bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancerviareadthrough transcription
Authors: Cameron Donald P. , Grosser Jan , Ladigan Swetlana , Kuzin Vladislav , Iliopoulou Evanthia , Wiegard Anika , Benredjem Hajar , Liffers Sven T. , Lueong Smiths , Cheung Phyllis F. , Vangala Deepak , Pohl Michael , Viebahn Richard , Teschendorf Christian , Wolters Heiner , Usta Selami , Geng Keyi , Kutter Claudia , Arsenian-Henriksson Marie , Siveke Jens T. , Tannapfel Andrea , Schmiegel Wolff , Hahn Stephan A. , Baranello Laura 
Published: February 2023

AbstractPancreatic carcinoma is one of the most lethal cancers and the absence of efficient therapeutic strategies results in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC impacts initiation, development, and survival of this tumor type. Using patient-derived xenografts of pancreatic carcinoma driven by KRAS and MYC oncogenic transcription, we show that co-inhibition of Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) synergistically induce tumor regression through targeting promoter pause-release, a rate-limiting step in transcription elongation. By comparing the nascent transcriptome with the recruitment of elongation and termination factors along genes, we found that co-inhibition of TOP1 and BRD4, while globally impairing RNA production, disturbs recruitment of proteins involved in termination. Thus, RNA polymerases continue transcribing downstream of genes for hundreds of kilobases leading to readthrough transcription. This pervasive transcription also occurs during replication, perturbing replisome progression and leading to DNA damage. The synergistic effect of TOP1 and BRD4 inhibition is specific for cancer cells leaving normal cells unharmed, highlighting the sensitivity of the tumor to these transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of high transcription and replication.One Sentence SummaryTOP1 and BRD4 inhibitors synergize to selectively kill pancreatic cancerin vivo viareadthrough transcription without emergence of drug resistance
Breast Density Analysis Using Digital Breast Tomosynthesis
Authors: Heine John , Fowler Erin E.E. , Weinfurtner R. Jared , Hume Emma , Tworoger Shelley S. 
Published: February 2023

AbstractWe evaluated an automated percentage of breast density (BD) technique (PDa) with digital breast tomosynthesis (DBT) data. The approach is based on the wavelet expansion followed by analyzing signal dependent noise. Several measures were investigated as risk factors: normalized volumetric; total dense volume; average of the DBT slices (slice-mean); a two-dimensional (2D) metric applied to the synthetic images; and the mean and standard deviations of the pixel values. Volumetric measures were derived theoretically, and PDawas modeled as a function of compressed breast thickness. An alternative method for constructing synthetic 2D mammograms was investigated using the volume results. A matched case-control study (n = 426 pairs) was analyzed. Conditional logistic regression modeling, controlling body mass index and ethnicity, was used to estimate odds ratios (ORs) for each measure with 95% confidence intervals provided parenthetically.There were several significant findings: volumetric measure [OR = 1.43 (1.18, 1.72)], which produced an identical OR as the slice-mean measure as predicted; [OR =1.44 (1.18, 1.75)] when applied to the synthetic images; and mean of the pixel values (volume or 2D synthetic) [ORs ∼ 1.31 (1.09, 1.57)]. PDawas modeled as 2nddegree polynomial (concave-down): its maximum value occurred at 0.41×(compressed breast thickness), which was similar across case-control groups, and was significant from this position [OR = 1.47 (1.21, 1.78)]. A standardized 2D synthetic image was produced, where each pixel value represents the percentage of BD above its location.The significant findings indicate the validity of the technique. Derivations supported by empirical analyses produced a new synthetic 2D standardized image technique. Ancillary to the objectives, the results provide evidence for understanding the percentage of BD measure applied to 2D mammograms. Notwithstanding the findings, the study design provides a template for investigating other measures such as texture.
Postnatal maturation ofin vivomembrane potential dynamics during hippocampal ripples
Authors: Noguchi Asako , Ikegaya Yuji 
Published: February 2023

AbstractSharp-wave ripples (SWRs) are transient high-frequency oscillations of local field potentials (LFPs) in the hippocampus and play a critical role in memory consolidation. During SWRs, CA1 pyramidal cells exhibit rapid spike sequences that often replay the sequential activity that occurred during behavior. This temporally organized firing activity gradually emerges during two weeks after the eye opening; however, it remains unclear how the organized spikes during SWRs mature at the intracellular membrane potential (Vm) level. Here, we recorded theVm of CA1 pyramidal cells simultaneously with hippocampal LFPs from immature mice after the developmental emergence of SWRs. On postnatal days 16–17,Vm dynamics around SWRs were premature, characterized by prolonged depolarizations without either pre- or post-SWR hyperpolarization. The biphasic hyperpolarizations, which are a typical feature of adult SWR-relevantVm, formed by approximately postnatal day 30. ThisVm maturation was associated with an increase in SWR-associated inhibitory inputs to pyramidal cells. Thus, the development of SWR-relevant inhibition restricts the temporal windows for spikes of pyramidal cells and allows CA1 pyramidal cells to organize their spike sequences during SWRs.Significance statementSharp-wave ripples (SWRs) are prominent hippocampal oscillations and play a critical role in memory consolidation. During SWRs, hippocampal neurons synchronously emit spikes with organized temporal patterns. This temporal structure of spikes during SWRs develops during the third and fourth postnatal weeks, but the underlying mechanisms are not well-understood. Here, we recordedin vivomembrane potentials from hippocampal neurons in premature mice and suggest that the maturation of SWR-associated inhibition enables hippocampal neurons to produce precisely controlled spike times during SWRs.
Insight on physicochemical properties governing peptide MS1 response in HPLC-ESI-MS/MS proteomics: A deep learning approach
Authors: Abdul-Khalek Naim , Wimmer Reinhard , Overgaard Michael Toft , Gregersen Echers Simon 
Published: February 2023

AbstractAccurate and absolute quantification of individual peptides in complex mixtures is a challenge not easily overcome. A potential solution is the use of quantitative mass spectrometry (MS) based methods, however, current state of the art requires foreground knowledge and isotopically labeled standards for each peptide to be accurately quantified. This increases analytical expenses, time consumption, and labor, limiting the number of peptides that can be quantified. A key step in developing less restrictive label-free quantitative peptidomics methods is understanding of the physicochemical properties of peptides that influence the MS response. In this work, a deep learning model was developed to identify the most relevant physicochemical properties based on repository MS data from equimolar peptide pools. Using an autoencoder with attention mechanism and correlating attention weights with corresponding physicochemical property indices from AAindex1, we were able to obtain insight on the properties governing the peptide-level MS1 response. These properties can be grouped in three main categories related to peptide hydrophobicity, charge, and structural propensities. Moreover, we present a model for predicting the MS1 intensity output based solely on peptide sequence input. Using a refined training dataset, the model predicted log-transformed peptide MS1 intensities with an average error of 11%.
Multiple hosts, multiple impacts: the role of vertebrate host diversity in shaping mosquito life history and pathogen transmission
Authors: Vantaux Amélie , Moiroux Nicolas , Dabiré Kounbobr Roch , Cohuet Anna , Lefèvre Thierry 
Published: February 2023

ABSTRACTThe transmission of malaria parasites from mosquito to human is largely determined by the dietary specialization ofAnophelesmosquitoes to feed on humans. Few studies have explored the impact of blood meal sources on the fitness of both the parasite and the mosquito. Our study investigated the effects of 3-4 consecutive blood meals from one of four vertebrate species (human, cattle, sheep, or chicken) on several fitness traits, including mosquito feeding rate, blood meal size, susceptibility to wild isolates ofPlasmodium falciparum, survival, fecundity, F1 offspring development time, and size. Our findings revealed no significant effect on parasite development. Similarly, parasite exposure had no overall effects on mosquito fitness. However, blood meal type did have a strong impact on mosquito feeding rate, survival, lifetime fecundity, and offspring size. Specifically, mosquitoes that were fed successive chicken blood meals produced fewer eggs and fewer and smaller F1 adults compared to those fed human blood. Combining our results in a theoretical model, we show a decrease in the vectorial capacity of mosquitoes fed chicken or cow blood and an increase in the capacity of those fed sheep blood compared to those fed human blood. These findings emphasize the importance of considering the diversity of blood meal sources in understanding mosquito ecology and their role in the transmission intensity of malaria parasites.
Decoding the content of working memory in school-aged children
Authors: Turoman Nora , Fiave Prosper Agbesi , Zahnd Clélia , deBettencourt Megan T. , Vergauwe Evie 
Published: February 2023

AbstractDevelopmental improvements in working memory (WM) maintenance predict many real-world outcomes, including educational attainment. It is thus critical to understand which WM mechanisms support these behavioral improvements, and how WM maintenance strategies might change through development. One challenge is that specific WM neural mechanisms cannot easily be measured behaviorally, especially in a child population. However, new multivariate decoding techniques have been designed, primarily in adult populations, that can sensitively decode the contents of WM. The goal of this study was to deploy multivariate decoding techniques known to decode memory representations in adults to decode the contents of WM in children. We created a simple computerized WM game for children, in which children maintained different categories of information (visual, spatial or verbal). We collected electroencephalography (EEG) data from 20 children (7-12-year-olds) while they played the game. Using Multivariate Pattern Analysis (MVPA) on children’s EEG signals, we reliably decoded the category of the maintained information during the sensory and maintenance period. Across exploratory reliability and validity analyses, we examined the robustness of these results when trained on less data, and how these patterns generalized within individuals throughout the testing session. Furthermore, these results matched theory-based predictions of WM across individuals and across ages. Our proof-of-concept study proposes a direct and age-appropriate potential alternative to exclusively behavioral WM maintenance measures in children. Our study demonstrates the utility of MVPA to measure and track the uninstructed representational content of children’s WM. Future research could use our technique to investigate children’s WM maintenance and strategies.
Towards a robust comparison of diversity between sampled TCR repertoires
Authors: de Greef Peter C. , de Boer Rob J. 
Published: February 2023

AbstractT-cell receptor (TCR) repertoire sequencing data provides quantitative insight into the distribution of T-cell clones. The diversity of the TCR repertoire in humans tends do decrease with age, which may be a key determinant explaining immune senescence in older individuals. To address this, we first analyze how the diversity of a potential T-cell response against an unseen pathogen changes with age. Next, we discuss the complications with interpreting the outcomes of such an analysis. Specifically, the changes in T-cell subset sizes confound analyses of TCR diversity, and typical sample sizes do not easily allow for a robust quantification of this diversity. Thus, explaining immune senescence as a result of decreasing TCR diversity is far from straightforward and requires a detailed, robust, and quantitative analysis.
Housing conditions affect adult zebrafish (Danio rerio) behavior but not their physiological status
Authors: Jorge Sara , Félix Luís , Costas Benjamín , Valentim Ana M 
Published: February 2023

AbstractZebrafish is a valuable model for neuroscience research, but the housing conditions to which it is daily exposed may be impairing its welfare status. The use of environmental enrichment and the refinement of methodology for cortisol measurement could reduce stress, improving its welfare and its suitability as an animal model used in stress research. Thus, this study aimed to evaluate (I) the influence of different housing conditions on zebrafish physiology and behavior and (II) skin mucus potential for cortisol measurement in adult zebrafish. For this, AB zebrafish were raised under barren or enriched (PVC pipes and gravel image) environmental conditions. After 6 months, the behavior was assessed by different behavioral paradigms (shoaling, white-black box test, and novel tank). The physiological response was also evaluated through cortisol levels (whole-body homogenates and skin mucus) and brain oxidative stress markers. Results revealed that enriched-housed fish had an increased nearest neighbors’ distance and reduced activity. However, no effect on body length or stress biomarkers was observed; whole-body and skin mucus cortisol levels had the same profile between groups. In conclusion, this study highlights the skin mucus potential as a matrix for cortisol quantification and how environmental enrichment could influence the data in future studies.Simple SummaryThe delivery of proper housing conditions may translate into good fish welfare. As zebrafish housing is usually poorly enriched, the fish could be unable to express some natural behaviors, leading to distress and/ or stress mechanisms’ dysregulation. This work focused on the examination of zebrafish welfare raised under different housing conditions (barren or environmentally enriched) and the testing of a low-invasive technique (skin mucus collection) to measure the main stress hormone (cortisol). The data was processed to assess body length, behavior, and physiological status. Results revealed that enrichment induced minor alterations on zebrafish behavior. Thus, the influence of housing conditions should be considered in future research, depending on the purpose of the study. Also, skin mucus appears to be a promising matrix to replace whole-body to measure cortisol in zebrafish, since its collection is nonlethal and showed similar results to the traditional method.
Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants
Authors: Traa Annika , Shields Hazel , AlOkda Abdelrahman , Rudich Zenith D. , Ko Bokang , Van Raamsdonk Jeremy M. 
Published: February 2023

AbstractMutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disruptingtbc-2on lifespan and stress resistance in the long-lived mitochondrial mutantsnuo-6andisp-1inC. elegans. Loss oftbc-2markedly reduced the long lifespans of both mitochondrial mutants. Disruption oftbc-2also decreased resistance to specific exogenous stressors innuo-6andisp-1mutants. In contrast,tbc-2inhibition had no effect on oxidative stress resistance or lifespan inisp-1worms when DAF-16 is absent suggesting that the effect oftbc-2on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion ofdaf-16markedly decreases both phenotypes inisp-1worms. Surprisingly, disruption oftbc-2did not prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants, suggesting the possibility that the effect oftbc-2on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function.
Evolution of connectivity architecture in theDrosophilamushroom body
Authors: Ellis Kaitlyn Elizabeth , Bervoets Sven , Smihula Hayley , Ganguly Ishani , Vigato Eva , Auer Thomas O. , Benton Richard , Litwin-Kumar Ashok , Caron Sophie Jeanne Cécile 
Published: February 2023

ABSTRACTBrain evolution has primarily been studied at the macroscopic level by comparing the relative size of homologous brain centers between species. How neuronal circuits change at the cellular level over evolutionary time remains largely unanswered. Here, using a phylogenetically informed framework, we compare the olfactory circuits of three closely relatedDrosophilaspecies that differ radically in their chemical ecology: the generalistsDrosophila melanogasterandDrosophila simulansthat feed on fermenting fruit, andDrosophila sechelliathat specializes on ripe noni fruit. We examine a central part of the olfactory circuit that has not yet been investigated in these species — the connections between the projection neurons of the antennal lobe and the Kenyon cells of the mushroom body, an associative brain center — to identify species-specific connectivity patterns. We found that neurons encoding food odors — the DC3 neurons inD. melanogasterandD. simulansand the DL2d neurons inD. sechellia— connect more frequently with Kenyon cells, giving rise to species-specific biases in connectivity. These species-specific differences in connectivity reflect two distinct neuronal phenotypes: in the number of projection neurons or in the number of presynaptic boutons formed by individual projection neurons. Finally, behavioral analyses suggest that such increased connectivity enhances learning performance in an associative task. Our study shows how fine-grained aspects of connectivity architecture in an associative brain center can change during evolution to reflect the chemical ecology of a species.
PyBrOpS: a Python package for breeding program simulation and optimization for multi-objective breeding
Authors: Shrote Robert Z. , Thompson Addie M. 
Published: February 2023

AbstractPlant breeding is a complex endeavor that is almost always multi-objective in nature. In recent years, stochastic breeding simulations have been used by breeders to assess the merits of alternative breeding strategies and assist in decision making. In addition to simulations, visualization of a Pareto frontier for multiple competing breeding objectives can assist breeders in decision making. This paper introduces Python Breeding Optimizer and Simulator (PyBrOpS), a Python package capable of performing multi-objective optimization of breeding objectives and stochastic simulations of breeding pipelines. PyBrOpS is unique among other simulation platforms in that it can perform multi-objective optimizations and incorporate these results into breeding simulations. PyBrOpS is built to be highly modular and has a script-based philosophy, making it highly extensible and customizable. In this paper, we describe some of the main features of PyBrOpS and demonstrate its ability to map Pareto frontiers for breeding possibilities and perform multi-objective selection in a simulated breeding pipeline.
Sensory innervation of masseter, temporal and lateral pterygoid muscles in common marmosets
Authors: Hovhannisyan Anahit H. , Lindquist Karen A. , Belugin Sergei , Mecklenburg Jennifer , Ibrahim Tarek , Tram Meilinn , Corey Tatiana M. , Salmon Adam B. , Perez Daniel , Ruparel Shivani , Akopian Armen N. 
Published: February 2023

AbstractMyogenous temporomandibular disorders (TMDM) is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid (MPM) and lateral pterygoid muscles (LPM). This study aimed to examine sensory nerve types innervating MM, TM and LPM of adult non-human primate - common marmosets. Sensory nerves are localized in specific regions of these muscles. Pgp9.5, marker for all nerves, and NFH, a marker for A-fibers, showed that masticatory muscles were predominantly innervated with A-fibers. The proportion of C- to A-fibers was highest in LPM, and minimal (6-8%) in MM. All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked mrgprD, trpV1 and CHRNA3, a silent nociceptive marker. All fibers in masticatory muscles were labeled with GFAP+, a myelin sheath marker. There were substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin. In contrast, a lesser number of TM and LPM nerves expressed trkC, and lacked trkB. Tyrosine hydroxylase antibodies, which did not label TG, highlighted sympathetic fibers around blood vessels of the masticatory muscles. Overall, masticatory muscle types of marmosets have distinct and different innervation patterns.
Genomic Resources for Asian (Elephas maximus) and African Savannah Elephant (Loxodonta africana) Conservation and Health Research
Authors: Prado Natalia A. , Armstrong Ellie E. , Brown Janine L. , Goldenberg Shifra Z. , Leimgruber Peter , Pearson Virginia R. , Maldonado Jesús E. , Campana Michael G. 
Published: February 2023

AbstractWe provide novel genomic resources to help understand the genomic traits involved in elephant health and to aid conservation efforts. We sequence 11 elephant genomes (5 African savannah, 6 Asian) from North American zoos, including 9de novoassemblies. We estimate elephant germline mutation rates and reconstruct demographic histories. Finally, we provide an in-solution capture assay to genotype Asian elephants. This assay is suitable for analyzing degraded museum and non-invasive samples, such as feces and hair. The elephant genomic resources we present here should allow for more detailed and uniform studies in the future to aid elephant conservation efforts and disease research.
Streamline unsupervised machine learning to survey and graph indel-based haplotypes from pan-genomes
Authors: Zhang Bosen , Huang Haiyan , Tibbs-Cortes Laura E. , Vanous Adam , Zhang Zhiwu , Sanguinet Karen , Garland-Campbell Kimberly A. , Yu Jianming , Li Xianran 
Published: February 2023

AbstractIdentification and visualization of large insertion and deletion (indel) polymorphisms, which contribute significantly to natural phenotypic variation, are challenge from a pan-genome. Here, through streamlining two unsupervised machine learning algorithms, we developed a BRIDGEcereal webapp for surveying and graphing indel-based haplotypes for genes of interest from publicly accessible pangenomes. Over hundreds of assemblies from five major cereals were compiled. We demonstrated the potential of BRIDGEcereal in exploring natural variation with wheat candidate genes within QTLs and GWAS intervals. BRIDGEcereal is available fromhttps://bridgecereal.scinet.usda.gov.