bluuebunny/crossref_metadata_2025_split huggingface dataset:
FFPE DNA shows two major error profiles derived from deamination of cytosine and methylcytosine that can be mitigated using distinct repair strategies
Authors: Chen Lixin , Chen Minyong , Heiter Dan , Samuelson Jim , Evans Tom , Ettwiller Laurence 
Published: March 2023

AbstractAvoiding damage-induced sequencing errors is a critical step for the accurate identification of medium to rare frequency mutations in DNA samples. In the case of FFPE samples, deamination of cytosine moieties represents a major damage resulting in the loss of DNA material and sequencing errors. In this study, we demonstrated that, while damage from deamination of both cytosine and methylated cytosine moieties results in elevated C to T transition, the error profiles and mediation strategies are different and easily distinguishable. While damage-induced sequencing errors from cytosine deamination is driven by the end-repair step commonly used in NGS workflow, DNA damage resulting from deamination of methylated cytosine is another major contributor to sequencing errors at CpG sites. Uracil DNA glycosylase and human thymine DNA glycosylase can respectively eliminate and mitigate both damages in FFPE DNA samples, therefore increasing sequencing accuracy notably for the identification of moderate allelic frequency variants.
LINC00261expression reduces mutation accumulation while conferring resistance to cisplatin and altering the tumor-immune microenvironment in lung adenocarcinoma
Authors: Castillo Jonathan , Xue Tianchun , Joseph Samantha , Norwood Mayela , Mullen Daniel J. , Berrellez Stephanie , James Sophia , Epstein Alan L. , McEachron Troy , Marconett Crystal N. 
Published: March 2023

AbstractImmunotherapy has emerged as a major breakthrough that has the ability to improve survival outcomes for multiple solid tumor types, however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, including PD-L1 and CTLA-4, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data generated by The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identifiedLINC00261as a top gene correlated to mutational burden (TMB), whose expression activates DNA damage response pathwaysin vitroalong with resistance to cisplatin.LINC00261expression was also significantly correlated to MHC Class II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmedin vitrothrough ectopic reintroduction ofLINC00261for key MHC Class II presentation genes. Interferon gamma-induced MHC gene activationin vitrowas also able to induce endogenous expression ofLINC00261. Our results suggest there is a mechanistic relationship betweenLINC00261expression and functional MHC Class II neoantigen presentation in LUAD. The silencing ofLINC00261in LUAD results in compromised DNA repair, accumulation of mutations, and reduced antitumor immune response.
Genetic regulation of cell-type specific chromatin accessibility shapes the etiology of brain diseases
Authors: Zeng Biao , Bendl Jaroslav , Deng Chengyu , Lee Donghoon , Misir Ruth , Reach Sarah M. , Kleopoulos Steven P. , Auluck Pavan , Marenco Stefano , Lewis David A. , Haroutunian Vahram , Ahituv Nadav , Fullard John F. , Hoffman Gabriel E. , Roussos Panos 
Published: March 2023

AbstractNucleotide variants in cell type-specific gene regulatory elements in the human brain are major risk factors of human disease. We measured chromatin accessibility in sorted neurons and glia from 1,932 samples of human postmortem brain and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTL). Only 10.4% of caQTL are shared between neurons and glia, supporting the cell type specificity of genetic regulation of the brain regulome. Incorporating allele specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms underlying disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs, identifying the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides novel insights into brain disease etiology.One sentence summaryCell-type specific chromatin accessibility QTL reveals regulatory mechanisms underlying brain diseases.
Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice
Authors: Gianessi C.A. , Gereau G.B. , Haun H.L. , Pati D. , Sides T. , D’Ambrosio S.L. , Boyt K. , Kelson W.P. , Hodge C.W. , Kash T.L. 
Published: March 2023

AbstractExcessive alcohol use causes a great deal of harm and negative health outcomes. Corticotrophin releasing factor (CRF), a stress-related neuropeptide, has been implicated in binge ethanol intake and ethanol dependence. CRF containing neurons in the bed nucleus of the stria terminalis (BNSTCRF) can control ethanol consumption. These BNSTCRFneurons also release GABA, raising the question, is it CRF or GABA release or both that is controlling alcohol consumption. Here, we used viral vectors to separate the effects of CRF and GABA release from BNSTCRFneurons on the escalation of ethanol intake in an operant self-administration paradigm in male and female mice. We found that CRF deletion in BNST neurons reduces ethanol intake in both sexes, with a stronger effect in males. For sucrose self-administration there was no effect of CRF deletion. Suppression of GABA release, via knockdown of vGAT, from BNSTCRFproduced a transient increase in ethanol operant self-administration following in male mice, and reduced in motivation to work for sucrose on a progressive ratio schedule of reinforcement in a sex-dependent manner. Together, these results highlight how different signaling molecules from the same populations of neurons can bidirectionally control behavior. Moreover, they suggest that BNST CRF release is important for high intensity ethanol drinking that precedes dependence, whereas GABA release from these neurons may play a role in regulating motivation.
Iodidimonas, a bacterium unable to degrade hydrocarbons, thrives in a bioreactor treating oil and gas produced water
Authors: Acharya Shwetha M. , Enalls Brandon C. , Walian Peter J , Van Houghton Brett D. , Rosenblum James S. , Cath Tzahi Y. , Tringe Susannah G. , Chakraborty Romy 
Published: March 2023

AbstractIodidimonasis a genus recently described in bioreactors treating oil and gas produced water and in iodide rich brines. Besides the ability to oxidize iodine, little is known about the metabolic capabilities that enableIodidimonassp. to occupy this unique ecological niche. We isolated, characterized, and sequenced three strains belonging to theIodidimonasgenus from the sludge of a membrane bioreactor treating produced water. We describe the genomic features of these isolates and compare them with the only other four isolate genomes reported from this genus, as well as a metagenome-assembled genome from the source bioreactor. To survive in the produced water,Iodidimonasisolates had several genes associated with mitigating salinity, heavy metal and organic compound stress. While the isolates could utilize a wide variety of carbon substrates, they failed to degrade aliphatic or aromatic hydrocarbons, consistent with the lack of genes associated with common hydrocarbon degradation pathways in their genomes. We hypothesize these microbes may lead a scavenging lifestyle in the bioreactor and similar iodide-rich brines.ImportanceOccupying a niche habitat and having few representative isolates, genusIodidimonasis a relatively understudied Alphaproteobacterial group. This genus has garnered attention due to its ability to corrode pipes in iodine production facilities and generate iodinated organic compounds during treatment of oil and gas produced water. The iodinated organic compounds are likely to be carcinogenic and may pose issues with recycling the treated water. Hence, detailed characterization of the metabolic potential of these isolates is not only of economic importance, but also sheds light on adaptation of this microbe to its environmental niche.
Mutational signatures in wild typeEscherichia colistrains reveal dominance of DNA polymerase errors
Authors: Garushyants Sofya K. , Sane Mrudula , Selifanova Maria V. , Agashe Deepa , Bazykin Georgii A. , Gelfand Mikhail S. 
Published: March 2023

AbstractWhile mutational processes operating in theEscherichia coligenome have been revealed by multiple laboratory experiments, the contribution of these processes to accumulation of bacterial polymorphism and evolution in natural environments is unknown. To address this question, we reconstruct signatures of distinct mutational processes from experimental data onE. colihypermutators, and ask how these processes contribute to differences between naturally occurringE. colistrains. We show that both mutations accumulated in the course of evolution of wild type strains in nature and in the lab-grown non-mutator laboratory strains are explained predominantly by the low fidelity of DNA polymerases II and III. By contrast, contributions specific to disruption of DNA repair systems cannot be detected, suggesting that temporary accelerations of mutagenesis associated with such disruptions are unimportant for within-species evolution. These observations demonstrate that accumulation of diversity in bacterial strains in nature is predominantly associated with errors of DNA polymerases.
Live-cell imaging uncovers the relationship between histone acetylation, transcription initiation, and nucleosome mobility
Authors: Saxton Matthew N. , Morisaki Tatsuya , Krapf Diego , Kimura Hiroshi , Stasevich Timothy J. 
Published: March 2023

AbstractPost-translational protein modifications play an important role in the regulation of gene dynamics. Certain modifications, such as histone acetylation and RNA polymerase II phosphorylation, are associated with transcriptionally active chromatin. However, the spatial and temporal relationship between chromatin and post-translational protein modifications, and how these dynamics facilitate selective gene expression, remain poorly understood. In this study, we address this problem by developing a general methodology for quantifying in live cells the dynamics of chromatin across multiple time and length scales in the context of residue-specific protein modifications. By combining Fab-based labeling of endogenous protein modifications with single-molecule imaging, we track the dynamics of chromatin enriched with histone H3 Lysine-27 acetylation (H3K27ac) and RNA polymerase II Serine-5 phosphorylation (RNAP2-Ser5ph). Our analysis reveals chromatin enriched with H3K27ac is separated from chromatin enriched with RNAP2-Ser5ph. Furthermore, in these separated sites, we show the presence of the two modifications are inversely correlated with one another on the minutes timescale. We then track single nucleosomes in both types of sites on the sub-second timescale and again find evidence for distinct and opposing changes in their diffusive behavior. While nucleosomes diffuse ∼15% faster in chromatin enriched with H3K27ac, they diffuse ∼15% slower in chromatin enriched with RNAP2-Ser5ph. Taken together, these results argue that high levels of H3K27ac and RNAP2-Ser5ph are not often present together at the same place and time, but rather each modification marks distinct sites that are transcriptionally poised or active, respectively.
Identifying promoter sequence architectures via a chunking-based algorithm using non-negative matrix factorisation
Authors: Nikumbh Sarvesh , Lenhard Boris 
Published: March 2023

AbstractCore promoters are stretches of DNA at the beginning of genes that contain information that facilitates the binding of transcription initiation complex. Different functional subsets of genes have core promoters with distinct architectures and characteristic motifs. Some of these motifs inform the selection of transcription start sites (TSS). By discovering motifs with fixed distances from known TSS positions, we could in principle classify promoters into different functional groups.Due to the variability and overlap of architectures, promoter classification is a difficult task that requires new approaches. In this study, we present a new method based on non-negative matrix factorisation (NMF) and the associated software called seqArchR that clusters promoter sequences based on their motifs at near-fixed distances from a reference point, such as TSS. When combined with experimental data from CAGE, seqArchR can efficiently identify TSS-directing motifs, including known ones like TATA, DPE, and nucleosome positioning signal, as well as novel lineage-specific motifs and the function of genes associated with them. By using seqArchR on developmental time courses, we reveal how relative use of promoter architectures changes over time with stage-specific expression.seqArchR is a powerful tool for initial genome-wide classification and functional characterization of promoters. Its use cases are more general: it can also be used to discover any motifs at near-fixed distances from a reference point, even if they are present in only a small subset of sequences. seqArchR is available athttp://www.bioconductor.org/packages/seqArchR.
Probing inter-areal computations with a cellular resolution two-photon holographic mesoscope
Authors: Abdeladim Lamiae , Shin Hyeyoung , Jagadisan Uday K. , Ogando Mora B. , Adesnik Hillel 
Published: March 2023

SummaryBrain computation depends on intricately connected yet highly distributed neural networks. Due to the absence of the requisite technologies, causally testing fundamental hypotheses on the nature of inter-areal processing have remained largely out-of-each. Here we developed the first two photon holographic mesoscope, a system capable of simultaneously reading and writing neural activity patterns with single cell resolution across large regions of the brain. We demonstrate the precise photo-activation of spatial and temporal sequences of neurons in one brain area while reading out the downstream effect in several other regions. Investigators can use this new platform to understand feed-forward and feed-back processing in distributed neural circuits with single cell precision for the first time.
Quantitative Nanohistology of aging dermal collagen
Authors: Huang Sophia , Strange Adam , Maeva Anna , Siddiqui Samera , Bastien Phillipe , Aguayo Sebastian , Vaez Mina , Montagu-Pollock Hubert , Ghibaudo Marion , Potter Anne , Pageon Herve , Bozec Laurent 
Published: March 2023

ABSTRACTWhile the external signs of skin aging have been well-defined throughout history, much less is known about aging within the ultrastructure of our skin. Our skin, the largest organ in our body, is structured by collagen through fibrils or large sheets. With the increased use of nanometrology tools in histology, it is now possible to explore how the aging process affects collagen at its most fundamental level, the collagen fibril. Here, we show how atomic force microscopy-based quantitative nanohistology can differentiate skin from different age groups and anatomical sites. Following the definition of specific collagen biomarkers at the nanoscale, we used a segmentation approach to quantify the prevalence of 4 structural biomarkers over a dataset of 42,000 images (30 donors) complemented by extensive nanomechanical analyses (30,000 indentation curves) on histological sections. Our results demonstrate that specific age-related collagen fingerprints could be found when comparing the % prevalence of each marker between the papillary and reticular dermis. A case of abnormal biological aging validated our markers and nanohistology approach. This first extensive study focusing on defining signs of dermal aging at the nanoscale proves we are all unique to our dermal collagen ultrastructure.
Capacitance measurements for assessing DNA origami nanostructures
Authors: Walawalkar Vismaya , Sajal Md. Sakibur , Gilpin Yann , Dandin Marc , Taylor Rebecca E. 
Published: March 2023

AbstractNanostructures fabricated with DNA are emerging as a practical approach for applications ranging from advanced manufacturing to therapeutics. To support the strides made in improving accessibility and facilitating commercialization of DNA nanostructure applications, we identify the need for a rapid characterization approach that aids nanostructure production. In our work, we introduce a low-fidelity characterization approach that provides an interdependent assessment of DNA origami formation, concentration and morphology using capacitance sensing. Change in charge is one of the transduction methods to determine capacitive loading on a substrate. It is known that cations in the solution stabilize DNA origami nanostructures. So, we hypothesized that the presence of cations and nanostructures in a buffer solution can induce capacitance change that is distinctive of the nanostructure present. In this study we were able to detect a change in the capacitance when the nanostructure solution was deposited on our capacitance sensor, and we could distinguish between pre-annealed and annealed structures at concentrations less than 15 nM. The capacitance measurements were affected by the concentration of Mg2+ions in the solution, the staple-to-scaffold stoichiometric ratio of the nanostructure and the nanostructure morphology. Maintaining a 12.5 mM Mg2+concentration in the nanostructure buffer, we discover a linear relationship between the relative capacitance change and the nanostructure concentration from 5 nM to 20 nM, which we call the characteristic curve. We find distinct characteristic curves for our three nanostructures with distinct morphologies but similar molecular weight - a rectangular plate, a sphere and a rod. Given that we can distinguish nanostructure formation, concentration and morphology, we expect that capacitance measurement will emerge as an affordable and rapid approach for quality control for nanostructure production.
Incremental improvements in tractometry-based brain-age modeling with deep learning
Authors: Rokem Ariel , Qiao Joanna , Yeatman Jason D. , Richie-Halford Adam 
Published: March 2023

AbstractMultivariate measurements of human brain white matter (WM) with diffusion MRI (dMRI) provide information about the role of WM in a variety of cognitive functions and in brain health. Statistical models take advantage of the regularities in these data to make inferences about individual differences. For example, dMRI data provide the basis for accurate brain-age models – models that predict the chronological age of participants from WM tissue properties. Deep learning (DL) models are powerful machine learning models, which have been shown to provide benefits in many multivariate analysis settings. We investigated whether DL would provide substantial improvements for brain-age models based on dMRI measurements of WM in a large sample of children and adolescents. We found that some DL models fit the data better than a linear baseline, but the differences are small. In particular, recurrent neural network architectures provide up to ∼6% improvement in accuracy. This suggests that information about WM development is mostly accessible with linear models, and does not require the additional invariance and non-linearity offered by DL models. However, in some applications this incremental improvement may prove critical. We provide open-source software that fits DL models to dMRI data (https://yeatmanlab.github.io/AFQ-Insight).
Mosquito thermal tolerance is remarkably constrained across a large climatic range
Authors: Couper Lisa I. , Farner Johannah E. , Lyberger Kelsey P. , Lee Alexandra S. , Mordecai Erin A. 
Published: March 2023

AbstractHow mosquitoes may respond to rapid climate warming remains unknown for most species, but will have major consequences for their future distributions, with cascading impacts on human well-being, biodiversity, and ecosystem function. We investigated the adaptive potential of a wide-ranging mosquito species,Aedes sierrensis, across a large climatic gradient by conducting a common garden experiment measuring the thermal limits of mosquito life history traits. Although field-collected populations originated from vastly different thermal environments that spanned over 1,200 km, we found remarkably limited variation in upper thermal tolerance between populations, with the upper thermal limits of fitness varying by <1°C across the species range. For one life history trait—pupal development rate—we did detect significant variation in upper thermal limits between populations, and this variation was strongly correlated with source temperatures, providing evidence of local thermal adaptation for pupal development. However, we found environmental temperatures already regularly exceed our highest estimated upper thermal limits throughout most of the species range, suggesting limited potential for mosquito thermal tolerance to evolve on pace with warming. Strategies for avoiding high temperatures such as diapause, phenological shifts, and behavioral thermoregulation are likely important for mosquito persistence.
Feature selection followed by a novel residuals-based normalization simplifies and improves single-cell gene expression analysis
Authors: Singh Amartya , Khiabanian Hossein 
Published: March 2023

AbstractNormalization is a crucial step in the analysis of single-cell RNA-sequencing (scRNA-seq) counts data. Its principal objectives are to reduce the systematic biases primarily introduced through technical sources and to transform the data to make it more amenable for application of established statistical frameworks. In the standard workflows, normalization is followed by feature selection to identify highly variable genes (HVGs) that capture most of the biologically meaningful variation across the cells. Here, we make the case for a revised workflow by proposing a simple feature selection method and showing that we can perform feature selection before normalization by relying on observed counts. We highlight that the feature selection step can be used to not only select HVGs but to also identify stable genes. We further propose a novel variance stabilization transformation inclusive residuals-based normalization method that in fact relies on the stable genes to inform the reduction of systematic biases. We demonstrate significant improvements in downstream clustering analyses through the application of our proposed methods on biological truth-known as well as simulated counts datasets. We have implemented this novel workflow for analyzing high-throughput scRNA-seq data in an R package called Piccolo.