bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane
Authors: Massidda Miles W. , Ashirov David , Demkov Andrei , Sices Aidan , Baker Aaron B. 
Published: June 2024

AbstractMechanical forces applied to cells are known to regulate a wide variety of biological processes. Recent studies have supported that mechanical forces can cause nuclear deformation, leading to significant alterations in the gene expression and chromatin landscape of the cell. While the stresses and strains applied to cells is it is often known or controlled experimentally on a macroscopic length scale, it is often unclear what the actual forces and displacements are at the microscopic level of the cell. In this work, we created a model of cell deformation during application of mechanical stretch to cultured cells growth on a flexible membrane. This configuration is commonly used is in experimental studies as a means to apply controlled mechanical strains to adherent cultured cells. The parameters used in the study were used for application of strain to a mesenchymal stem cell stretched on a membrane. computational model was created to simulate the stresses and strains within the cell under a variety of stain amplitudes, waveforms and frequencies of mechanical loading with the range of commonly used experimental systems. The results demonstrate the connection between mechanical loading parameters applied through the flexible membrane and the resulting stresses and strains within the cell and nucleus. Using a viscoelastic model of chromatin, we connected the results provide to a rough model of resulting deformation within chromatin from the forces applied to the nucleus. Overall, the model is useful in providing insight between experimentally applied mechanical forces and the actual forces within the cell to better interpret the results of experimental studies.Statement of SignificanceIn this work, we created a computational model of the mechanical stretching of cell on a flexible membrane under cyclic mechanical loading. This model provides insight into the forces and displacements inside of cell that result from that application of stretch. As many experiments use this set up, our work is relevant to interpreting many studies that use mechanical stretch to stimulate mechanotransduction.
Pancreatic cancer cells exchange ribosomes through tunnelling nanotubes
Authors: Martínková Stanislava , Jansová Denisa , Vorel Jana , Lamačová Lucie Josefa , Daniel Petr , Hudec Michael , Boďo Mário , Hajer Jan , Susor Andrej , Trnka Jan 
Published: June 2024

ABSTRACTBackgroundPancreatic ductal adenocarcinoma (PDAC) is considered as one of the deadliest types of cancer. Tunnelling nanotubes (TNTs) are thin, membranous, intercellular communication structuresobserved in normal and cancer cells, where they mediate the exchange of intracellular material and promote cell fitness, cancer spread and treatment resistance.ResultsPDAC cells increase the formation of TNTs upon exposure to gemcitabine. In the PANC-1 cell line and in tumour explants from patients, we observe polyadenylated mRNA, 5.8S rRNA, ribosomal proteins and assembled 80S ribosomes within the TNTs. Using HaloTag-labelled small ribosomal subunit component RPS9 we demonstrate the transport of ribosomes via TNTs into acceptor cells.ConclusionsPDAC cells can exchange components of the translational machinery, including mRNA, which may contribute to the resistance to therapy, highlighting the potential of targeting TNT dynamics as a therapeutic approach for PDAC.Main pointspancreatic tumor cells from patient biopsies form tunnelling nanotubes in 2D cultureformation of tunnelling nanotubes is promoted by gemcitabinepolyadenylated mRNAs, ribosomal components and assembled ribosomes are present in tunnelling nanotubesribosomes or their components are transferred via nanotubes to acceptor cells
Malnutrition disrupts adaptive immunity during visceral leishmaniasis by enhancing IL-10 production
Authors: Sacramento Laís Amorim , Lombana Claudia , Scott Phillip 
Published: June 2024

AbstractProtein-energy malnutrition (PEM) is a risk factor for developing visceral leishmaniasis (VL). However, the impact on adaptive immunity during infection is unknown. To study the effect of malnutrition on chronic VL, we used a polynutrient-deficient diet (deficient protein, energy, zinc, and iron), which mimics moderate human malnutrition, followed byLeishmania infantuminfection. The polynutrient-deficient diet leads to growth stunting and reduced mass of visceral organs. Malnourished-infected mice harbored more parasites in the spleen and liver, had a reduced number of T lymphocytes, reduced production of IFN-γ by T cells, and exhibited enhanced IL-10 production. To test whether IL-10 blockade would lessen disease in the malnourished mice, we treated infected mice with monoclonal antibody α-IL-10R. α-IL-10R treatment reduced the parasite number of malnourished mice, restored the number of T cells producing IFN-γ, and enhanced hepatic granuloma formation. Our results indicate that malnutrition increases VL susceptibility due to a defective IFN-γ-mediated immunity attributable to increased IL-10 production.Author SummaryMalnutrition contributes to the development of VL. Despite the advances regarding this association, how malnutrition affects the adaptive immune mechanisms in VL is still unclear. We found that malnutrition disrupts the ability to control parasite replication in the spleen and liver in VL due to defective IFN-γ-mediated immunity, reduced hepatic granuloma formation, and enhanced IL-10 production. Blocking IL-10R signaling restored the protective mechanisms to control parasite replication in the malnourished mice without interfering with the undernutrition state. Thus, we demonstrate that malnutrition disrupts the adaptive immunity against VL due to an aberrant IL-10 production. Understanding the association between malnutrition and VL will provide insights into therapeutic approaches.
Defining cellular determinants of resistance to PD-1 pathway blockade in non-small-cell lung cancer
Authors: Liu Baolin , Feng Kaichao , Yu Kezhuo , Gao Ranran , Hu Xueda , Qin Boyu , Wang Jinliang , Xue Zhiqiang , Han Weidong , Zhang Zemin 
Published: June 2024

SummaryDespite sustained clinical responses to immune-checkpoint blockade (ICB) therapies in non-small-cell lung cancer (NSCLC), the majority of patients derive no clinical benefits, and the cellular and molecular underpinnings of such resistance remain incompletely understood. To identify cell types that may influence immunotherapy responses, we first integrated newly generated and previously published single-cell RNA sequencing data from 110 treatment-naïve patients with NSCLC. Among tumor-resident cell types, we identifiedMMP1+cancer-associated fibroblasts (CAFs), which were inversely correlated with the level of tumor-reactive T cells—a key determinant of response to ICB. Further single-cell analysis for newly collected 21 tumor samples from NSCLC patients treated with anti-PD-1/PD-L1 agents revealed thatMMP1+fibroblasts were indeed enriched in treatment-refractory patients, and this observation was also validated in an independent dataset of bulk RNA sequencing from 344 NSCLC patients treated with PD-L1 agents. Examination of the spatial architecture showed thatMMP1+fibroblasts were located at the tumor-stroma boundary, forming a single-cell layer that encircled the cancer cell aggregates, and we hence definedMMP1+fibroblasts as tumor-stroma boundary (tsb)CAFs. Such tsbCAFs likely promote resistance to ICB by functioning as a physical barrier that prevents tumor-reactive T cells from recognizing and killing cancer cells. Our study provides a new framework to identify cellular underpinnings of resistance to ICB and suggests new strategies to overcome ICB resistance.Highlights◊ Identification and characterization ofMMP1+fibroblasts in lung cancer.◊ Single-cell meta-analysis reveals cell populations impeding the accumulation of tumor-reactive T cells.◊MMP1+fibroblasts correlate with the low infiltration of tumor-reactive T cells and the resistance to anti-PD-1/PD-L1 treatment.◊MMP1+fibroblasts appear to form a space barrier between malignant and T cells.
Accounting for salmon body size declines in fishery management can reduce conservation risks
Authors: Ohlberger Jan , Schindler Daniel E. , Staton Benjamin A. 
Published: June 2024

ABSTRACTChanges in population demographic structure can have tangible but unknown effects on management effectiveness. Fishery management of Pacific salmon is often informed by estimates of the number of spawners expected to produce maximum sustainable yield (SMSY), which implicitly assumes that reproductive output per spawner does not change over time. However, many salmon populations have experienced long-term trends in age, sex, and length-at-age compositions that have resulted in smaller body sizes of mature fish. We present an empirically-based simulation approach for evaluating management implications of declining reproductive output that results from shifting demographics. We simulated populations with or without demographic trends, selective or unselective harvests, and harvest policies based on assessment methods that did or did not account for demographic trends when estimating SMSY. A management strategy evaluation showed that expected mean harvests and run sizes were reduced when populations exhibited negative demographic trends. Reduced abundances and increased conservation risks could be partially mitigated by using a stock-recruit analysis based on egg mass instead of spawner abundance, or by using a precautionary management strategy where target escapements were higher than the estimated SMSY, especially in fisheries that selectively removed large fish. Accounting for demographic trends in stock-recruit analyses resulted in up to 25% higher run sizes and up to 20% lower conservation risks compared to traditional methods when trends toward smaller, younger, and male-biased runs were present in the population. Conservation of population demographic structure may be critical for sustaining productive fish populations and their benefits to ecosystems and people.
Landscape and meteorological variables associated withAedes aegyptiandAedes albopictusmosquito infestation in two southeastern USA coastal cities
Authors: Costa-da-Silva Andre Luis , Dye-Braumuller Kyndall C , Wagner-Coello Helen Urpi , Li Huixuan , Johnson-Carson Danielle , Gunter Sarah M , Nolan Melissa S , DeGennaro Matthew 
Published: June 2024

AbstractAedestransmitted arboviral human cases are increasing worldwide and spreading to new areas of the United States of America (USA). These diseases continue to re-emerge likely due to changes in vector ecology, urbanization, human migration, and larger range of climatic suitability. Recent shifts in landscape and weather variables are predicted to impact the habitat patterns of urban mosquitoes such asAedes aegyptiandAedes albopictus. Miami (FL) is in the tropical zone and an established hotspot for arboviruses, while Charleston (SC) is in the humid subtropical zone and newly vulnerable. Although these coastal cities have distinct climates, both have hot summers. To understand mosquito infestation in both cities and potentiate our surveillance effort, we performed egg collections in the warmest season. We applied remote sensing with land-use cover and weather variation to identify mosquito infestation patterns. Our study found predominant occurrence ofAe. aegyptiand, to a lesser extent,Ae. albopictusin both cities. We detected statistically significant positive and negative associations between entomological indicators and most weather variables in combined data from both cities. For all entomological indices, weekly wind speed and relative humidity were significantly positively associated, while precipitation and maximum temperature were significantly negatively associated.Aedesegg abundance was significantly positively associated with open land in Charleston but was negatively associated with vegetation cover in combined data. There is a clear need for further observational studies to determine the impact of climate change onAe. aegyptiandAe. albopictusinfestation in the Southeastern region of the USA.
Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury
Authors: Hamilton Adam M. , Blackmer-Raynolds Lisa , Li Yaqing , Kelly Sean , Kebede Nardos , Williams Anna , Chang Jianjun , Garraway Sandra M. , Srinivasan Shanthi , Sampson Timothy R. 
Published: June 2024

AbstractSpinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.
CXIP4 depletion causes early lethality and pre-mRNA missplicing in Arabidopsis
Authors: Aceituno-Valenzuela Uri Israel , Fontcuberta-Cervera Sara , Micol-Ponce Rosa , Sarmiento-Mañús Raquel , Ruiz-Bayón Alejandro , Ponce María Rosa 
Published: June 2024

ABSTRACTZinc knuckle (ZCCHC) motif-containing proteins are present in unicellular and multicellular eukaryotes and most ZCCHC proteins with known functions participate in the metabolism of various classes of RNA, such as mRNAs, ribosomal RNAs, and microRNAs. The Arabidopsis (Arabidopsis thaliana) genome encodes 69 ZCCHC-containing proteins, but the functions of most remain unclear. One of these proteins is CAX-INTERACTING PROTEIN 4 (CXIP4), which has been classified as a PTHR31437 family member, along with human SREK1-interacting protein 1 (SREK1IP1), which is thought to function in pre-mRNA splicing and RNA methylation. Metazoan SREK1IP1-like and plant CXIP4-like proteins only share a ZCCHC motif, and their functions remain almost entirely unknown. We studied two loss-of-function alleles of ArabidopsisCXIP4, the first mutations in PTHR31437 family genes described to date:cxip4-1is likely null and shows early lethality, andcxip4-2is hypomorphic and viable, with pleiotropic morphological defects. Thecxip4-2mutant exhibited deregulation of defense genes and upregulation of transcription factor encoding genes, some of which might explain its developmental defects. This mutant also exhibited increased intron retention events, and the specific functions of misspliced genes, such as those involved in “gene silencing by DNA methylation” and “mRNA polyadenylation factor” suggest that CXIP4 has additional functions. The CXIP4 protein localizes to the nucleus in a pattern resembling nuclear speckles, which are rich in splicing factors. Therefore,CXIP4is required for plant survival and proper development, and mRNA maturation.
RNA-TorsionBERT: leveraging language models for RNA 3D torsion angles prediction
Authors: Bernard Clément , Postic Guillaume , Ghannay Sahar , Tahi Fariza 
Published: June 2024

Predicting the 3D structure of RNA is an ongoing challenge that has yet to be completely addressed despite continuous advancements. RNA 3D structures rely on distances between residues and base interactions but also backbone torsional angles. Knowing the torsional angles for each residue could help reconstruct its global folding, which is what we tackle in this work. This paper presents a novel approach for directly predicting RNA torsional angles from raw sequence data. Our method draws inspiration from the successful application of language models in various domains and adapts them to RNA. We have developed a language-based model, RNA-TorsionBERT, incorporating better sequential interactions for predicting RNA torsional and pseudo-torsional angles from the sequence only. Through extensive benchmarking, we demonstrate that our method improves the prediction of torsional angles compared to state-of-the-art methods. In addition, by using our predictive model, we have inferred a torsion angle-dependent scoring function, called RNA-Torsion-A, that replaces the true reference angles by our model prediction. We show that it accurately evaluates the quality of near-native predicted structures, in terms of RNA backbone torsion and pseudo-torsion angle values. Our work demonstrates promising results, suggesting the potential utility of language models in advancing RNA 3D structure prediction.The source code is freely available on the EvryRNA platform:https://evryrna.ibisc.univ-evry.fr/evryrna/RNA-TorsionBERT.
An atomistic model of myosin interacting heads motif dynamics and their modification by 2’-deoxy-ADP
Authors: Childers Matthew Carter , Geeves Michael A. , Regnier Michael 
Published: June 2024

AbstractThe contraction of striated muscle is driven by cycling myosin motor proteins embedded within the thick filaments of sarcomeres. In addition to cross-bridge cycling with actin, these myosin proteins can enter an inactive, sequestered state in which the globular S1 heads rest along the thick filament surface and are unable to perform motor activities. Structurally, this state is called the interacting heads motif (IHM) and is a critical conformational state of myosin that regulates muscle contractility and energy expenditure. Structural perturbation of the sequestered state via missense mutations can pathologically disrupt the mechanical performance of muscle tissue. Thus, the IHM state has become a target for therapeutic intervention. An ATP analogue called 2’-deoxy-ATP (dATP) is a potent myosin activator which destabilizes the IHM. Here we use molecular dynamics simulations to study the molecular mechanisms by which dATP modifies the structure and dynamics of myosin in a sequestered state. Simulations with IHM containing ADP.Pi in both nucleotide binding pockets revealed residual dynamics in an otherwise ‘inactive’ and ‘sequestered’ state of a motor protein. Replacement of ADP.Pi by dADP.Pi triggered a series of structural changes that modify the protein-protein interface that stabilizes the sequestered state, and changes to this interface were accompanied by allosteric changes in remote regions of the protein complex. A comparative analysis of these dynamics predicted new structural sites that may affect IHM stability.
Nanoporous Platinum Microelectrode Arrays for Neuroscience Applications
Authors: Winter-Hjelm Nicolai , Isdal Leik , Köllensperger Peter A. , Sandvig Axel , Sandvig Ioanna , Sikorski Pawel 
Published: June 2024

AbstractMicroelectrode arrays are invaluable tools for investigating the electrophysiological behaviour of neuronal networks with high spatiotemporal precision. In recent years, it has become increasingly common to functionalize such electrodes with highly porous platinum to increase their effective surface area, and hence their signal-to-noise ratio. Although such functionalization significantly improves the electrochemical performance of the electrodes, the impact of various electrode morphologies on biocompatibility and electrophysiological performance in cell cultures remains poorly understood. In this study, we introduce reproducible protocols for depositing highly porous platinum with varying morphologies on microelectrodes designed for neural cell cultures. We also evaluate the impact of morphology and electrode size on the signal-to-noise ratio in recordings from rat cortical neurons cultured on these electrodes. Our results indicate that electrodes with a uniform layer of highly nanoporous platinum offer the best trade-off between biocompatibility, electrochemical, and electrophysiological performance. While more microporous electrodes exhibited lower impedance, nanoporous electrodes detected higher extracellular signal amplitudes from neurons, suggesting reduced distance between perisomatic neuronal areas and the electrodes. Additionally, these nanoporous electrodes showed fewer thickness variations at their edges compared to the more porous electrodes. Such edges can be mechanically broken off during cell culturing and contribute to long-term cytotoxic effects, which is highly undesirable. We hope this work will contribute to better standardization in creating and utilizing nanoporous platinum microelectrodes for neuroscience applications. Improving the accessibility and reproducibility of this technology is crucial for enhancing the quality of electrophysiological data and advancing our understanding of neuronal network function and dysfunction.
TheCapicuaC1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein
Authors: Luck Cuyler , Jacobs Kyle A. , Okimoto Ross A. 
Published: June 2024

AbstractRearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation ofCICtarget genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.Significance StatementFusion oncogenes are neomorphic entities comprised of fractional coding sequences from two partner genes that have been inappropriately rearranged. The functional domains contributed by the partner genes shape the function of the resulting fusion. We use CIC::DUX4, a transcription factor fusion that drives an ultra-rare soft tissue sarcoma, to explore how preferential retention of a partner gene domain may influence the activity of the overall fusion. Our results indicate that the capicua C1 domain is retained in most CIC::DUX4 transcripts and is required for full activity of the CIC::DUX4 oncoprotein. We demonstrate that knowledge of where breakpoints occur and the resulting impact this has on the retention of functional domains can teach us about fusion behavior.