bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation
Authors: Dong Zheng (Joe) , Schaffner Samantha , Fu Maggie , Whitehead Joanne , MacIsaac Julia L. , Rehkopf David H. , Boyce W. Thomas , Rosero-Bixby Luis , Quintana-Murci Lluis , Patin Etienne , Miller Gregory E. , Korthauer Keegan , Kobor Michael S. 
Published: November 2024

AbstractDNA methylation (DNAm) is a key epigenetic mark that modulates regulatory elements and gene expression, playing a crucial role in mammalian development and physiological function. Despite extensive characterization of DNAm profiles across species, little is known about its evolutionary conservation. Here, we conducted a comparative epigenome-wide analysis of great apes to identify and characterize sequence- and methylation-conserved CpGs (MCCs). Using 202 DNAm arrays, alongside 6 matched genotype and 13 matched transcriptomic datasets, we identified 11,500 MCCs for which methylation was evolutionarily related to sequences of CpGs and methylation quantitative trait loci. MCCs were the most stable across healthy human tissues and exhibited weaker genetic associations than other CpGs. Moreover, MCCs showed minimal associations with demographic, environmental factors, and noncancer diseases, yet demonstrated stronger associations with certain cancers than other CpGs, particularly gastrointestinal cancers. Functional enrichment analysis revealed that genes associated with MCC methylation in cancer were enriched for cancer driver genes and canonical cancer pathways, highlighting a significant regulatory role for MCCs in tumorigenesis. Collectively, our findings reveal the extent of DNAm conservation in great ape evolution, its association with genetic conservation, and its relevance to human diseases. These integrative analyses offer evolutionary insights into epigenetic variation and its functional implications in human populations.
Computational Modeling and Analysis of the TGF-β-induced ERK and SMAD Pathways
Authors: Chung Seung-Wook , Cooper Carlton R. , Farach-Carson Mary C. , Ogunnaike Babatunde A. 
Published: November 2024

AbstractTGF-β, an important cytokine that plays a key role in many diseases regulates a wide array of cellular and physiologic processes via several TGF-β-driven signaling cascades, including the SMAD and non-SMAD-driven pathways. However, the detailed mechanisms by which TGF-β induces such diverse responses remain poorly understood. In particular, compared to the SMAD-dependent pathway, SMAD-independent pathways such as the ERK/MAPK pathway, which is critical in cancer progression, are less characterized. Here, we develop an integrated mechanistic model of the TGF-β-triggered ERK activation pathway and its crosstalk with the SMAD pathway, an analysis of which demonstrates how SMAD dynamics can be significantly modulated and regulated by the ERK pathway. In particular, SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the linker of SMAD by TGF-β-activated ERK; and enhanced ERK activity, but attenuated SMAD activity, can be achieved simultaneously by fast turnover of TGF-β receptors via lipid-rafts. Also,in silicomutations of the TGF-β pathways reveal that the dynamic characteristics of both SMAD and ERK signaling may change significantly during cancer development. Specifically, normal cells may exhibit enhanced and sustained SMAD signaling with transient ERK activation, whereas cancerous cells may produce elevated and prolonged ERK signaling with enervated SMAD activation. These distinctive differences between normal and cancerous signaling behavior provide clues concerning, and potential explanations for, the seemingly contradictory roles played by TGF-β during cancer progression. We demonstrate how crosstalk among various branch pathways of TGF-β can influence overall cellular behavior. Based on model analysis, we hypothesize that aberrant molecular alterations drive changes in the intensity and duration of SMAD and ERK signaling during cancer progression and ultimately lead to an imbalance between the SMAD and ERK pathways in favor of tumor promotion. Thus, to treat cancer patients with a genetic signature of oncogenic Ras effectively may requireat leasta combination therapy to restoreboththe expression of TGF-β receptors and the GTPase activity of Ras.
Morpho-molecular features of Epithelial Mesenchymal Transition associate with clinical outcome in patients with rectal cancer
Authors: Gwerder Mauro , Demir Cansaran Saygili , Williams Hannah L. , Lugli Alessandro , Martinez Cristina Graham , Kowal Joanna , Khan Amjad , Kirchner Philipp , Koessler Thibaud , Berger Martin D. , Weigert Martin , Zlobec Inti 
Published: November 2024

AbstractIn rectal cancer, where part of the patients undergoes chemoradiotherapy, there is a need for improved pretreatment biomarkers applicable to biopsies. Tumor budding (TB) is a biomarker used in colon cancer, and due to its link to epithelial-mesenchymal transition (EMT), is hypothesized to be a potential marker for therapy resistance. Assessment of the utility of tumor buds in rectal biopsies is challenging due to their rarity. As EMT-related processes are also seen in other morphological features beyond tumor buds, we investigated EMT in tumor tissue including morphological features such as tumorcluster sizeand fibril-like structures. To do so, we leveraged a cohort of colon cancer whole-slide images and another cohort consisting of rectal cancer biopsies, visualized using hyperplex immunofluorescence to identify tumor and EMT-associated proteins. We built a custom image analysis pipeline to detect and segment tumor buds and other morphological features and correlated them with molecular expression intensities. We found strong correlations of EMT up-regulation and morphological transition states, both at the invasive margin and the tumor center. We furthermore observed a link between morpho-molecular transitions and histological growth patterns, which in turn can inform novel biomarkers. Finally, quantification of these morpho-molecular transition states in rectal biopsies showed their impact on survival after neoadjuvant chemoradiotherapy.
Bayesian nonparametric analysis of residence times for protein-lipid interactions in Molecular Dynamics simulations
Authors: Sexton Ricky , Fazel Mohamadreza , Schweiger Maxwell , Pressé Steve , Beckstein Oliver 
Published: November 2024

AbstractMolecular Dynamics (MD) simulations are a versatile tool to investigate the interactions of proteins within their environments, in particular of membrane proteins with the surrounding lipids. However, quantitative analysis of lipid-protein binding kinetics has remained challenging due to considerable noise and low frequency of long binding events, even in hundreds of microseconds of simulation data. Here we apply Bayesian nonparametrics to compute residue-resolved residence time distributions from MD trajectories. Such an analysis characterizes binding processes at different timescales (quantified by their kinetic off-rate) and assigns to each trajectory frame a probability of belonging to a specific process. In this way, we classify trajectory frames in an unsupervised manner and obtain, for example, different binding poses or molecular densities based on the timescale of the process. We demonstrate our approach by characterizing interactions of cholesterol with six different G-protein coupled receptors (A2AAR,β2AR, CB1R, CB2R, CCK1R, CCK2R) simulated with coarse-grained MD simulations with the MARTINI model. The nonparametric Bayesian analysis allows us to connect the coarse binding time series data to the underlying molecular picture and, thus, not only infers accurate binding kinetics with error distributions from MD simulations but also describes molecular events responsible for the broad range of kinetic rates.
RIBOSS detects novel translational events by combining long- and short-read transcriptome and translatome profiling
Authors: Lim Chun Shen , Brown Chris M. 
Published: November 2024

ABSTRACTRibosome profiling is a high-throughput sequencing technique that captures the positions of translating ribosomes on RNAs. Recent advancements in ribosome profiling include achieving highly-phased ribosome footprints for plant translatomes and more recently for bacterial translatomes. This substantially increases the specificity of detecting open reading frames (ORFs) that can be translated, such as small ORFs located upstream and downstream of the annotated ORFs. However, most genomes (e.g. bacterial genomes) lack the annotations for the transcription start and termination sites. This hinders the systematic discovery of novel ORFs in the ‘untranslated’ regions in ribosome profiling data. Here we develop a new computational pipeline called RIBOSS. We use RIBOSS to leverage long-read and short-read data forde novotranscriptome assembly, and highly-phased ribosome profiling data for detecting novel translational events in the newly assembled transcriptome. We demonstrate the capability of RIBOSS using recently published metatranscriptome and translatome data forSalmonella entericaserovar Typhimurium. The RIBOSS Python modules are versatile and can be used to analyse prokaryotic or eukaryotic data. In sum, RIBOSS is the first computational pipeline to integrate long- and short-read sequencing technologies to investigate translation. RIBOSS is freely available athttps://github.com/lcscs12345/riboss.
Neural Context Reinstatement of Recurring Events
Authors: Broitman Adam W. , Kahana Michael J. 
Published: November 2024

AbstractEpisodic recollection involves retrieving context information bound to specific events. However, autobiographical memory largely comprises recurrent, similar experiences that become integrated into joint representations. In the current study, we extracted a neural signature of temporal context from scalp electroencephalography (EEG) to investigate whether recalling a recurring event accompanies the reinstatement of one or multiple instances of its occurrence. We asked 52 young adults to study and recall lists of words that included both once-presented and repeated items. Participants recalled repeated items in association with neighboring list items from each occurrence, but with stronger clustering around the repetition’s initial occurrence. Furthermore, multivariate spectral EEG analyses revealed that neural activity from just prior to the recall of these words resembled patterns of activity observed near the item’s first occurrence, but not its second. Together, these results suggest that the initial occurrence of an event carries stronger temporal context associations than later repetitions.Research Transparency StatementThe authors report no conflicts of interest with respect to the authorship or publication of this article. This research was conducted with support from National Institutes of Health grant MH55687. The current study was not preregistered. Data are available upon reasonable request and with proper approval from the University of Pennsylvania research and ethics entities. Requests should be directed to Adam Broitman. Key EEG and behavioral data analysis scripts are available for download at https://github.com/awb99cu/repFRcode.Studymaterialsareavailablefordownloadathttps://memory.psych.upenn.edu/PEERS.
Tidyplots empowers life scientists with easy code-based data visualization
Authors: Engler Jan Broder 
Published: November 2024

AbstractCode-based data visualization is a crucial tool for understanding and communicating experimental findings while ensuring scalability and reproducibility. However, complex programming interfaces pose a significant barrier for life scientists. To address this challenge, tidyplots provides a user-friendly code-based interface for creating customizable and insightful plots. With its consistent and intuitive syntax, tidyplots empowers researchers to leverage automated data visualization pipelines while minimizing required programming skills.Tidyplots is available on CRAN athttps://CRAN.R-project.org/package=tidyplotsand GitHub athttps://github.com/jbengler/tidyplots. The full documentation is available athttps://tidyplots.org.
A bacterial cell wall repair and modification system to resist host antibacterial factors
Authors: Burnier Jessica , Gallay Clement , Bruce Kevin , Bjånes Elisabet , Martin Louise , Jim Kinki , Tsui Ho-Ching Tiffany , Cremers Amelieke , Mignolet Johann , Vollmer Daniela , Biboy Jacob , Nizet Victor , Vollmer Waldemar , Winkler Malcolm E. , Veening Jan-Willem 
Published: November 2024

AbstractPathogenic bacteria have acquired the ability to resist antibacterial defense mechanisms of the host. Streptococci are common in animal microbiota and include opportunistic pathogens like Group A Streptococcus (GAS) andStreptococcus pneumoniae(pneumococcus). While the conserved streptococcal S protein has been identified as a key factor in GAS virulence, its exact function is unclear. Here, we show that the pneumococcal S protein is crucial for resisting against host-derived antimicrobials by coordinating cell wall modification and repair. Specifically, we show that S proteins are septally localized through their transmembrane domain and contain an extracellular peptidoglycan (PG) binding LysM domain which is required for its function. Protein-protein and genetic interaction studies demonstrate that the pneumococcal S protein directly interacts with a PG synthase, class A penicillin binding protein PBP1a, and the PG deacetylase PgdA. Single-molecule experiments reveal that the fraction of circumferentially moving PBP1a molecules is reduced in the absence of S protein. Consistent with an impaired PBP1a function, streptococci lacking S protein exhibit increased susceptibility to cell wall targeting antibiotics and altered cell morphologies. PG analysis showed reduced N-deacetylation of glycans in theS. pneumoniaeS protein mutant, indicating reduced PgdA activity. We show that pneumococci lacking the S protein cannot persist transient penicillin treatment, are more susceptible to the human antimicrobial peptide LL-37 and to lysozyme, and show decreased virulence in zebrafish and mice. Our data support a model in which S proteins regulate PBP1a activity and play a key role in coordinating PG repair and modification. This cell wall ‘sentinel’ control system provides defense against host-derived and environmental antimicrobial attack.
Risk factors, prognostic factors, and nomograms for distant metastasis in patients with triple-negative breast cancer: a population-based study
Authors: Guo Hongguo , Qiao Song , Cheng Cai , Liu Jun , Yang Shangzhen , Lu Wanling 
Published: November 2024

ABSTRACTBackgroundTriple-negative breast cancer (TNBC) is associated with a poor prognosis, higher invasiveness compared to other breast cancer variants, and limited treatment options. Due to the lack of conventional treatment methods, TNBC patients are prone to distant metastasis. The purpose of this study is to evaluate the clinical and pathological characteristics of TNBC patients, predict the impact of risk factors on their prognosis, and establish a predictive model to assist doctors in treating TNBC patients and improving their outcomes.MethodsWe conducted a retrospective study on patients with TNBC from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. We gathered tumor characteristics and treatment data from these patients. Univariate and multivariate logistic regression analyses were employed to identify independent risk factors for distant metastasis in TNBC patients, while univariate and multivariate Cox proportional hazards regression analyses were utilized to determine independent prognostic factors for TNBC patients with distant metastasis. Based on these factors, a new nomogram was constructed, and patients were categorized into high and low-risk groups using the nomogram scores. The prognosis of the patients was analyzed using Kaplan-Meier (K-M) survival analysis.ResultsThis study enrolled a total of 16,959 patients with TNBC, among whom 730 (4.3%) had distant metastasis at the time of diagnosis. Independent risk factors for distant metastasis in TNBC patients encompass being married, having an invasive lobular carcinoma (ILC) pathology, advanced T stage, advanced N stage, no radiotherapy, no surgery, and tumor size exceeding 50mm. The area under the curve (AUCs) for the training set and validation set were 0.892 and 0.907, respectively. The independent prognostic factors for patients with distant metastasis were being unmarried (P < 0.001), not undergoing surgery (P < 0.001), and not receiving chemotherapy (P < 0.001). The AUCs for the training set at 12, 36, and 60 months were 0.751, 0.709, and 0.691, respectively, while the AUCs for the validation set at 12, 36, and 60 months were 0.690, 0.690, and 0.732, respectively. The AUCs for the extended test set at 12, 36, and 60 months were 0.741, 0.727, and 0.718 respectively. The results of the calibration curve, decision curve analysis (DCA), and K-M survival curve confirm that both nomograms can accurately predict the occurrence of distant metastasis and prognosis in TNBC patients.ConclusionWe constructed two nomograms to predict distant metastasis risk in TNBC patients and prognosis in patients with distant metastasis. Our findings suggest that they could serve as effective predictive tools and may assist in clinical decision-making.
Precise Lineage Tracking Using Molecular Barcodes Demonstrates Fitness Trade-offs for Ivermectin Resistance in Nematodes
Authors: Stevenson Zachary C. , Laufer Eleanor , Estevez Annette O. , Robinson Kristin , Phillips Patrick C. 
Published: November 2024

AbstractA fundamental tenet of evolutionary genetics is that the direction and strength of selection on individual loci varies with the environment. Barcoded evolutionary lineage tracking is a powerful approach for high-throughput measurement of selection within experimental evolution that to date has largely been restricted to studies within microbial systems, largely because the random integration of barcodes within animals is limited by physical and molecular protection of the germline. Here, we use the recently developed TARDIS barcoding system inCaenorhabditis elegans(Stevenson et al., 2023) to implement the first randomly inserted genomic-barcode experimental evolution animal model and use this system to precisely measure the influence of the concentration of the anthelmintic compound ivermectin on the strength of selection on an ivermectin resistance cassette. The combination of the trio of knockouts in neuronally expressed GluCl channels,avr-14,avr-15, andglc-1, has been previously demonstrated to provide resistance to ivermectin at high concentrations. Varying the concentration of ivermectin in liquid culture allows the strength of selection on these genes to be precisely controlled within populations of millions of individuals, yielding the largest animal experimental evolution study to date. The frequency of each barcode was determined at multiple time points via sequencing at deep coverage and then used to estimate the fitness of the individual lineages in the population. The mutations display a high cost to resistance at low concentrations, rapidly losing out to wildtype genotypes, but the balance tips in their favor when the ivermectin concentration exceeds 2nM. This trade-off in resistance is likely generated by a hindered rate of development in resistant individuals. Our results demonstrate thatC. eleganscan be used to generate high precision estimates of fitness using a high-throughput barcoding approach to yield novel insights into evolutionarily and economically important traits.
Assessing reliability and accuracy of qPCR, dPCR and ddPCR for estimating mtDNA copy number in songbird blood and sperm cells
Authors: Bagdonaitė Laima , Leder Erica H. , Lifjeld Jan T. , Johnsen Arild , Mauvisseau Quentin 
Published: November 2024

AbstractMitochondrial DNA copy number varies across species, individuals and cell types. Two avian cell types carrying a relatively low number of mitochondria are the red blood cells and spermatozoa. While previous studies investigating variation of mitochondrial abundance in animal sperm have generally used quantitative PCR (qPCR), this method shows potential limitations when quantifying low abundant targets. To mitigate such issues, we investigated and compared the reliability and accuracy of qPCR, digital PCR (dPCR) and droplet digital PCR (ddPCR) to quantify high and low concentration DNA. Using synthetic DNA, we found that both dPCR and ddPCR displayed lower Limit of Detection and Limit of Quantification than qPCR. Using DNA extracted from blood and sperm cells of Eurasian Siskin, we found that qPCR, dPCR and ddPCR reliably quantified mitochondrial DNA in sperm samples, but showed significant differences when analyzing typically lower levels of mtDNA in blood. We found that ddPCR consistently showed lower variation among replicates. These analyses provide critical insights and recommendations for future studies aiming to quantify target mtDNA. Our study indicates that dPCR and ddPCR are the preferred methods when working with samples with low abundance of mtDNA.
A Systematic Review of the Impacts of El Niño-Driven Drought, Fire, and Smoke on Non-Human Primates in Southeast Asia
Authors: Barrow Elizabeth J. , Erb Wendy M. 
Published: November 2024

AbstractDuring the El Niño phase of the El Niño-Southern Oscillation (ENSO), much of Southeast Asia experiences intense droughts and surging temperatures, exacerbating wildfires and creating a blanket of hazardous haze across much of the region. These patterns are predicted to worsen with climate change, further exacerbating the vulnerability of the regions’ primate species, 94% of which are threatened with extinction. Here, we report findings from a systematic search of the literature and synthesise the current state of knowledge regarding the impacts of El Niño-driven drought, fire, and smoke on non-human primates in Southeast Asia. Our review shows that habitat loss and degradation driven by El Niño-induced drought and fire causes changes to diet, activity patterns, social interactions, and physical condition, and leads to population crowding, reduced group sizes, increased infant mortality, displacement of individuals, and even local extirpation. Further, prolonged exposure to smoke alters behaviour and worsens the health of primates. Notably, two studies presented evidence for the recovery of primate populations in habitats damaged by fire if forest is allowed to regenerate. We highlight significant gaps in our understanding of the impacts of El Niño on non-human primates, particularly the need for research that encompasses the interconnected factors of rainfall, temperature, fire, and smoke, as well as long-term effects on reproduction and mortality. Due to the unpredictable nature of El Niño, we acknowledge the difficulties of planning research in this area and emphasise the potential of long-term research sites to add to our understanding of this key conservation issue.