bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anesthetic-Binding Induced Motion of GABAAReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations
Authors: Nakata Shuya , Mori Yoshiharu , Tanaka Shigenori 
Published: March 2023

AbstractGeneral anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of γ-aminobutyric acid A (GABAA) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic-binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl−permeability of GABAAreceptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABAAreceptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABAAreceptors. The results showed large structural fluctuations in GABAAreceptors, correlations of motion between the amino-acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABAAreceptors.
Homoeologous non-reciprocal translocation explains a major QTL for seed lignin content in oilseed rape (Brassica napusL.)
Authors: Schilbert Hanna Marie , Holzenkamp Karin , Viehöver Prisca , Holtgräwe Daniela , Möllers Christian 
Published: March 2023

AbstractOilseed rape is a major oil crop and a valuable protein source for animal and human nutrition. Lignin is a non-digestible, major component of the seed coat with negative effect on sensory quality, bioavailability and usage of oilseed rape’s protein. Hence, seed lignin reduction is of economic and nutritional importance. In this study, the major QTL for reduced lignin content found on chromosome C05 in the DH population SGDH14 x Express 617 was further examined. SGDH14 had lower seed lignin content than Express 617. Harvested seeds from a F2 population of the same cross were additionally field tested and used for seed quality analysis. The F2 population showed a bimodal distribution for seed lignin content. F2 plants with low lignin content had thinner seed coats compared to high lignin lines. Both groups showed a dark seed colour with a slightly lighter colour in the low lignin group indicating that a low lignin content is not necessarily associated with yellow seed colour. Mapping of genomic long-reads from SGDH14 against the Express 617 genome assembly revealed a homoeologous non-reciprocal translocation (HNRT) in the confidence interval of the major QTL for lignin content. A homologous A05 region is duplicated and replaced the C05 region in SGDH14. As consequence several genes located in the C05 region were lost in SGDH14. Thus, a HNRT was identified in the major QTL region for reduced lignin content in the low lignin line SGDH14. The most promising candidate gene related to lignin biosynthesis on C05,PAL4, was deleted.Key messageA homoeologous non-reciprocal translocation was identified in the major QTL for seed lignin content in the low lignin line SGDH14. The lignin biosynthetic genePAL4was deleted.
Disequilibrium betweenBRCA1andBRCA2circular and messenger RNAs plays a role in breast cancer
Authors: Levacher C. , Viennot M. , Drouet A. , Beaussire L. , Coutant S. , Théry JC , Baert-Desurmont S. , Laé M. , Ruminy P. , Houdayer C. 
Published: March 2023

AbstractBreast cancer is a frequent disease for which the discovery of markers for early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops, produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated cotranscriptionally and backsplicing and linear splicing compete against each other. As mRNAs are key players in tumorigenesis, we hypothesize that a balance disruption between circRNAs and mRNAs could promote breast cancer. Hence, we developed an assay for a simultaneous study of circRNAs and mRNAs, called Splice and Expression Analyses by exon Ligation and High Throughput Sequencing (SEALigTHS). Following SEALigHTS validation forBRCA1andBRCA2, our hypothesis was tested using an independent research set of 95 pairs of tumour and adjacent normal breast tissues. On this research set, ratios ofBRCA1andBRCA2circRNAs/mRNAs were significantly lower in tumour breast tissue compared to normal tissue (p=1.6e-09 and p=4.4e-05 forBRCA1andBRCA2, respectively). Overall, we developed an innovative method to study linear and backsplicing, described the repertoire ofBRCA1andBRCA2circRNAs, including 10 novel ones, and showed for the first time that a disequilibrium betweenBRCA1andBRCA2circRNAs and mRNAs plays a role in breast cancer.
The effects of artificial light at night (ALAN) on the gaping activity and feeding of mussels
Authors: Christoforou Eleni , Dominoni Davide , Lindström Jan , Diamantopoulou Christina , Czyzewski Jakub , Mirzai Nosrat , Spatharis Sofie 
Published: March 2023

AbstractArtificial light at night (ALAN) is one of the most widespread forms of environmental pollution. Studies on terrestrial organisms have shown that the effects of ALAN can be pervasive, and importantly, can depend on the colour (i.e., wavelength) of light. ALAN also affects marine environments as it is present in more than 22% of the world’s coastlines and can reach depths of up to 100m. However, the impact of different colour ALAN on coastal marine organisms is under-investigated. In this study, we tested the effects of different ALAN colours onMytilus edulis, a widespread coastal bivalve known for its high phytoplankton clearance capacity amongst other valuable ecosystem services. Using a lab-based valvometry system, we recorded the impact of red, green, and white ALAN on gaping activity patterns and phytoplankton clearance capacity of individual mussels and compared these to dark night control. Mussels exhibited a semi-diel activity pattern in both proportion of time open and gaping frequency. Although ALAN did not have significant effects on the proportion of time open it did significantly affect the gaping frequency. This effect was colour-specific with red and white ALAN resulting in lower activity compared to the dark night control but there were no effects on the phytoplankton consumption. Under green light, however, mussels showed a higher gaping frequency and reduced phytoplankton consumption with increasing time spent open compared to the other ALAN treatments and the dark control. Our findings suggest that ALAN does have colour-specific effects on mussels and indicate the importance of further investigating the physiological mechanisms behind these patterns, and their potential ecological consequences.
OptEnvelope: a target point guided method for growth-coupled production using knockouts
Authors: Motamedian Ehsan , Berzins Kristaps , Muiznieks Reinis , Stalidzans Egils 
Published: March 2023

AbstractFinding the best knockout strategy for coupling biomass growth and production of a target metabolite using a metabolic model is a challenge in biotechnology. In this research, a three-step method named OptEnvelope is developed based on finding minimal active reactions for a target point in the feasible solution space using a mixed-integer linear programming formula. The method initially finds the reduced desirable solution space (envelope) in the product versus biomass plot by removing all inactive reactions. Then, with reinsertion of the deleted reactions, OptEnvelope attempts to reduce the number of knockouts so that the desirable envelope is preserved. Additionally, OptEnvelope searches for envelopes with higher minimum production rates or fewer knockouts by evaluating different target points within the desired solution space. It is possible to limit the maximal number of knockouts. The method was implemented on metabolic models ofE. coliandS. cerevisiaeto test the method benchmarking the capability of these industrial microbes for overproduction of acetate and glycerol under aerobic conditions and succinate and ethanol under anaerobic conditions. The results indicate thatE. coliis more appropriate to produce acetate and succinate whileS. cerevisiaeis a better host for glycerol production. Gene deletions for some of the proposed reaction knockouts have been previously reported to increase the production of these metabolites in experiments. Both organisms are suitable for ethanol production, however, more knockouts for the adaptation ofE. coliare required. OptEnvelope is available athttps://github.com/lv-csbg/optEnvelope.
Ship-to-Shore Training for Active Deep-Sea Capacity Development
Authors: Barnhill Kelsey Archer , Vinha Beatriz , Smith Alycia J. , de Jonge Daniëlle S.W. , Gaurisas Daniela Y. , Segura Roger Mocholí , Madureira Pedro , Albuquerque Mónica , Huvenne Veerle A.I. , Orejas Covadonga , Gunn Vikki 
Published: March 2023

AbstractSailing on scientific expeditions as an early career researcher (ECR) offers the beneficial opportunity to gain field experience and training. However, the number of available berths to achieve the scientific goals of an expedition limits the number of onboard participants. Telepresence and remote learning can be utilised to increase the number of active participants, broadening the reach of capacity development. The 2021 iMirabilis2 expedition on board the Spanish Research VesselSarmiento de Gamboaused telepresence to virtually involve ECRs from several countries in deep-sea science. One year post-expedition, a survey of onshore participants was conducted to assess and quantify the effectiveness of the peer-to-peer ECR ship-to-shore scheme. During the expedition, live, interactive training via WhatsApp and Zoom was utilised by onshore ECRs more than traditional static, uni-directional methods of blog posts and pre-recorded videos. All respondents either agreed or strongly agreed that the scheme provided an inclusive and accessible platform to share deep-sea science. These results suggest similar schemes could be used to supplement shorter duration at-sea-training, used prior to a seagoing experience to better prepare ECRs, or to allow members of the science community unable to join an expedition in person to actively participate remotely, increasing inclusivity.
Neural manifolds and learning regimes in neural-interface tasks
Authors: Payeur Alexandre , Orsborn Amy L. , Lajoie Guillaume 
Published: March 2023

AbstractNeural activity tends to reside on manifolds whose dimension is lower than the dimension of the whole neural state space. Experiments using brain-computer interfaces (BCIs) with microelectrode arrays implanted in the motor cortex of nonhuman primates have provided ways to test whether neural manifolds influence learning-related neural computations. Starting from a learned BCI-controlled motor task, these experiments explored the effect of changing the BCI decoder to implement perturbations that were either “aligned” or not with the pre-existing neural manifold. In a series of studies, researchers found that within-manifold perturbations (WMPs) evoked fast reassociations of existing neural patterns for rapid adaptation, while outside-manifold perturbations (OMPs) triggered a slower adaptation process that led to the emergence of new neural patterns. Together, these findings have been interpreted as suggesting that these different rates of adaptation might be associated with distinct learning mechanisms. Here, we investigated whether gradient-descent learning could alone explain these differences. Using an idealized model that captures the fixed-point dynamics of recurrent neural networks, we uncovered gradient-based learning dynamics consistent with experimental findings. Crucially, this experimental match arose only when the network was initialized in a lazier learning regime, a concept inherited from deep learning theory. A lazy learning regime—in contrast with a rich regime—implies small changes on synaptic strengths throughout learning. For OMPs, these small changes were less effective at increasing performance and could lead to unstable adaptation with a heightened sensitivity to learning rates. For WMPs, they helped reproduce the reassociation mechanism on short adaptation time scales, especially with large input variances. Since gradient descent has many biologically plausible variants, our findings establish lazy gradient-based learning as a plausible mechanism for adaptation under network-level constraints and unify several experimental results from the literature.
Data-Driven Mathematical Approach for Removing Rare Features in Zero-Inflated Datasets
Authors: Ortiz-Velez Adrian N , Kelley Scott T 
Published: March 2023

AbstractSparse feature tables, in which many features are present in very few samples, are common in big biological data (e.g., metagenomics, transcriptomics). Ignoring the problem of zero-inflation can result in biased statistical estimates and decrease power in downstream analyses. Zeros are also a particular issue for compositional data analysis using log-ratios since the log of zero is undefined. Researchers typically deal with zero-inflated data by removing low frequency features, but the thresholds for removal differ markedly between studies with little or no justification. Here, we present CurvCut, a data-driven mathematical approach to zero-inflated feature removal based on curvature analysis of a “ball rolling down a hill”, where the hill is a histogram of feature distribution. These histograms typically contain a point of regime change, a discontinuity with a sharp change in the characteristics of the distribution, that can be used as a cutoff point for low frequency feature removal that considers the data-specific nature of the feature distribution. Our results show that CurvCut works well across a variety of biological data types, including ones with both right- and left-skewed feature distributions, and rapidly generates clear visual results allowing researchers to select data-appropriate cutoffs for feature removal.
IL-15 promotes inflammatory Th17 cells in the intestine
Authors: Golob Jonathan G. , Hou Guoqing , Lee Allen , Grassberger Helmut , Berinstein Elliott M , Zataari Mohamed El , Khaykin Valerie , Fry Christopher , Berinstein Jeff B. , Nemzek Jean , Kamada Nobuhiko , Kao John Y , Bishu Shrinivas 
Published: March 2023

ABSTRACTUlcerative Colitis (UC) is a chronic gastrointestinal condition with high morbidity. While modern medical therapies have revolutionized the care of UC, 10-25% of patients fail medications and still progress to surgery. Thus, developing new treatments is a core problem in UC. T-cells, especially Th17 cells, are strongly linked with UC and are major targets of medications in UC. Tissue-resident memory T-cells (TRM) are a distinct class of T-cells that are highly enriched in the intestine, closely aligned with the microbiota, and are implicated in the pathogenesis of UC. Unlike circulating T-cells, TRMare difficult to target because they do not recirculate. Thus, we focused on cytokines like IL-15 which act as a tissue danger signal and regulate T-cellsin situ. We found that theIL15axis is upregulated in UC and predicts treatment response. IL-15 was redundant for Th17 differentiation but could activate terminally differentiated Th17 cells to promote intestinal inflammation. Finally, in CD4+TRMfrom patients with UC, IL-15 upregulatedRORC, the master transcription factor for Th17 cells, via a Janus Kinase (JAK)1 pathway. Thus, IL-15 promotes terminally differentiated inflammatory Th17 cells in the intestine raising the possibility that IL-15 may be a target for UC treatments.
Antibody targeting of aging damaged isoDGR-proteins doubles lifespan in a mouse model of chronic inflammation
Authors: Kalailingam Pazhanichamy , Mohd-Kahliab Khalilatul-Hanisah , Ngan SoFong Cam , Iyappan Ranjith , Melekh Evelin , Lu Tian , Zien Gan Wei , Sharma Bhargy , Guo Tiannan , MacNeil Adam J. , Macpherson Rebecca E. K. , Tsiani Evangelia Litsa , O’Leary Deborah D. , Lim Kah Leong , Su I Hsin , Gao Yong-Gui , Richard A Mark , Kalaria Raj N. , Chen Christopher P. , McCarthy Neil E. , Sze Siu Kwan 
Published: March 2023

ABSTRACTAging is the result of the accumulation of molecular damages that impair normal biochemical activities. We previously reported that aging-damaged amino acid sequence NGR (Asn-Gly-Arg) results in a ‘gain-of-function’ conformational switching to isoDGR (isoAsp-Gly-Arg) motif. This integrin-binding motif activates leukocytes to induce chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy doubles lifespan in mouse model of chronic inflammation. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-KO and old WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1mg/kg) was sufficient to significantly reduce isoDGR-modified proteins and pro-inflammatory cytokine expression, improve behaviour and coordination, and double the average lifespan of Pcmt1-KO mice. Mechanistically, isoDGR-mAb mediated the immune clearance of damaged isoDGR-proteins by antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting aging-damaged proteins may represent effective interventions for a range of age-linked degenerative disorders.Graphical AbstractAnti-isoDGR immunotherapy induces immune clearance of aging damaged isoDGR-proteins to reduce chronic inflammation, improve behaviour and coordination, and double lifespan in PCMT-/-mice.
Benchmarking large language models for genomic knowledge with GeneTuring
Authors: Hou Wenpin , Shang Xinyi , Ji Zhicheng 
Published: March 2023

ABSTRACTLarge language models have demonstrated great potential in biomedical research. However, their ability to serve as a knowledge base for genomic research remains unknown. We developed GeneTuring, a comprehensive Q&A database containing 1,200 questions in genomics, and manually scored 25,200 answers provided by six GPT models, including GPT-4o, Claude 3.5, and Gemini Advanced. GPT-4o with web access showed the best overall performance and excelled in most tasks. However, it still failed to correctly answer all questions and may not be fully reliable for providing answers to genomic inquiries.
Characterization of extracellular matrix deposited by segmental trabecular meshwork cells
Authors: Raghunathan VijayKrishna , Nartey Andrews , Dhamodaran Kamesh , Baidouri Hasna , Staverosky Julia A. , Keller Kate E , Zientek Keith , Reddy Ashok , Acott Ted , Vranka Janice A 
Published: March 2023

ABSTRACTBiophysical and biochemical attributes of the extracellular matrix are major determinants of cell fate in homeostasis and disease. Ocular hypertension and glaucoma are diseases where the trabecular meshwork tissue responsible for aqueous humor egress becomes stiffer accompanied by changes in its matrisome in a segmental manner with regions of high or low flow. Prior studies demonstrate these alterations in the matrix are dynamic in response to age and pressure changes. The underlying reason for segmentation or differential response to pressure and stiffening are unknown. This is largely due to a lack of appropriate models (in vitroorex vivo) to study this phenomena. In this study, we characterize the biomechanical attributes, matrisome, and incidence of crosslinks in the matrix deposited by primary cells isolated from segmental flow regions and when treated with glucocorticosteroid. Data demonstrate that matrix deposited by cells from low flow regions are stiffer and exhibit a greater number of immature and mature crosslinks, and that these are exacerbated in the presence of steroid. We also show a differential response of high or low flow cells to steroid via changes observed in the matrix composition. We conclude that although a mechanistic basis for matrix stiffness was undetermined in this study, it is a viable tool to study cell-matrix interactions and further our understanding of trabecular meshwork pathobiology.
The analytical Flory random coil is a simple-to-use reference model for unfolded and disordered proteins
Authors: Alston Jhullian J. , Ginell Garrett M. , Soranno Andrea , Holehouse Alex S. 
Published: March 2023

ABSTRACTDenatured, unfolded, and intrinsically disordered proteins (collectively referred to here as unfolded proteins) can be described using analytical polymer models. These models capture various polymeric properties and can be fit to simulation results or experimental data. However, the model parameters commonly require users’ decisions, making them useful for data interpretation but less clearly applicable as stand-alone reference models. Here we use all-atom simulations of polypeptides in conjunction with polymer scaling theory to parameterize an analytical model of unfolded polypeptides that behave as ideal chains (ν = 0.50). The model, which we call the analytical Flory Random Coil (AFRC), requires only the amino acid sequence as input and provides direct access to probability distributions of global and local conformational order parameters. The model defines a specific reference state to which experimental and computational results can be compared and normalized. As a proof-of-concept, we use the AFRC to identify sequence-specific intramolecular interactions in simulations of disordered proteins. We also use the AFRC to contextualize a curated set of 145 different radii of gyration obtained from previously published small-angle X-ray scattering experiments of disordered proteins. The AFRC is implemented as a stand-alone software package and is also available via a Google colab notebook. In summary, the AFRC provides a simple-to-use reference polymer model that can guide intuition and aid in interpreting experimental or simulation results.
Cortical changes during the learning of sequences of simultaneous finger presses
Authors: Garzón Benjamín , Helms Gunther , Olsson Hampus , Brozzoli Claudio , Ullén Fredrik , Diedrichsen Jörn , Lövdén Martin 
Published: March 2023

AbstractThe cortical alterations underpinning the acquisition of motor skills remain debated. In this longitudinal study in younger adults, we acquired performance and neuroimaging (7T MRI) measures weekly over the course of 6 weeks to investigate neural changes associated with learning sequences of simultaneous finger presses executed with the non-dominant hand. Both the intervention group (n= 33) and the control group (n= 30) showed general performance improvements, but performance improved more and became more consistent for sequences that were intensively trained by the intervention group, relative to those that were not. Brain activity for trained sequences decreased compared with untrained sequences in the bilateral parietal and premotor cortices. No training-related changes in the primary sensorimotor areas were detected. The similarity of activation patterns between trained and untrained sequences decreased in secondary, but not primary, sensorimotor areas, while the similarity of the activation patterns between different trained sequences did not show reliable changes. Neither the variability of activation patterns across trials, nor the estimates of brain structure displayed practice-related changes that reached statistical significance. Overall, the main correlate of learning configural sequences was a reduction in brain activity in secondary motor areas.