
Published: August 2019

AbstractProtein kinases direct polarized growth by regulating the cytoskeleton in time and space, and could play similar roles in cell division. We found that the Cdc42-activated polarity kinase Pak1 colocalizes with the assembling contractile actomyosin ring (CAR) and remains at the division site during septation. Mutations inpak1led to defects in CAR assembly and genetic interactions with cytokinesis mutants. Through a phosphoproteomic screen, we identified novel Pak1 substrates that function in polarized growth and cytokinesis. For cytokinesis, we found that Pak1 regulates the localization of its substrates Mid1 and Cdc15 to the CAR. Mechanistically, Pak1 phosphorylates the Mid1 N-terminus to promote its association with cortical nodes that act as CAR precursors. Defects in Pak1-Mid1 signaling lead to misplaced and defective division planes, but these phenotypes can be rescued by synthetic tethering of Mid1 to cortical nodes. Our work defines a new signaling mechanism driven by a cell polarity kinase that promotes CAR assembly in the correct time and place.SummaryMagliozzi et al. show that fission yeast cell polarity kinase Pak1 regulates cytokinesis. Through a phosphoproteomic screen and subsequent mutant analysis, their work uncovers direct targets and mechanisms for Pak1 activity during cell division.
Measurement of Atom Resolvability in CryoEM Maps with Q-scores
Authors: Pintilie Grigore , Zhang Kaiming , Su Zhaoming , Li Shanshan , Schmid Michael F. , Chiu Wah 
Published: August 2019

AbstractCryoEM density maps are now at the point where resolvability of individual atoms can be achieved. However, resolvability is not necessarily uniform throughout the map. We introduce a quantitative parameter to characterize the resolvability of individual atoms in cryoEM maps, the map Q-score. Q-scores can be calculated for atoms in proteins, nucleic acids, water, ligands, and other solvent atoms, using models fitted to or derived from cryoEM maps. Q-scores can also be averaged to represent larger features such as entire residues and nucleotides. Averaged over entire models, Q-scores correlate very well with the estimated resolution of cryoEM maps for both protein and RNA. Assuming the models they are calculated from are well-fitted to the map, Q-scores can thus be used as another measure to indicate resolvability of features in cryoEM maps at various scales, from entire complexes down to individual atoms. Q-score analysis of multiple cryoEM maps of the same proteins derived from different labs confirms reproducibility of structural features down to water and ion atoms.