bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of yeast RPL22B splicing depends on intact pre-mRNA context of the intron
Authors: Abrhámová Kateřina , Folk Petr 
Published: November 2019

AbstractYeast RPL22A and RPL22B genes form an intergenic regulatory loop modulating the ratio of paralogous transcripts in response to changing levels of proteins. Gabunilas and Chanfreau (Gabunilas and Chanfreau, PLoS Genet 12, e1005999, 2016) and our group (Abrhámová et al., PLoS ONE 13, e0190685, 2018) described that Rpl22 proteins bound to the divergent introns of RPL22 paralogs and inhibited splicing in dosage dependent manner. Here, we continued to study the splicing regulation in more detail and designed constructs for in vivo analyses of splicing efficiency. We also tested Rpl22 binding to RPL22B intron in three-hybrid system. We were able to confirm the findings reported originally by Gabunilas and Chanfreau on the importance of a stem loop structure within the RPL22B intron. Mutations which lowered the stability of the structure abolished Rpl22-mediated inhibition. In contrast, we were not able to confirm the sequence specificity with respect to either Rpl22 binding or splicing inhibition within this region, which they reported. We contradict their results that the ‘RNA internal loop’ of RPL22Bi (nt 178CCCU181 and 221UGAA224) is crucial for mediating the Rpl22 effects. We assume that this discrepancy reflects the difference in constructs, as the reporters used by Gabunilas and Chanfreau lacked the alternative 5’ splice site as well as surrounding exons. Our own comparison confirms that deleting the sequence spanning alternative 5’ splice site lowers splicing efficiency, hinting to possible disturbances of the regulatory mechanism. We argue that the structural context of the ‘regulatory element’ may reach across the intron or into the surrounding sequences, similarly to what was found previously for other genes, such as RPL30. Apparently, more detailed analyses are needed to discern this intriguing example of splicing regulation.
Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs
Authors: Do Catherine , Dumont Emmanuel LP , Salas Martha , Castano Angelica , Mujahed Huthayfa , Maldonado Leonel , Singh Arunjot , DaSilva-Arnold Sonia C. , Bhagat Govind , Lehman Soren , Christiano Angela M. , Madhavan Subha , Nagy Peter L. , Green Peter H.R. , Feinman Rena , Trimble Cornelia , Illsley Nicholas P. , Marder Karen , Honig Lawrence , Monk Catherine , Goy Andre , Chow Kar , Goldlust Samuel , Kaptain George , Siegel David , Tycko Benjamin 
Published: November 2019

AbstractBackgroundMapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). However, the advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.ResultsWe performed whole genome methyl-seq on diverse normal cells and tissues and three types of cancers (multiple myeloma, lymphoma, glioblastoma multiforme). After excluding imprinting, the data pinpointed 15,114 high-confidence ASM differentially methylated regions (DMRs), of which 1,842 contained SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies were increased 5 to 9-fold in cancers vs. matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancers showed increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor (TF) binding motifs were similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes tracked with de novo ASM in the cancers. Allele-specific TF binding from ChIP-seq was enriched among ASM loci, but most ASM DMRs lacked such annotations, and some were found in otherwise uninformative “chromatin deserts”.ConclusionsASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and TF binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, neuropsychiatric, and neoplastic diseases. Custom genome browser tracks with annotated ASM loci can be viewed at a UCSC browser session hosted by our laboratory (https://bit.ly/tycko-asm)
Simulating the human tumor microenvironment in colorectal cancer organoids in vitro and in vivo
Authors: Devarasetty Mahesh , Dominijanni Anthony , Herberg Samuel , Shelkey Ethan , Skardal Aleksander , Soker Shay 
Published: November 2019

AbstractThe tumor microenvironment (TME) plays a significant role in cancer growth and metastasis. Bioengineered models of the TME will advance our understanding of cancer progression and facilitate identification of novel anti-cancer therapeutics that target TME components such as extracellular matrix (ECM) and stromal cells. However, most current in vitro models fail to recapitulate the extensive features of the human tumor stroma, especially ECM architecture, and are not exposed to intact body physiology. On the other hand, in vivo animal models do not accurately capture human tumor architecture. Using the features of biopsied colorectal cancer (CRC) tissue as a guide, we address these deficiencies by creating human organoids containing a colonic stromal ECM layer and CRC spheroids. Organoids were studied in vitro and upon implantation in mice for 28 days. We show that the stromal ECM micro-architecture, generated in vitro, was maintained in vivo for at least 28 days. Furthermore, comparisons with biopsied CRC tumors revealed that organoids with orderly structured TMEs induce an epithelial phenotype in CRC cells, similar to low-grade tumors, compared to a mesenchymal phenotype observed in disordered TMEs, similar to high-grade tumors. Altogether, these results are the first demonstration of replicating the human tumor ECM architecture in biofabricated tumor organoids under ex vivo and in vivo conditions.
Photosynthesis and crop productivity is enhanced by glucose-functionalized fluorescent carbon dots
Authors: Swift Thomas A. , Fagan Daniel , Benito-Alifonso David , Hill Stephen A. , Yallop Marian L. , Oliver Thomas A. A. , Lawson Tracy , Galan M. Carmen , Whitney Heather M. 
Published: November 2019

ABSTRACTFrom global food security to textile production and biofuels, the demands currently made on plant photosynthetic productivity will continue to increase. Enhancing photosynthesis using designer, green and sustainable materials offers an attractive alternative to current genetic-based strategies and promising work with nanomaterials has recently started to emerge. Here we describe in planta use of carbon-based nanoparticles produced by low-cost renewable routes that are bioavailable to mature plants. Uptake of these functionalised nanoparticles from the soil improves photosynthesis and also increases crop production. We show for the first time that glucose-functionalization enhances nanoparticle uptake, photoprotection and pigment production, unlocking enhanced yields. This is demonstrated in Triticum aestivum ‘Apogee’ (dwarf bread wheat) and results in an 18% increase in grain yield. This establishes the viability of a functional nanomaterial to augment photosynthesis as a route to increased crop productivity.
Stochasticity in bacterial division control: Preliminary consequences for protein concentration
Authors: Nieto Acuna Cesar Augusto , Vargas Garcia Cesar Augusto , Pedraza Juan Manuel 
Published: November 2019

ABSTRACTThe stochastic nature of protein concentration inside cells can have important consequences in their physiology and population fitness. Classical models of gene expression consider these processes as first-order reactions with little dependence with the cell size. However, the concentrations of the relevant molecules depend directly on the cellular volume. Here we model the cell size dynamics as exponential growth followed by division with occurrence rate proportional to the size. This framework, together with known models of chromosome replication and both protein and mRNA synthesis, lets us predict relationships between cell size and both protein number and concentration. As a main result, we find that protein production strategies (constant rate or rate proportional to either chromosome number, cell size or chromosome number times cell size) can be experimentally distinguished from the correlation between protein concentration and cell size.
Climate change and deforestation boost post-fire grass invasion of Amazonian forests
Authors: De Faria Bruno L. , Staal Arie , Martin Philip A. , Panday Prajjwal K. , Castanho Andrea D. , Dantas Vinícius L. 
Published: November 2019

ABSTRACTInteractions among climate change, deforestation and fires are changing the stability of the Amazon forest, and may promote transitions to degraded grassy ecosystem states. However, our ability to predict the locations in the Amazon that are most vulnerable to these transitions is limited. In this study we used a dynamic carbon model to evaluate how drought, climate change and deforestation could affect the probability of post-fire grass invasion across the Amazon, and identify where grass-fire feedbacks may promote the persistence of species-poor degraded forests with savanna-like structure. Our results suggest that, under current climatic conditions, post-fire grass invasion could affect 11% of the Amazon, with the south-eastern Amazon at highest risk of invasion. We forecast that under business as usual climate change, by the end of the century areas with a high probability of post-fire grass invasion will increase to 20% of the Amazon. In 10% of the Amazon fire return interval will be shorter than the time required for canopy recovery, implying high risk of irreversible shifts to a fire-maintained degraded ecosystem state. Although resilience in canopy regeneration is evident in areas with low fire frequency, increased fire frequency could inhibit regeneration even in forests where grass is currently excluded, and push the Amazon forests towards a tipping point causing large areas of forest to transition to low tree cover state.
The clinical drug candidate ebselen attenuates inflammation and promotes microbiome recovery after antibiotic treatment for Clostridium difficile infection
Authors: Garland Megan , Hryckowian Andrew J , Tholen Martina , Loscher Sebastian , Van Treuren William W. , Bender Kristina Oresic , Sonnenburg Justin L , Bogyo Matthew 
Published: November 2019

SummaryClostridium difficile infection (CDI) is an enteric bacterial disease that is increasing in prevalence worldwide. C. difficile capitalizes on gut inflammation and microbiome dysbiosis to establish infection, with symptoms ranging from watery diarrhea to toxic megacolon. We recently reported that the safe in human clinical drug candidate ebselen (NCT03013400, NCT01452607, NCT00762671, NCT02603081) has biochemical, cell-based and in vivo efficacy against the bacterial toxins of C. difficile. Here, we show that ebselen treatment reduces recurrence rates and decreases colitis in a hamster relapse model of CDI. Furthermore, ebselen treatment does not alter microbiome diversity but promotes its recovery back to that of healthy controls after antibiotic-induced dysbiosis in both healthy and C. difficile-infected mice. This increased microbiome recovery upon ebselen treatment correlates with a decrease in host-derived inflammatory markers suggesting that the anti-inflammatory properties of ebselen, combined with its anti-toxin function, help to mitigate the major clinical challenges of CDI, including recurrence, microbial dysbiosis, and colitis.
One-step Generation of Zebrafish Carrying a Conditional Knockout-Knockin Visible Switch via CRISPR/Cas9-Mediated Intron Targeting
Authors: Li Jia , Li Hong-yu , Gu Shan-ye , Zi Hua-Xing , Jiang Lai , Du Jiu-lin 
Published: November 2019

SUMMARYThe zebrafish has been becoming a popular vertebrate animal model in biomedical research. However, it is still challenging for making conditional gene knockout (CKO) zebrafish due to the low efficiency of homologous recombination (HR). Here we report an efficient non-HR-based method for generating zebrafish carrying a CKO and knockin (KI) switch (zCKOIS) coupled with dual-color fluorescent reporters. Using this strategy, we generated hey2zCKOIS which served as a hey2 KI reporter with EGFP expression. Upon Cre induction in targeted cells, the hey2zCKOIS was switched to a non-functional CKO allele hey2zCKOIS-inv associated with TagRFP expression, enabling to visualize CKO alleles. Thus, the simplification of the design, and the visibility and combination of both CKO and KI alleles’ engineering make our zCKOIS strategy an applicable CKO approach for zebrafish.
Preparatory delta phase response is correlated with naturalistic speech comprehension performance
Authors: Li Jiawei , Hong Bo , Nolte Guido , Engel Andreas K. , Zhang Dan 
Published: November 2019

AbstractWhile human speech comprehension is thought to be an active process that involves top-down predictions, it remains unclear how predictive information is used to prepare for the processing of upcoming speech information. We aimed to identify the neural signatures of the preparatory processing of upcoming speech. Participants selectively attended to one of two competing naturalistic, narrative speech streams, and a temporal response function (TRF) method was applied to derive event-related-like neural responses from electroencephalographic data. The phase responses to the attended speech at the delta band (1–4 Hz) were correlated with the comprehension performance of individual participants, with a latency of -200–0 ms before onset over the fronto-central and left-lateralized parietal regions. The phase responses to the attended speech at the alpha band also correlated with comprehension performance, but with a latency of 650–980 ms post-onset over fronto-central regions. Distinct neural signatures were found for the attentional modulation, taking the form of TRF-based amplitude responses at a latency of 240–320 ms post-onset over the left-lateralized fronto-central and occipital regions. Our findings reveal how the brain gets prepared to process an upcoming speech in a continuous, naturalistic speech context.
A Small-Molecule Activity-Based Probe for Monitoring Ubiquitin C-terminal Hydrolase L1 (UCHL1) Activity in Live Cells and Zebrafish Embryos
Authors: Geurink Paul P. , Kooij Raymond , Sapmaz Aysegul , Liu Sijia , Xin Bo-Tao , Janssen George M. C. , van Veelen Peter A. , Dijke Peter ten , Ovaa Huib 
Published: November 2019

ABSTRACTMany reagents have been emerged to study the function of specific enzymesin vitro. On the other hand, target specific reagents are scarce or need improvement allowing investigations of the function of individual enzymes in a cellular context. We here report the development of a target-selective fluorescent small-molecule activity-based DUB probe that is active in live cells and whole animals. The probe labels active Ubiquitin Carboxy-terminal Hydrolase L1 (UCHL1), also known as neuron-specific protein PGP9.5 (PGP9.5) and parkinson disease 5 (PARK5), a DUB active in neurons that constitutes 1-2% of total brain protein. UCHL1 variants have been linked with the neurodegenerative disorders Parkinson’s and Alzheimer’s disease. In addition, high levels of UCHL1 also correlate often with cancer and especially metastasis. The function of UCHL1 or its role in cancer and neurodegenerative disease is poorly understood and few UCHL1 specific research tools exist. We show that the reagents reported here are specific for UCHL1 over all other DUBs detectable by competitive activity-based protein profiling and by mass spectrometry. Our probe, which contains a cyanimide reactive moiety, binds to the active-site cysteine residue of UCHL1 irreversibly in an activity-dependent manner. Its use is demonstrated by labelling of UCHL1 bothin vitroand in cells. We furthermore show that this probe can report UCHL1 activity during the development of zebrafish embryos.
Panoramic visual representation in the dorsal visual pathway and its role in reorientation
Authors: Li Tianyi , Arleo Angelo , Sheynikhovich Denis 
Published: November 2019

AbstractWhile primates are primarily visual animals, how visual information is processed on its way to memory structures and contributes to the generation of visuospatial behaviors is poorly understood. Recent imaging data demonstrate the existence of scene-sensitive areas in the dorsal visual path that are likely to combine visual information from successive egocentric views, while behavioral evidence indicates the memory of surrounding visual space in extraretinal coordinates. The present work focuses on the computational nature of a panoramic representation that is proposed to link visual and mnemonic functions during natural behavior. In a spiking neural network model of the dorsal visual path it is shown how time-integration of spatial views can give rise to such a representation and how it can subsequently be used to perform memory-based spatial reorientation and visual search. More generally, the model predicts a common role of view-based allocentric memory storage in spatial and non-spatial mnemonic behaviors.
Geographic assessment of cancer genome profiling studies
Authors: Cordo Paula Carrio , Acheson Elise , Huang Qingyao , Baudis Michael 
Published: November 2019

Cancers arise from the accumulation of somatic genome mutations, which can be influenced by inherited genomic variants and external factors such as environmental or lifestyle-related exposure. Due to the heterogeneity of cancers, precise information about the genomic composition of germline and malignant tissues has to be correlated with morphological, clinical and extrinsic features to advance medical knowledge and treatment options. With global differences in cancer frequencies and disease types, geographic data is of importance to understand the interplay between genetic ancestry and environmental influence in cancer incidence, progression and treatment outcome.In this study, we analysed the current landscape of oncogenomic screening publications for geographic information content and quality, to address underrepresented study populations and thereby to fill prominent gaps in our understanding of interactions between somatic variations, population genetics and environmental factors in oncogenesis. We conclude that while the use of proxy derived geographic annotations can be useful for coarse-grained associations, the study of geo-correlated factors in cancer causation and progression will benefit from standardized geographic provenance annotations. Additionally, publication derived geographic provenance data allowed us to highlight stark inequality in the geographies of cancer genome profiling, with a near lack of sizeable studies from Africa and other large regions.
Diet induces parallel changes to the gut microbiota and problem solving performance in a wild bird
Authors: Davidson Gabrielle L. , Wiley Niamh , Cooke Amy C. , Johnson Crystal N. , Fouhy Fiona , Reichert Michael S. , de la Hera Iván , Crane Jodie M.S. , Kulahci Ipek G. , Ross R. Paul , Stanton Catherine , Quinn John L. 
Published: November 2019

ABSTRACTThe microbial community in the gut is influenced by environmental factors, especially diet, which can moderate host behaviour through the microbiome-gut-brain axis. However, the ecological relevance of microbiome-mediated behavioural plasticity in wild animals is unknown. We presented wild-caught great tits (Parus major) with a problem-solving task and showed that performance was weakly associated with variation in the gut microbiome. We then manipulated the gut microbiome by feeding birds one of two diets that differed in their relative levels of fat, protein and fibre content: an insect diet (low content), or a seed diet (high content). Microbial communities were less diverse among individuals given the insect compared to those on the seed diet. Individuals were less likely to problem-solve after being given the insect diet, and the same microbiota metrics that were altered as a consequence of diet were also those that correlated with variation in problem solving performance. Although the effect on problem-solving behaviour could have been caused by motivational or nutritional differences between our treatments, our results nevertheless raise the possibility that dietary induced changes in the gut microbiota could be an important mechanism underlying individual behavioural plasticity in wild populations.
A MAP of tumor-host interactions in glioma at single cell resolution
Authors: Caruso Francesca Pia , Garofano Luciano , D’Angelo Fulvio , Yu Kai , Tang Fuchou , Yuan Jinzhou , Zhang Jing , Cerulo Luigi , Bedognetti Davide , Sims Peter A. , Suvà Mario , Su Xiao-Dong , Lasorella Anna , Iavarone Antonio , Ceccarelli Michele 
Published: November 2019

ABSTRACTSingle-cell RNA sequencing is the reference technique to characterize the heterogeneity of tumor microenvironment and can be efficiently used to discover cross-talk mechanisms between immune cells and cancer cells. We present a novel method, single cell Tumor-Host Interaction tool (scTHI), to identify significantly activated ligand-receptor interactions across clusters of cells from single-cell RNA sequencing data. We apply our approach to uncover the ligand-receptor interactions in glioma using six publicly available human glioma datasets encompassing 71 patients. We provide a comprehensive map of the signalling mechanisms between malignant cells and non-malignant cells in glioma uncovering potential novel therapeutic targets.