bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using graph-based model to identify cell specific synthetic lethal effects
Authors: Pu Mengchen , Cheng Kaiyang , Li Xiaorong , Xin Yucui , Wei Lanying , Jin Sutong , Zheng Weisheng , Peng Gongxin , Tang Qihong , Zhou Jielong , Zhang Yingsheng 
Published: July 2023

ABSTRACTSynthetic lethal (SL) pairs are pairs of genes whose simultaneous loss-of-function results in cell death, while a damaging mutation of either gene alone does not affect the cell’s survival. This makes SL pairs attractive targets for precision cancer therapies, as targeting the unimpaired gene of the SL pair can selectively kill cancer cells that already harbor the impaired gene. Limited by the difficulty of finding true SL pairs, especially on specific cell types, the identification of SL targets still relies on expensive, time-consuming experimental approaches. In this work, we utilized various cell-line specific omics data to design a deep learning model for predicting SL pairs on particular cell-lines. By incorporating multiple types of cell-specific omics data with a self-attention module, we represent gene relationships as graphs. Our approach demonstrates the potential to facilitate the discovery of cell-specific SL targets for cancer therapeutics, providing a tool to unearth mechanisms underlying the origin of SL in cancer biology. Our approach allows for prediction of SL pairs in a cell-specific manner and enhances cancer precision medicine. The code and data of our approach can be found athttps://github.com/promethiume/SLwiseHighlightsFew computational methods can systematically predict SL pairs at a cell-specific level, and their performance may not generalize well to clinical scenarios due to the heterogeneity of cancer types.The SLWise utilizes various cell-line specific omics data to design a deep learning model with a graph-based representation and self-attention mechanism.This approach allows for the prediction of SL pairs in a cell-specific manner, providing valuable insights on effectively identifying the cell-type specific SL targets for personalized treatment strategies.
M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain
Authors: Sharples Simon A. , Broadhead Matthew J. , Gray James A. , Miles Gareth B. 
Published: July 2023

AbstractThe size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage-sensitive ion channels that create non-linearities in their input-output functions. Here we describe a role for the M-type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole-cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M-currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the expression of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed-firing motoneurons afforded a greater proportion of the total M-current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M-currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M-type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage-sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force.Key PointsM-currents exert an inhibitory influence on spinal motor output.This inhibitory influence is exerted by controlling the recruitment, but not the firing rate, of high-threshold fast-like motoneurons, with limited influence on low-threshold slow-like motoneurons.Preferential control of fast motoneurons may be linked to a larger M-current that is activated within the subthreshold voltage range compared to slow motoneurons.Larger M-currents in fast compared to slow motoneurons are not accounted for by differences in Kv7.2 or Kv7.3 channel composition.The orderly recruitment of motoneuron subtypes is shaped by differences in the contribution of voltage-gated ion channels, including KCNQ channels.KCNQ channels may provide a target to dynamically modulate the recruitment gain across the motor pool and readily adjust movement vigour.
Protein Assembly Modulation: A New Approach to ALS Therapeutics
Authors: feng Yu Shao , Paulvannan Kumar , Solas Dennis , Lingappa Anuradha F. , Moreira Ana Raquel , Sahu Shriya , Michon Maya , Goldsmith Danielle , DeYarman Nicholas , Mallesh Suguna , Prasad M. Dharma , Maios Claudia , Ruan Kai , Tomassy Giulio S. , Jensen Elizabeth , McGuirk Emma , Bader Verian , Mueller-Schiffmann Andreas , Reed Jonathan C. , Lingappa Jaisri R. , Asundi Vinod , Hong Shi , Jacobsen Steve , Ostrow Lyle , Lloyd Tom , Parker Alex , Staats Kim A. , Ichida Justin , Dodge James , Dey Debendranath , Korth Carsten , Selvarajah Suganya , Lingappa Vishwanath R. , Rosenfeld Jeffrey 
Published: July 2023

AbstractAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.
Solar Induced Fluorescence Retrieved from Avocado (Persea americanaMill.) Canopies Along the Season Correlates with Sugar Levels in the Developing Fruit
Authors: Vitrack-Tamam S. , Yasour H. , Hamus-Cohen D. , Erel R. , Rubinovich L. , Liran O. 
Published: July 2023

AbstractSolar Induced Fluorescence (SIF) emitted from the photosynthetic apparatus is related indirectly to biomass production. It can be remotely sensed from airborne platforms, yet, the spatial resolution from satellites, for example, is too low for commercial agricultural uses. We used a non-imager point spectroradiometer mounted on SIF-UAV (Unmanned Aerial Vehicle) system, and retrieved SIF at high spatial resolution, which is fitted for precision agriculture applications. In this study, we tracked the spatial variation of SIF along the season over a commercial avocado (P. americana Mill) orchard. The retrieved SIF signals were Krieg-interpolated to create a continuous SIF layer that allowed the estimation of SIF values for each tree in the orchard. We show that the SIF signal retrieved over the canopies in the main fruit development stage is highly correlated with the levels of sugars accumulated in the ripening avocado fruit. It established the foundations for high-spatial resolution detection of the natural variation of photosynthesis activity, which may lead to in-season adjustments of agronomic inputs using precision agriculture technologies.
Revisiting structural organization of proteins at high temperature from network perspective
Authors: Hait Suman , Kundu Sudip 
Published: July 2023

ABSTRACTInteractions between distantly placed amino acids in the primary chain (long-range) play a very crucial role in the formation and stabilization of the tertiary structure of a protein, while interactions between closely placed amino acids in the primary chain (short-range) mostly stabilize the secondary structures. Every protein needs to maintain marginal stability in order to perform its physiological functions in its native environment. The requirements for this stability in mesophilic and thermophilic proteins are different. Thermophilic proteins need to form more interactions as well as more stable interactions to survive in the extreme environment, they live in. Here, we aim to find out how the interacting amino acids in three-dimensional space are positioned in the primary chains in thermophilic and mesophilic. How does this arrangement help thermophiles to maintain their structural integrity at high temperatures? Working on a dataset of 1560 orthologous pairs we perceive that thermophiles are not only enriched with long-range interactions, they feature bigger connected clusters and higher network densities compared to their mesophilic orthologs, at higher interaction strengths between the amino acids. Moreover, we have observed the enrichment of different types of interactions at different secondary structural regions.
Interpersonal heart rate synchrony predicts effective information processing in a naturalistic group decision-making task
Authors: Sharika K. M. , Thaikkandi Swarag , Nivedita  , Platt Michael L. 
Published: July 2023

AbstractGroups often outperform individuals in problem-solving. Nevertheless, failure to critically evaluate ideas risks sub-optimal outcomes through so-calledgroupthink. Prior studies have shown that people who hold shared goals, perspectives or understanding of the environment show similar patterns of brain activity, which itself can be enhanced by consensus building discussions. Whether shared arousal alone can predict collective decision-making outcomes, however, remains unknown. To address this gap, we computed interpersonal heart rate synchrony, a peripheral index of shared arousal associated with joint attention, empathic accuracy and group cohesion, in 44 groups (n=204) performing a collective decision-making task. The task required critical examination of all available information to override inferior, default options and make the right choice. Using multi-dimensional recurrence quantification analysis (MdRQA) and machine learning, we found that heart rate synchrony predicted the probability of groups reaching the correct consensus decision with greater than 70% cross-validation accuracy—significantly higher than that predicted by the duration of discussions, subjective assessment of team function or baseline heart rates alone. We propose that heart rate synchrony during group discussion provides a biomarker of interpersonal engagement that facilitates adaptive learning and effective information sharing during collective decision-making.
Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model
Authors: Han Han V. , Efem Richard , Rosati Barbara , Lu Kevin , Maimouni Sara , Jiang Ya-Ping , Montoya Valeria , Van Der Velden Adrianus W. M. , Zong Wei-Xing , Lin Richard Z. 
Published: July 2023

ABSTRACTMost human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation ofPik3cain KPC (KrasG12D;Trp53R172H;Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation ofPik3ca-/-KPC (named αKO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted anin vivogenome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally expanded CD8+T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally expanded T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate thatPccbcan modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
Coding dynamics of the striatal networks during learning
Authors: Villet Maxime , Reynaud-Bouret Patricia , Poitreau Julien , Baldi Jacopo , Jaffard Sophie , James Ashwin , Muzy Alexandre , Sargolini Francesca , Bethus Ingrid 
Published: July 2023

AbstractThe rat dorsomedial (DMS) and dorsolateral striatum (DMS), equivalent to caudate nucleus and putamen in primates, are generally required for goal-directed and habit behaviour, respectively. However, it is still unclear whether and how this functional dychotomy emerges in the course of learning. In this study we investigated this issue by recording DMS and DLS single neuron activity in rats performing a continuous spatial alternation task, from the acquisition to optimized performance. We first applied a classical analytical approach to identify task-related activity based on the modifications of single neuron firing rate in relation to specific task events or maze trajectories. We then used an innovative approach based on Hawkes process to reconstruct a directed connectivity graph of simultaneously recorded neurons, that was used to decode animal behavior. This approach enabled us to better unravel the role of DMS and DLS neural networks across learning stages. We showed that DMS and DLS display different task-related activity throughout learning stages, and the proportion of coding neurons over time decreases in the DMS and increases in the DLS. Despite theses major differences, the decoding power of both networks increases during learning. These results suggest that DMS and DLS neural networks gradually reorganize in different ways in order to progressively increase their control over the behavioral performance.
The influence of carbon dioxide on cerebral metabolism and oxygen consumption: combining multimodal monitoring with dynamic systems modelling
Authors: Highton David , Caldwell Matthew , Tachtsidis Ilias , Elwell Clare E , Smith Martin , Cooper Chris E 
Published: July 2023

ABSTRACTHypercapnia increases cerebral blood flow, but the effect on cerebral metabolism in humans remains incompletely understood. Either increased or reduced oxygen consumption has been predicted from Fick models incorporating cerebral oxygen extraction fraction and cerebral blood flow. Hypercapnia also results in oxidation of cytochromecoxidase, complex IV of the mitochondrial respiratory chain, implicating a change in cellular metabolism. The aim of this study was to combine systems modelling with non-invasive measurements of cerebral tissue oxygenation, cerebral blood flow, and cytochromecoxidase redox state to evaluate any metabolic effects of hypercapnia. Cerebral tissue oxygen saturation and cytochrome oxidase redox state were measured with broadband near infrared spectroscopy and cerebral blood flow velocity using transcranial Doppler ultrasound. Data collected during 5-minutes hypercapnia in human volunteers were analyzed using a Fick model to determine changes in brain oxygen consumption and a mathematical model of cerebral hemodynamics and metabolism (BrainSignals) to inform on the potential mechanisms of any observed changes. Systemic physiology - blood pressure, arterial oxygen saturations and end-tidal carbon dioxide - served as model inputs. The extent of the hypercapnic oxidation of cytochrome oxidase required modifications of the BrainSignals model; simulations compared two possible modifications that could cause this oxidation - adecreasein metabolic substrate supply or anincreasein metabolic demand. Only the decrease in substrate supply was able to explain both the enzyme redox state changes and the Fick calculated drop in brain oxygen consumption. These modelled outputs are consistent with, but do not prove, previous reports of CO2inhibition of succinate dehydrogenase, complex II of the mitochondrial respiratory chain. These findings suggest that hypercapnia may have physiologically significant effects suppressing oxidative metabolism in humans and perturbing mitochondrial signaling pathways in health and disease.
Nonlinear fusion is optimal for a wide class of multisensory tasks
Authors: Ghosh Marcus , Béna Gabriel , Bormuth Volker , Goodman Dan F. M. 
Published: July 2023

AbstractAnimals continuously detect information via multiple sensory channels, like vision and hearing, and integrate these signals to realise faster and more accurate decisions; a fundamental neural computation known as multisensory integration. A widespread view of this process is that multimodal neurons linearly fuse information across sensory channels. However, does linear fusion generalise beyond the classical tasks used to explore multisensory integration? Here, we develop novel multisensory tasks, which focus on the underlying statistical relationships between channels, and deploy models at three levels of abstraction: from probabilistic ideal observers to artificial and spiking neural networks. Using these models, we demonstrate that when information provided by different channels is not independent, linear fusion performs sub-optimally and even fails in extreme cases. This leads us to propose a simple nonlinear algorithm for multisensory integration which is compatible with our current knowledge of multimodal circuits, excels in naturalistic settings and is optimal for a wide class of multisensory tasks. Thus, our work emphasises the role of nonlinear fusion in multisensory integration, and provides testable hypotheses for the field to explore at multiple levels: from single neurons to behaviour.Key PointsWe introduce a novel set of tasks, based on comodulating the signals from multiple channels.We show that linear fusion performs sub-optimally on these tasks and even fails in extreme cases.In contrast,nonlinear fusionis optimal and excels in naturalistic settings, like predator-prey interactions.We demonstrate that networks of spiking neurons approximate the behaviour of this nonlinear algorithm, when trained on these tasks.Finally, we explore how single neuron properties allow networks to approximate nonlinear fusion.
Estimating foraging behavior in rodents using a modified paradigm measuring threat imminence dynamics
Authors: Meng Xianzong , Chen Ping , Veltien Andor , Palavra Tony , Veld Sjors In’t , Grandjean Joanes , Homberg Judith R 
Published: July 2023

SummaryAnimals display defensive behaviors in response to threats to avoid danger and approach rewards. In nature, these responses did not evolve alone but are always accompanied by motivational conflict. A semi-naturalistic threat imminence continuum model models the approach-avoidance conflict and is able to integrate multiple defensive behaviors into a single paradigm. However, its comprehensive application is hampered by the lack of a detailed protocol and data about some fundamental factors including sex, age, and motivational level. Here, we modified a previously established paradigm measuring threat imminence continuum dynamics, involving modifications of training and testing protocols, and utilization of commercial materials combined with open science codes, making it more standardized and easier to replicate. We demonstrate that foraging behavior is modulated by age, hunger level, and sex. This paradigm can be used to study defensive behaviors in animals in a more naturalistic manner with relevance to human approach-avoid conflicts and associated psychopathologies.HighlightsWe provide detailed guidance for setting up a modified paradigm for the threat imminence continuum model with commercial materials and open-source codes.We propose a modified paradigm for the threat imminence continuum model to quantify foraging behaviors.Our method enables comparison between groups as a function of multiple factors including age and food restriction.Graphic Summary
A host shift as the origin of tomato bacterial canker caused byClavibacter michiganensis
Authors: Yañez-Olvera Alan G. , Gómez-Díaz Ámbar G. , Selem-Mojica Nelly , Rodríguez-Orduña Lorena , Lara-Ávila José Pablo , Varni Vanina , Alcoba Florencia , Croce Valentina , Siri María Inés ,   Clavibacter Consortium, Barona-Gómez Francisco 
Published: July 2023

AbstractClavibacter, a plant endophytic actinobacterial genus, includes phytopathogens with devasting effects on several crops.C. michiganensis, the seed-borne and causal agent of bacterial canker in tomato, is arguably the most notorious species of the genus. Yet, its origin and natural reservoirs remain elusive. Moreover,C. michiganensispopulations show different genetic pathogenicity profiles with equally unpredictable plant disease outcomes. To tackle these uncertainties, here we analyze genomic data generated during a decade-long survey ofClavibacterin wild and commercial tomato cultivars, providing evolutionary insights that informed on the pathogenicity of this phytopathogen. Unexpectedly, our phylogeny situate the last common ancestor ofC. michiganensisnext toClavibacterisolates from grasses rather than to the sole strain we could isolate from wild tomato, which is closer toC. capsiciassociated with pepper. Pathogenicity profiling of selectedC. michiganensisisolates, together withC. phaseoliandC. californiensisas sister taxa of the grass clade, and the newly isolatedC. capsicifrom wild tomato, was found to be congruent with the proposed phylogenetic relationships. Furthermore, we identified gene enrichment after an evolutionary bottleneck leading to the appearance ofC. michiganesis, including known pathogenicity factors but also hitherto unnoticed genes with such potential,i.e.,nutrient acquisition and specialized metabolite metabolic gene clusters. The holistic perspective provided by our long-term and in-depth analyses hints towards a host shift event as the origin of the causative agent of bacterial canker in tomato, leading to a complex ofC. michiganensiswith pathogenicity factors that remain to be characterized.