bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-sectional and longitudinal changes in category-selectivity in visual cortex following pediatric cortical resection
Authors: Liu Tina T. , Granovetter Michael C. , Maallo Anne Margarette S. , Robert Sophia , Fu Jason Z. , Patterson Christina , Plaut David C. , Behrmann Marlene 
Published: December 2024

AbstractThe topographic organization of category-selective responses in human ventral occipitotemporal cortex (VOTC) and its relationship to regions subserving language functions is remarkably uniform across individuals. This arrangement is thought to result from the clustering of neurons responding to similar inputs, constrained by intrinsic architecture and tuned by experience. We examined the malleability of this organization in individuals with unilateral resection of VOTC during childhood for the management of drug-resistant epilepsy. In cross-sectional and longitudinal functional imaging studies, we compared the topography and neural representations of 17 category-selective regions in individuals with a VOTC resection, a ‘control patient’ with resection outside VOTC, and typically developing matched controls. We demonstrated both adherence to and deviation from the standard topography and uncovered fine-grained competitive dynamics between word- and face-selectivity over time in the single, preserved VOTC. The findings elucidate the nature and extent of cortical plasticity and highlight the potential for remodeling of extrastriate architecture and function.TeaserAfter pediatric cortical resection, deviations from the constraints of standard topography in visual cortex reflect plasticity.
Development of Molecular Digital Twins Based on Ambient Ionization Mass Spectrometry Imaging for Application in Cancer Surgery
Authors: Zirem Yanis , Ledoux Léa , Ogrinc Nina , Lagache Laurine , Bourette Roland , Lagadec Chann , Chaillou Paul , Salzet Michel , Fournier Isabelle 
Published: December 2024

SummaryCancer surgery is a fundamental component of oncology treatment, its quality significantly impacts patient outcomes, influencing both relapse rates and survival. However, achieving this customization is contingent upon early collection of robust molecular data during surgery, providing accurate information for diagnosis, prognosis, and delineating surgical margins. The introduction of digital twin (DT) technology has recently opened a new era of precision and effectiveness in cancer surgery. Expanding from its successful implementations in the industrial sector, DT concept has evolved into a highly promising breakthrough in healthcare. Therefore, our study goal is on creating DT by using accurate and high-throughput molecular data obtained through mass spectrometry imaging. We developed a machine-learning-based pipeline that allow to depict infiltration of cancer cells into normal tissue that offer precise delineation of tumor margins thanks to SpiderMass. This process also enables the prediction of relative presence of bacterial strains in tumoral and healthy mammary glands.
Motor network activation and white matter connectivity patterns are related to clinical outcomes following perinatal and childhood arterial ischemic stroke
Authors: Curnow SR , Chen J , Warren AEL , Beare R , Mackay MT , Yang JYM 
Published: December 2024

AbstractBackgroundMotor outcomes following perinatal and childhood stroke are highly variable and likely reflect complex structural and functional changes within motor-related brain networks. Greater understanding of these network mechanisms is needed to improve patient-specific prognostication and develop targeted therapies to restore motor function. This study explored post-stroke motor-related reorganization patterns through assessment of functional MRI (fMRI) activation and white matter connectivity patterns.HypothesisWe hypothesized that activation and connectivity patterns would differ between children with and without hemiparesis following stroke.MethodsTwelve children (age 9-19 years) with a history of perinatal or childhood stroke underwent 3T MRI with diffusion-weighted imaging and task-related hand-motor fMRI. The Paediatric Stroke Outcome Measure was used to assess motor outcome and dichotomized into two groups. MRI data were processed and analyzed for whole-brain fMRI activation patterns and white matter track-weighted functional connectivity (TW-FC) profiles, in relation to motor outcomes.ResultsDivergent fMRI activation and TW-FC patterns were seen between the two groups. Children in the no hemiparesis group were more likely to retain an ipsilesional fMRI activation pattern while children in the hemiparesis group were more likely to demonstrate bilateral or contralesional patterns. Increased utilization of cortical-subcortical pathways was identified by TW-FC in both groups. Greater TW-FC strength when moving the stroke-affected hand was also seen in the no hemiparesis group compared to the hemiparesis group.ConclusionsWe identified distinct patterns of motor network activation and white matter connectivity relating to clinical outcomes after perinatal and childhood stroke. These patterns have potential to improve prognostic ability and aid identification of infants and children who would most benefit from targeted therapy to improve long-term motor outcomes.
The human RAD52 complex undergoes phase separation and facilitates bundling and end-to-end tethering of RAD51 presynaptic filaments
Authors: Alshareedah Ibraheem , Pangeni Sushil , Dewan Paul A. , Honda Masayoshi , Liao Ting-Wei , Spies Maria , Ha Taekjip 
Published: December 2024

AbstractHuman RAD52 is a prime target for synthetical lethality approaches to treat cancers with deficiency in homologous recombination. Among multiple cellular roles of RAD52, its functions in homologous recombination repair and protection of stalled replication forks appear to substitute those of the tumor suppressor protein BRCA2. However, the mechanistic details of how RAD52 can substitute BRCA2 functions are only beginning to emerge. RAD52 forms an undecameric ring that is enveloped by eleven ∼200 residue-long disordered regions, making it a highly multivalent and branched protein complex that potentiates supramolecular assembly. Here, we show that RAD52 exhibits homotypic phase separation capacity, and its condensates recruit key players in homologous recombination such as single-stranded (ss)DNA, RPA, and the RAD51 recombinase. Moreover, we show that RAD52 phase separation is regulated by its interaction partners such as ssDNA and RPA. Using fluorescence microscopy, we show that RAD52 can induce the formation of RAD51-ssDNA fibrillar structures. To probe the fine structure of these fibrils, we utilized single-molecule super-resolution imaging via DNA-PAINT and atomic force microscopy and showed that RAD51 fibrils are bundles of individual RAD51 nucleoprotein filaments. We further show that RAD52 induces end-to-end tethering of RAD51 nucleoprotein filaments. Overall, we demonstrate unique macromolecular organizational features of RAD52 that may underlie its various functions in the cell.
Secretome analysis of cancer-associated fibroblasts from prostate cancer to identify potential therapeutic targets
Authors: Abikar Apoorva , Subhani Mustafa Mohammad Mehaboob , Athalye Radhika Rajiv , Nadig Namratha , Tamboli Ninad , Babu Vinod , Keshavamurthy Ramaiah , Ranganathan Prathibha 
Published: December 2024

AbstractTumor microenvironment (TME) is a complex entity comprising of several cell types secreted factors as well as an extracellular matrix. A dynamic interaction between tumor cells and their environment profoundly influences tumor survival, aggressiveness, and progression. Cancer- associated fibroblasts (CAFs) are one of the major cellular components of TME and serve as a major source of various secreted factors. These factors are known to modulate tumor survival and progression, as well as their response to therapy. Despite the importance of the TME factors on various aspects of tumor cell behavior, to date factors unique to CAFs that could be potential therapeutic targets are not identified in most systems. This study was aimed at identifying such factors from CAFs which may impact tumor behavior such as the ability to metastasize, response to therapy, relapse, etc. This would aid in identifying therapeutic targets originating from the TME. Furthermore, targeting those factors along with conventional chemotherapeutic drugs is likely to enhance the overall efficacy of the therapy. This study has used fibroblasts derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer for comparing the secretome using a quantitative proteomics approach. 66 proteins unique to CAFs and 24 unique to control (BPH) fibroblasts have been identified. Besides 236 proteins are differentially expressed between control and cancer- associated fibroblasts. Using in-silico approaches the potential processes that may be influenced by the differentially expressed proteins have also been identified. This study has identified both qualitative and quantitative differences between the secretomes of normal and cancer-associated fibroblasts with further validation, this paves the way for identifying therapeutic targets.
Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses
Authors: Lei Jonathan T. , Dobrolecki Lacey E. , Huang Chen , Srinivasan Ramakrishnan R. , Vasaikar Suhas V. , Lewis Alaina N. , Sallas Christina , Zhao Na , Cao Jin , Landua John D. , Moon Chang In , Liao Yuxing , Hilsenbeck Susan G. , Osborne C. Kent , Rimawi Mothaffar F. , Ellis Matthew J. , Petrosyan Varduhi , Wen Bo , Li Kai , Saltzman Alexander B. , Jain Antrix , Malovannaya Anna , Wulf Gerburg M. , Marangoni Elisabetta , Li Shunqiang , Kraushaar Daniel C. , Wang Tao , Damodaran Senthil , Zheng Xiaofeng , Meric-Bernstam Funda , Echeverria Gloria V. , Anurag Meenakshi , Chen Xi , Welm Bryan E. , Welm Alana L. , Zhang Bing , Lewis Michael T. 
Published: December 2024

SummaryCombination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to multiple single agents cannot be delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination. Combination responses were usually no better than the best single agent, with enhanced response in only ∼13% of PDX, and apparent antagonism in a comparable percentage. Single-omic comparisons showed largely non-overlapping results between genes associated with single agent and combination treatments that could be validated in independent patient cohorts. Multi-omic analyses of PDXs identified agent-specific biomarkers/biomarker combinations, nominating high Cytokeratin-5 (KRT5) as a general marker of responsiveness. Notably, integrating proteomic with transcriptomic data improved predictive modeling of pathologic complete response to combination chemotherapy. PDXs refractory to all treatments were enriched for signatures of dysregulated mitochondrial function. Targeting this process indirectly in a PDX with HDAC inhibition plus chemotherapyin vivoovercomes chemoresistance. These results suggest possible resistance mechanisms and therapeutic strategies in TNBC to overcome chemoresistance, and potentially allow optimization of chemotherapeutic regimens.HighlightsMinable multi-omic resource of baseline TNBC PDX tumors matched with single and combination chemotherapy responses yields candidate resistance mechanisms and potentially targetable processesCombination carboplatin/docetaxel is largely ineffective at enhancing response versus the best single agent in TNBC PDXs, and they can antagonize one another in some PDXsProteomics data enhances predictions of platinum- and taxane-based chemotherapy responseTargeted agents can enhance chemotherapy response in TNBC PDXs
Perivascular Macrophages Convert Physical Wound Signals Into Rapid Vascular Responses
Authors: Gelashvili Zaza , Shen Zhouyang , Ma Yanan , Jelcic Mark , Niethammer Philipp 
Published: December 2024

Leukocytes detect distant wounds within seconds to minutes, which is essential for effective pathogen defense, tissue healing, and regeneration. Blood vessels must detect distant wounds just as rapidly to initiate local leukocyte extravasation, but the mechanism behind this immediate vascular response remains unclear. Using high-speed imaging of live zebrafish larvae, we investigated how blood vessels achieve rapid wound detection. We monitored two hallmark vascular responses: vessel dilation and serum exudation. Our experiments—including genetic, pharmacologic, and osmotic perturbations, along with chemogenetic leukocyte depletion—revealed that the cPla2nuclear shape sensing pathway in perivascular macrophages converts a fast (∼50 μm/s) osmotic wound signal into a vessel-permeabilizing, 5-lipoxygenase (Alox5a) derived lipid within seconds of injury.These findings demonstrate that perivascular macrophages act as physicochemical relays, bridging osmotic wound signals and vascular responses. By uncovering this novel type of communication, we provide new insights into the coordination of immune and vascular responses to injury.
What challenges remain in harmonizing cytomegalovirus viral load quantification across laboratories?
Authors: Boutolleau D. , L’Honneur A-S. , Germi R. , Chanzy B. , Archimbaud-Jallat C. , Rzadkowolski C. , Raimbourg J.B. , Gauthier D. , Thibault V. 
Published: December 2024

SummaryCytomegalovirus (CMV) infection monitoring is a key element in the management of immunocompromised patients. CMV DNA quantification in plasma or whole blood is the best indicator for clinicians to adjust immunosuppressive or antiviral therapies. Despite the availability of internationally standardized material, the commutability of CMV quantification results across laboratories remains inadequate. To assess inter-laboratory variability in CMV DNA quantification, we conducted a blinded study in seven independent laboratories. Each participant received a panel of 92 specimens for CMV quantification using their routinely used standard platform. While quantifications were highly correlated and reproducible, large discrepancies were observed with differences up to 1.45 log10IU/mL between techniques for identical specimens. However, quantification scattering was lower for the WHO international standard or a commercially tested control (IQR=0.129) than for clinical specimens (0.469; p=0.0142). Blind quantification of the WHO or the commercial standard indicated that all techniques, except for fully integrated platforms, did not align well with the expected values and most platforms tended to quantify specimens and standards differently. Recalibration of all platforms against the same standard improved the spread of results, but differences of up to 1.19 log10IU/mL remained for the same specimens. Achieving commutability in CMV quantification remains an elusive goal. Efforts should focus on improving both the assay calibrators and the run controls, which currently do not appear to simulate the unique characteristics of circulating CMV in patients. Until this is resolved, each transplanted patient should be consistently monitored by the same laboratory on the same platform.
Pervasive divergence in protein thermostability is mediated by both structural changes and cellular environments
Authors: Walunjkar Nilima , Lai Timothy Y. , Akhter Nasima , Miller James H. , Bettinger John Q. , Marcus Erin , Phizicky Eric M. , Ghaemmaghami Sina , Fay Justin C. 
Published: December 2024

AbstractTemperature is a universal environmental constraint and organisms have evolved diverse mechanisms of thermotolerance. A central feature of thermophiles relative to mesophiles is a universal shift in protein stability, implying that it is a major constituent of thermotolerance. However, organisms have also evolved extensive buffering systems, such as those that disaggregate and refold denatured proteins and enable survival of heat shock. Here, we show that both cellular and protein structural changes contribute to divergence in protein thermostability between two closely relatedSaccharomycesspecies that differ by 8°C in their thermotolerance. Using thermal proteomic profiling we find that 85% ofS. cerevisiaeproteins are more stable than theirS. uvarumhomologs and there is an average shift of 1.6°C in temperature induced protein aggregation. In an interspecific hybrid of the two species,S. cerevisiaeproteins retain their thermostability, while the thermostability of theirS. uvarumhomologs is enhanced, indicating that cellular context contributes to protein stability differences. By purifying orthologous proteins we show that amino acid substitutions underlie melting temperature differences for two proteins, Guk1 and Aha1. Amino acid substitutions are also computationally predicted to contribute to stability differences for most of the proteome. Our results imply that coordinated changes in protein thermostability impose a significant constraint on the time scales over which thermotolerance can evolve.
H3.1K27M-induced misregulation of the TSK/TONSL-H3.1 pathway causes genomic instability
Authors: Yuan Wenxin , Huang Yi-Chun , LeBlanc Chantal , Poulet Axel , Valsakumar Devisree , van Wolfswinkel Josien C. , Voigt Philipp , Jacob Yannick 
Published: December 2024

AbstractThe oncomutation lysine 27-to-methionine in histone H3 (H3K27M) is frequently identified in tumors of patients with diffuse midline glioma-H3K27 altered (DMG-H3K27a). H3K27M inhibits the deposition of the histone mark H3K27me3, which affects the maintenance of transcriptional programs and cell identity. Cells expressing H3K27M are also characterized by defects in genome integrity, but the mechanisms linking expression of the oncohistone to DNA damage remain mostly unknown. In this study, we demonstrate that expression of H3.1K27M in the model plantArabidopsis thalianainterferes with post-replicative chromatin maturation mediated by the H3.1K27 methyltransferases ATXR5 and ATXR6. As a result, H3.1 variants on nascent chromatin remain unmethylated at K27 (H3.1K27me0), leading to ectopic activity of TONSOKU (TSK), which induces DNA damage and genomic alterations. Elimination of TSK activity suppresses the genome stability defects associated with H3.1K27M expression, while inactivation of specific DNA repair pathways prevents survival of H3.1K27M-expressing plants. Overall, our results suggest that H3.1K27M disrupts the chromatin-based mechanisms regulating TSK/TONSL activity, which causes genomic instability and may contribute to the etiology of DMG-H3K27a.
Ctenophores and parahoxozoans independently evolved complex and functionally diverse sets of voltage-gated K+channels
Authors: Simonson Benjamin T. , Jiang Zhaoyang , Ryan Joseph F. , Jegla Timothy 
Published: December 2024

AbstractThe ctenophore speciesMnemiopsis leidyiis known to have a large set of voltage-gated K+channels, but little is known about the functional diversity of these channels or the evolutionary history of this gene family in other ctenophore species. Here, we searched the genomes of two additional ctenophore species,Beroe ovataandHormiphora californensis, for voltage-gated K+channels and functionally expressed a subset ofM. leidyichannels. We found that the last common ancestor of these three disparate ctenophore lineages probably had at least 33 voltage-gated K+channels. Two of these genes belong to the EAG family, and the remaining 31 belong to the Shaker family and form a single clade within the animal/choanoflagellate Shaker phylogeny. We additionally found evidence for 10 of these Shaker channels in a transcriptome of the early branching ctenophore lineageEuplokamis dunlapae, suggesting that the diversification of these channels was already underway early in ctenophore evolution. We functionally expressed 16MnemiopsisShakers and found that they encode a functionally diverse array of voltage-gated K+conductances with functional orthologs for many classic Shaker family subtypes found in cnidarians and bilaterians. Ctenophores therefore appear to have independently evolved much of the voltage-gated K+channel diversity that is shared between cnidarians and bilaterians.
Predicting plant traits using large conglomerate RNA-seq datasets
Authors: Hadish John Anthony , Honaas Loren A. , Ficklin Stephen Patrick 
Published: December 2024

ABSTRACTRNA-seq datasets offer potential for predicting phenotypic traits, but the optimal dataset size for reliable predictions remains unclear. To explore this question, we compiled large-scale transcriptomic datasets across 12 plant species and used them to predict the phenotypic variables of tissue type and age. Predictions were made using random forest models. We created these models using an increasing number of samples to create performance curves.These curves show that only a few hundred samples are required to achieve maximum accuracy for tissue classification, while predicting age demands a few thousand samples. Acceptable prediction accuracy can be achieved at even lower numbers of samples. Our findings provide a benchmark for designing transcriptomic studies aimed at phenotype prediction and highlight the differing complexities involved in predicting simple versus more complex traits.CORE IDEAS-Plant transcriptomes are highly dynamic in response to internal and external conditions-There is interest in using transcriptomes for predicting phenotypic traits and disorders-It is unknown how many samples are required for accurate phenotype prediction-We created 12 massive RNA-seq datasets and corresponding phenotypic data and used these to create prediction models-Performance curves from our models provide insight into the required number of samples for accurate prediction