bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Motor Adaptation via Population-level Modulation of Cerebellar Error Signals
Authors: Nguyen Vinh , Stell Brandon M. 
Published: January 2024

AbstractA core principle of cerebellar learning theories is that climbing fibers from the inferior olive convey error signals about movement execution to Purkinje cells in the cerebellar cortex. These inputs trigger synaptic changes which are purported to drive progressive adjustment of future movements. Individually, binary complex spike signals lack information about the sign and magnitude of errors which presents a problem for cerebellar learning paradigms exhibiting fast adaptation. Using a newly developed behavioral paradigm in mice, we introduced sensorimotor perturbations into a simple joystick pulling behavior and found parasagittal bands of Purkinje cells with reciprocal modulation of complex spike activity. Whereas complex spiking showed little modulation in the unperturbed condition, alternating bands were activated or inhibited when the perturbation was introduced, and this modulation encoded the sign and magnitude of the resulting sensorimotor mismatch. These findings provide an important piece of information for the understanding of cerebellar learning that helps to explain how the cerebellum could use supervised learning to quickly adapt motor behavior in response to perturbations.One-Sentence SummaryPopulations of Purkinje cells in the cerebellum facilitate trial-by-trial movement refinement by converting binary signals from movement errors into graded signals that encode the error’s direction and magnitude.
Cell-cycle dependent DNA repair and replication unifies patterns of chromosome instability
Authors: Lu Bingxin , Winnall Samuel , Cross William , Barnes Chris P. 
Published: January 2024

AbstractChromosomal instability (CIN) is pervasive in human tumours and often leads to structural or numerical chromosomal aberrations. Somatic structural variants (SVs) are intimately related to copy number alterations but the two types of variant are often studied independently. In addition, despite numerous studies on detecting various SV patterns, there are still no general quantitative models of SV generation. To address this issue, we develop a computational cell-cycle model for the generation of SVs from end-joining repair and replication after double strand break formation. Our model provides quantitative information on the relationship between breakage fusion bridge cycle, chromothripsis, seismic amplification, and extra-chromosomal circular DNA. Given single-cell whole-genome sequencing data, the model also allows us to infer important parameters in SV generation with Bayesian inference. Our quantitative framework unifies disparate genomic patterns resulted from CIN, provides a null mutational model for SV, and reveals new insights into the impact of genome rearrangement on tumour evolution.
VLP-Based Model for Study of Airborne Viral Pathogens
Authors: Caffrey Michael , Jayakumar Nitin , Caffrey Veronique , Anirudan Varada , Rong Lijun , Paprotny Igor 
Published: January 2024

AbstractThe recent COVID-19 pandemic has underscored the danger of airborne viral pathogens. The lack of model systems to study airborne pathogens limits the understanding of airborne pathogen distribution, as well as potential surveillance and mitigation strategies. In this work, we develop a novel model system to study airborne pathogens using virus like particles (VLP). Specifically, we demonstrate the ability to aerosolize VLP and detect and quantify aerosolized VLP RNA by Reverse Transcription-Loop-Mediated Isothermal Amplification (RT-LAMP) in real-time fluorescent and colorimetric assays. Importantly, the VLP model presents many advantages for the study of airborne viral pathogens: (i) similarity in size and surface components; (ii) ease of generation and noninfectious nature enabling study of BSL3 and BSL4 viruses; (iii) facile characterization of aerosolization parameters; (iv) ability to adapt the system to other viral envelope proteins including those of newly discovered pathogens and mutant variants; (v) the ability to introduce viral sequences to develop nucleic acid amplification assays.ImportanceStudy and detection of airborne pathogens is hampered by the lack of appropriate model systems. In this work we demonstrate that noninfectious Virus Like Particles (VLP) represent attractive models to study airborne viral pathogens. Specifically, VLP are readily prepared, are similar in size and composition to infectious viruses, and are amenable to highly sensitive nucleic acid amplification techniques.
Genomic dissection and mutation-specific target discovery for breast cancerPIK3CAhotspot mutations
Authors: Miranda Adam X. , Kemp Justin , Davidson Brad , Bellomo Sara Erika , Agan Verda , Manoni Alexandra , Marchiò Caterina , Croessmann Sarah , Park Ben H. , Hodges Emily 
Published: January 2024

ABSTRACTBackgroundRecent advancements in high-throughput genomics and targeted therapies have provided tremendous potential to identify and therapeutically target distinct mutations associated with cancers. However, to date the majority of targeted therapies are used to treat all functional mutations within the same gene, regardless of affected codon or phenotype.ResultsIn this study, we developed a functional genomic analysis workflow with a unique isogenic cell line panel bearing two distinct hotspotPIK3CAmutations, E545K and H1047R, to accurately identify targetable differences between mutations within the same gene. We performed RNA-seq and ATAC-seq and identified distinct transcriptomic and epigenomic differences associated with eachPIK3CAhotspot mutation. We used this data to curate a select CRISPR knock out screen to identify mutation-specific gene pathway vulnerabilities. These data revealed AREG as a E545K-preferential target that was further validated throughin vitroanalysis and publicly available patient databases.ConclusionsUsing our multi-modal genomics framework, we discover distinct differences in genomic regulation betweenPIK3CAhotspot mutations, suggesting thePIK3CAmutations have different regulatory effects on the function and downstream signaling of the PI3K complex. Our results demonstrate the potential to rapidly uncover mutation specific molecular targets, specifically AREG and a proximal gene regulatory region, that may provide clinically relevant therapeutic targets. The methods outlined provide investigators with an integrative strategy to identify mutation-specific targets for the treatment of other oncogenic mutations in an isogenic system.
Consistent accumulation of transposable elements in species of the HawaiianTetragnathaspiny-leg adaptive radiation across the archipelago chronosequence
Authors: Yang Heidi , Goubert Clément , Cotoras Darko D. , Graham Natalie R , Cerca José , Gillespie Rosemary G. 
Published: January 2024

AbstractThe ecological and phenotypic diversity observed in oceanic island radiations presents an evolutionary paradox: a high level of genetic variation is typically required for diversification, but species colonizing a new island typically suffer from founder effects. This reduction in population size leads to a reduction in genetic diversity, which ultimately results in a reduction in the efficiency of natural selection. Then, what is the source of genetic variation which acts as the raw material for ecological and phenotypic diversification in oceanic archipelagos? Transposable elements (TEs) are mobile genetic elements that have been linked to the generation of genetic diversity, and evidence suggests that TE activity and accumulation along the genome can result from reductions in population size. Here, we use the Hawaiian spiny-leg spider radiation (Tetragnatha) to test whether TE accumulation increases due to demographic processes associated with island colonization. We sequenced and quantified TEs in 23 individuals from the spiny-leg radiation and 4 individuals from its sister radiation, the Hawaiian web-buildingTetragnatha. Our results show that founder effects resulting from colonization of new islands have not resulted in TE accumulation over evolutionary time. Specifically, we found no evidence for increase in abundance of specific TE superfamilies, nor an accumulation of ‘young TEs’ in lineages which have recently colonized a new island or are present in islands with active volcanoes. We also found that the DNA/hAT transposon superfamily is by far the most abundant TE superfamily in theTetragnatharadiation. This work shows that TE abundance has remained constant for the spiny-leg radiation across the archipelago chronosequence, and TE accumulation is not affected by population oscillations associated with island colonization events. Therefore, despite their known role in the generation of genetic diversity, TE activity does not appear to be the mechanism to explain the evolutionary paradox of the insularTetragnathaspiny-leg radiation.
NeuroMechanics: Electrophysiological and Computational Methods to Accurately Estimate the Neural Drive to Muscles in HumansIn Vivo
Authors: Caillet Arnault H. , Phillips Andrew T.M. , Modenese Luca , Farina Dario 
Published: January 2024

AbstractThe ultimate neural signal for muscle control is the neural drive sent from the spinal cord to muscles. This neural signal comprises the ensemble of action potentials discharged by the active spinal motoneurons, which is transmitted to the innervated muscle fibres to generate forces. Accurately estimating the neural drive to muscles in humansin vivois challenging since it requires the identification of the activity of a sample of motor units (MUs) that is representative of the active MU population. Current electrophysiological recordings usually fail in this task by identifying small MU samples with over-representation of higher-threshold with respect to lower-threshold MUs. Here, we describe recent advances in electrophysiological methods that allow the identification of more representative samples of greater numbers of MUs than previously possible. This is obtained with large and very dense arrays of electromyographic electrodes. Moreover, recently developed computational methods of data augmentation further extend experimental MU samples to infer the activity of the full MU pool. In conclusion, the combination of new electrode technologies and computational modelling allows for an accurate estimate of the neural drive to muscles and opens new perspectives in the study of the neural control of movement and in neural interfacing.
The Regulatory-Associated Protein of the Target of Rapamycin Complex, RAPTOR1B, interconnects with the photoperiod pathway to promote flowering inArabidopsis
Authors: Urrea-Castellanos Reynel , Calderan-Rodrigues Maria J. , Musialak-Lange Magdalena , Macharanda-Ganesh Appanna , Wahl Vanessa , Caldana Camila 
Published: January 2024

AbstractTransition from vegetative to reproductive growth (floral transition) is a strictly regulated energy-demanding process. InArabidopsis, light perception coupled with internal circadian rhythms allows sensing changes in the duration of the light period (photoperiod) to accelerate flowering under long days (LD) in spring. This photoperiod-mediated floral induction relies on the accumulation of CONSTANS (CO) at dusk, a transcription factor that upregulatesFLOWERING LOCUS T(FT) in leaves. Subsequently, FT protein moves into the shoot apical meristem to trigger the floral transition. Light and circadian clock-related signals are known to control CO at the genetic and protein levels; however, less is known about how energy sensing regulates components of the photoperiod pathway to modulate flowering. Here, we found that RAPTOR, a component of the Target Of Rapamycin complex (TORC), contributes to the induction of specific flowering genes that are under CO control. While transcription ofCOremains intact inraptormutants, its protein levels are reduced at dusk compared to wild-type (Col-0). This is due to increased protein degradation. Remarkably, GIGANTEA (GI) protein levels, which contributes to CO stabilization at dusk, are likewise hampered in the mutant. We show that RAPTOR interacts with and co-localizes at the nucleus with GI, altering GI levels through an unknown posttranscriptional mechanism. Phenotypic and molecular analysis of genetic crosses placed RAPTOR upstream of CO and GI. Since TORC is an energy sensor, our work suggests that RAPTOR could convey energy status information into the photoperiod sensing mechanism to fine-tune flowering behavior.Significance statementFor annual plants, such asArabidopsis, the correct timing of flowering in spring/summer is critical for reproductive success. Molecular mechanisms through which plants perceive and integrate day length with internal rhythms to accelerate flowering under long days are well described. However, little is known about the pathways sensing and conveying energy availability to the flowering programs. We found that RAPTOR, the regulatory unit of Target of Rapamycin complex (TORC), regulates CONSTANS post-transcriptionally through GIGANTEA. Both proteins are components of the photoperiod pathway of the flowering network and their miss-regulation inraptormutants hampers the upregulation of genes promoting flowering. Our work suggests that the high energy available in long days is sensed and integrated into the photoperiod pathway by TORC.
PRMT5 orchestrates EGFR and AKT networks to activate NFκB and promote EMT
Authors: Huang Lei , Ravi Manasa , Zhang Xiao-Ou , Verdejo-Torres Odette , Shendy Noha A.M. , Nezhady Mohammad A.M. , Gopalan Sneha , Wang Gang , Durbin Adam D. , Fazzio Thomas G. , Wu Qiong 
Published: January 2024

AbstractNeuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NFκB, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growthin vivo. Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.
Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling
Authors: Shim Abraham , Luan Xiaohan , Zhou Wen , Crow Yanick , Maciejowski John 
Published: January 2024

ABSTRACTThe cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associatedTREX1mutations - particularly those outside of the core catalytic domains - remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupt TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenousTREX1locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization.
ROSALINDprotects the mitochondrial translational machinery from oxidative damage
Authors: Katopodi Vicky , Verheyden Yvessa , Cinque Sonia , Jimenez Elena Lara , Demesmaeker Ewout , Marino Alessandro , Derua Rita , Groaz Elisabetta , Leucci Eleonora 
Published: January 2024

AbstractUpregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognizing and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNAROSALINDas an interacting partner of ribosomes.ROSALINDis upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content,ROSALINDserves as a substrate for oxidation. Consequently, inhibitingROSALINDleads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity bothin vitroandex vivoin preclinical humanized cancer models. These findings underscore the role ofROSALINDas a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.
3-epicaryoptin induces G2/M phase cell cycle arrest and apoptosis in human breast cancer cells by disrupting the microtubule network, anin vitroandin silicoinvestigation
Authors: Barman Manabendu , Roy Sujit , Singh Nanda , Sarkar Debanjan , Barman Niharendu , Pal Amit , Bhattacharyya Sankar , Ray Sanjib 
Published: January 2024

AbstractBreast cancer (BC) is a prevalent form of cancer observed in women across the globe, constituting over a quarter of all female BC cases. The treatment of BC continues to require significant efficacy, aiming to achieve high success rates while minimizing adverse effects on the body as a whole. In the current study, 3-epicaryoptin was tested for the molecular mechanism of its anti-cancer activity in the human breast cancer cell line, MCF-7. We investigated cell viability by MTT assay, cell cycle kinetics and apoptosis, immunofluorescence straining, molecular modelling, and ADMET profiling. MTT assay results showed that 3-epicaryoptin was found cytotoxic against MCF-7 cells with an IC50value of 344.64 µg mL-1for 48 h. Flow cytometric analysis exhibited that 3-epicaryoptin halted the MCF-7 cells in the G2/M phase and subsequently induced apoptosis in a time-dependent manner. Our immunofluorescence studies indicated that 3-epicaryoptin inhibited microtubule polymerization in MCF-7 cells. Furthermore, molecular docking followed by molecular dynamics (MD) simulation studies demonstrated the ability of 3-epicaryoptin to interact with the tubulin protein at the colchicine binding pockets. Overall, our results suggest that 3-epicaryoptin can inhibit the proliferation of human breast cancer cells by depolymerizing of cellular microtubule networks, which causes cell cycle arrest and promotes apoptotic cell death. Therefore, it has been indicated that the natural product 3-epicaryoptin exhibited considerable promise as a potent therapeutic agent capable of inducing apoptosis in breast cancer cells.
Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons
Authors: Aerts Tania , Boonen Anneleen , Geenen Lieve , Stulens Anne , Masin Luca , Pancho Anna , Francis Annick , Roy Frans Van , Wöhr Markus , Seuntjens Eve 
Published: January 2024

AbstractAutism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 (Pcdh10) has been implicated in the etiology of ASD.Pcdh10is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression ofPcdh10in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressedPcdh10in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched inPcdh10-expressing neurons in adult mice. To further investigate the involvement ofPcdh10in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated withGsh2-lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss ofPcdh10specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.