bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting plasma membrane and mitochondrial instability in breast cancer cells and breast epithelial to mesenchymal transition-model cells by adamantyl diaza-crown ether ZG613
Authors: Ester Katja , Mioč Marija , Spurny Pavel , Bonhenry Daniel , Marjanović Marko , Uzelac Lidija , Gabrilo Jelena , Šumanovac Tatjana , Schreibmayer Wolfgang , Majerski Kata , Minofar Babak , Ludwig Jost , Kralj Marijeta 
Published: October 2022

AbstractThe adamantane derived diaza-crown ether ZG613 was assessed as a potential breast cancer cells and breast epithelial to mesenchymal transition (EMT)-model cells targeting agent. We postulated that ZG613 activity relies on its plasma/mitochondria membrane disruption ability based on adamantane hydrophobicity and/or crown ether related ionophoric properties. We performed molecular dynamics (MD) simulations and next generation sequencing, followed by in vitro study of cell death, membrane perturbations and ionophoric ability, as well as in vivo study of effects on the tumour growth. MD simulation and RNA sequencing pointed toward physical disruption of plasma membrane by ZG613, corroborated by measured increase in membrane permeability leading to cell death. Measurements of ion fluxes confirmed ZG613 inability to transport Na+ and K+, as predicted by MD simulation. EMT-model cells exhibit changes in mitochondrial morphology and ATP levels, successfully targeted by ZG613. ZG613 caused mild retardation of tumour growth in vivo. In conclusion, ZG613 kills breast cancer cells and breast EMT-model cells by physical disruption of plasma membrane and impairments of mitochondrial functions. Breast EMT cells represent good potential targets within the breast tumour, due to their plasma membrane and mitochondrial instability.
Host-plant adaptation as a driver of incipient speciation in the fall armyworm (Spodoptera frugiperda)
Authors: Fiteni Estelle , Durand Karine , Gimenez Sylvie , Meagher Robert L. , Legeai Fabrice , Kergoat Gael J. , Nègre Nicolas , d’Alençon Emmanuelle , Nam Kiwoong 
Published: October 2022

ABSTRACTBackgroundDivergent selection on host-plants is one of the main evolutionary forces driving ecological speciation in phytophagous insects. The ecological speciation might be challenging in the presence of gene flow and assortative mating because the direction of divergence is not necessarily the same between ecological selection (through host-plant adaptation) and assortative mating. The fall armyworm (FAW), a major lepidopteran pest species, is composed of two sympatric strains, corn and rice strains, named after two of their preferred host-plants. These two strains have been hypothesized to undergo incipient speciation, based on (i) several lines of evidence encompassing both pre- and post-zygotic reproductive isolation, and (ii) the presence of a substantial level of genetic differentiation. Even though the status of these two strains has been established a long time ago, it is still yet to be found whether these two strains indeed exhibit a marked level of genetic differentiation from a large number of genomic loci. Here, we analyzed whole genome sequences from 56 FAW individuals either collected from pasture grasses (a part of the favored host range of the rice strain) or corn to assess the role of host-plant adaptation in incipient speciation.ResultsPrincipal component analysis of whole genome data shows that the pattern of divergence in the fall armyworm is predominantly explained by the genetic differentiation associated with host-plants. The level of genetic differentiation between corn and rice strains is particularly marked in the Z chromosome. We identified one autosomal locus and two Z chromosome loci targeted by selective sweeps specific to rice strain and corn strain, respectively. The autosomal locus has both increased DXYand FSTwhile the Z chromosome loci had decreased DXYand increased FST.ConclusionThese results show that the FAW population structure is dominated by the genetic differentiation between corn and rice strains. This differentiation involves divergent selection targeting at least three loci, which include a locus potentially causing reproductive isolation. Taken together, these results suggest the evolutionary scenario that host-plant speciation is a driver of incipient speciation in the fall armyworm.
Protein Language Model Predicts Mutation Pathogenicity and Clinical Prognosis
Authors: Liu Xiangling , Yang Xinyu , Ouyang Linkun , Guo Guibing , Su Jin , Xi Ruibin , Yuan Ke , Yuan Fajie 
Published: October 2022

AbstractAccurately predicting the effects of mutations in cancer has the potential to improve existing treatments and identify novel therapeutic targets. In this paper, we evidence for the first time that the large-scale pre-trained protein language models (PPLMs) are zero-shot predictors for twoclinicallyrelevant tasks: identifying diseasecausing mutations and predicting patient survival rate. Then we benchmark a series of state-of-the-art (SOTA) PPLMs on 2279 protein variants across 20 cancer-related genes. Our empirical results show that the PPLMs outperform the SOTA baseline, EVE [1], trained on multiple sequence alignment (MSA) data. We also demonstrate that the evolutionary index score, generated from the PPLM’s softmax layer, is good indicator for both mutation pathogenicity and patient survival rate. Our paper has taken a key step toward the clinical utility of large-scale PPLMs.
Whole-brain multivariate hemodynamic deconvolution for multi-echo fMRI with stability selection
Authors: Uruñuela Eneko , Gonzalez-Castillo Javier , Zheng Charles , Bandettini Peter , Caballero-Gaudes César 
Published: October 2022

AbstractConventionally, analysis of functional MRI (fMRI) data relies on available information about the experimental paradigm to establish hypothesized models of brain activity. However, this information can be inaccurate, incomplete or unavailable in multiple scenarios such as resting-state, naturalistic paradigms or clinical conditions. In these cases, blind estimates of neuronal-related activity can be obtained with paradigm-free analysis methods such as hemodynamic deconvolution. Yet, current formulations of the hemodynamic deconvolution problem have three important limitations: 1) their efficacy strongly depends on the appropriate selection of regularization parameters, 2) being univariate, they do not take advantage of the information present across the brain, and 3) they do not provide any measure of statistical certainty associated with each detected event. Here we propose a novel approach that addresses all these limitations. Specifically, we introduce MvME-SPFM (multivariate multi-echo sparse paradigm free mapping), a novel hemodynamic deconvolution algorithm that operates at the whole brain level and adds spatial information via a mixed-norm regularization term over all voxels. Additionally, MvME-SPFM employs a stability selection procedure that removes the need to select regularization parameters and also lets us obtain an estimate of the true probability of having a neuronal-related BOLD event at each voxel and time-point based on the area under the curve (AUC) of the stability paths. Besides, the formulation is tailored for multi-echo fMRI acquisitions, which allows us to better isolate fluctuations of BOLD origin on the basis of their linear dependence with Echo Time (TE) and to assign physiologically interpretable units (i.e., changes in the apparent transverse relaxation) to the resulting deconvolved events. We demonstrate that this algorithm outperforms existing state-of-the-art deconvolution approaches, and shows higher spatial and temporal agreement with the activation maps and BOLD signals obtained with a standard model-based linear regression approach, even at the level of individual neuronal events. Consequently, the proposed algorithm provides more reliable estimates of neuronal-related activity, here in terms of, for the study of the dynamics of brain activity when no information about the timings of the BOLD events is available. This algorithm will be made publicly available as part of thesploraPython package.
Optogenetic stimulation of septal somatostatin neurons disrupts locomotory behavior and regulates hippocampus cholinergic theta oscillations
Authors: Espinosa Nelson , Caneo Mauricio , Alonso Alejandra , Moran Constanza , Fuentealba Pablo 
Published: October 2022

AbstractThe septal complex regulates both motivated and innate behaviors, chiefly by the action of its diverse population of long-range projection neurons. Among those cells are lateral septum somatostatin neurons which collateral axons profusely innervate cortically-projecting neurons located in the medial septum. Thus, somatostatin cells are ideally positioned at the crossroads of ascending and descending modulatory pathways, likely supporting functional roles in both anatomical directions. Here, we used optogenetic stimulation and extracellular recordings in acutely anesthetized transgenic mice to show that septal somatostatin neurons can disinhibit the cholinergic septo-hippocampal pathway, thus enhancing the amplitude and synchrony of theta oscillations, while depressing sharp wave ripple episodes in the dorsal hippocampus. Nonetheless, photosuppressing septal somatostatin cells hindered goal-directed behavior in a spatial memory task by disrupting task engagement, evidenced in increased immobility, followed by repetitive self-grooming, a hallmark innate behavior. These results suggest that septal somatostatin cells can recruit ascending cholinergic pathways to promote hippocampal theta oscillations, while gating repetitive displacement behaviors mediated by descending subcortical pathways.Significance StatementA small population of somatostatin-expressing GABAergic cells in the lateral septum projects deep into subcortical regions, yet on its way it also targets neighboring medial septum neurons that profusely innervate cortical targets. We show here that selective inhibition of septal somatostatin cells exerts significant consequences in both ascending and descending synaptic pathways. Indeed, cortical targets increased the expression of hippocampal theta oscillations, which are relevant for sensorimotor processing, temporal coding, and a marker of anxious behaviour; whereas subcortical targets triggered repetitive self-grooming, an innate displacement behaviour. Our results suggest that septal somatostatin cells are a potential target for the control of altered innate behaviors in translational neuroscience.
Therapeutic depletion of CD8+ T-cells prevents myelin pathology in Globoid Cell Leukodystrophy
Authors: Sutter Pearl A. , Ménoret Antoine , Jellison Evan R. , Nicaise Alexandra M. , Bradbury Allison M. , Vella Anthony T. , Bongarzone Ernesto R. , Crocker Stephen J. 
Published: October 2022

AbstractGloboid cell leukodystrophy (GLD) or Krabbe’s disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function blocking antibody against CD8α effectively prevented disease onset, reduced morbidity and mortality and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD.One-Sentence SummaryCD8 T-cells mediate demyelination and neuroinflammation in a genetic white matter disease.
Native doublet microtubules fromTetrahymena thermophilareveal the importance of outer junction proteins
Authors: Kubo Shintaroh , Black Corbin , Joachimiak Ewa , Yang Shun Kai , Legal Thibault , Peri Katya , Khalifa Ahmad , Ghanaeian Avrin , Valente-Paterno Melissa , De Bellis Chelsea , Huynh Phuong , Fan Zhe , Wloga Dorota , Bui Khanh Huy 
Published: October 2022

AbstractCilia are ubiquitous eukaryotic organelles responsible for cellular motility and sensory functions. The ciliary axoneme is a microtubule-based cytoskeleton consisting of two central singlets and nine outer doublet microtubules. Cryo-electron microscopy-based studies have revealed a complex network inside the lumen of both tubules composed of microtubule-inner proteins (MIPs). However, the functions of most MIPs remain unknown. Here, we present single-particle cryo-EM-based analyses of theTetrahymena thermophilanative doublet microtubule and identify 38 MIPs. These data shed light on the evolutionarily conserved and diversified roles of MIPs. In addition, we identified MIPs potentially responsible for the assembly and stability of the doublet outer junction. Knockout of the evolutionarily conserved outer junction component CFAP77 moderately diminishesTetrahymenaswimming speed and beat frequency, indicating the important role of CFAP77 and outer junction stability in cilia beating generation and/or regulation.
The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD
Authors: Cicardi ME , Kankate V , Sriramoji S , Krishnamurthy K , Markandaiah SS , Verdone BM , Girdhar A , Nelson A , Rivas LB , Boehringer A , Haeusler AR , Pasinelli P , Guo L , Trotti D. 
Published: October 2022

SummaryExpanded intronic G4C2repeats in theC9orf72gene cause several cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeats are translated through a non-AUG-dependent mechanism into five different dipeptides (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and eventually neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating in primary neuronsin-vitroand CNS tissuein-vivo. Importantly, this interaction improves the overall survival of neurons expressing GR. Downregulation of Kap β2 is detrimental to the survival of neurons only if GR is expressed, whereas increased Kap β2 levels mitigate GR-mediated neurotoxicity. notably, we did not find any changes in TDP-43 localization nor in the dynamic properties of the GR aggregates when Kapβ2 was over-expressed. These findings support the design of therapeutic strategies aimed at modulating Kap β2 levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.
Active antennal movements in Drosophila tune wind encoding
Authors: Suver Marie P , Medina Ashley M , Nagel Katherine I 
Published: October 2022

SummaryMany insects actively move their antennae, but how these movements influence sensory encoding is not fully understood. Antennae are used to smell odors1,2, detect auditory cues3,4, and sense mechanosensory stimuli such as wind5 and objects6–8, frequently by combining active movement with sensation. Genetic access to antennal motor systems would thus provide a powerful tool for dissecting the circuit mechanisms underlying active sensing, but little is known about how the most genetically tractable insect, Drosophila melanogaster, moves its antennae. Here we use DeepLabCut to measure how tethered Drosophila move their antennae in the presence of sensory stimuli, and identify genetic reagents for controlling antennal movement. We find that flies perform both slow and fast antennal movements in response to wind-induced deflections, but not the attractive odor apple cider vinegar. We describe four muscles in the first antennal segment that control antennal movements, and identify genetic driver lines that provide access to two groups of antennal motor neurons and an antennal muscle. Through optogenetic inactivation, we provide evidence that antennal motor neurons are specialized for different movement speeds. Finally, we show that activation of antennal motor neurons and muscles can improve the gain and acuity of wind direction encoding. Together, our experiments provide insight into the neural control of antennal movement and suggest that Drosophila actively position their antennae to tune the precision of wind encoding.
Optical Metabolic Imaging Uncovers Sex- and Diet-dependent Lipid Changes in Aging Drosophila Brain
Authors: Li Yajuan , Chang Phyllis , Sankaran Shiriya , Jang Hongje , Nie Yuhang , Zeng Audrey , Hussain Sahran , Wu Jane Y. , Chen Xu , Shi Lingyan 
Published: October 2022

AbstractAging is associated with progressive declines in physiological integrity and functions alongside increases in vulnerability to develop a number of diseases. The brain regulates sensory and motor functions as well as endocrine functions, and age-associated changes in brain are likely prerequisite for the organismal aging. Lipid metabolism has been associated with brain aging, which could be easily intervened by diets and lifestyles. However, the underlying mechanism through which brain lipid metabolism is regulated by diet during aging is elusive. Using stimulated Raman scattering (SRS) imaging combined with deuterium water (D2O) labeling, we visualized that lipid metabolic activities were changed by diet manipulation in agingDrosophilabrain. Furthermore, we illuminated that insulin/IGF-1 signaling (IIS) pathway mediates the transformation of brain lipid metabolic changes in both an aging- and a diet-dependent manner. The lipid droplets (LDs) in the brain gradually became inert in both activities of lipid synthesis and mobilization with aging. High sugar diets enhanced the metabolic activity through promoting lipogenesis while dietary restriction increased the metabolic activity in both lipogenesis and lipolysis in brain LDs. However, these effects were impaired in bothchico1/+anddfoxo Drosophilamutants. We also observed that oldchico1/+brains maintained high metabolic activities, whilst the ageddfoxobrains acted exactly the opposite. More interestingly, the sexual dimorphism in brain lipid metabolism was impaired under diet regulation in bothchico1/+anddfoxomutants. Locally reduced IIS activity in glial cells can mimic the systemic changes in systematic IIS mutants to maintain lipogenesis and lipolysis in aged brains, providing mechanistic insight into the anti-aging effects of IIS pathway. Our results highlight the manipulation of glia-specific IIS activity as a promising strategy in anti-aging treatments.
Memory CD4 T cell subset organization in the female reproductive tract is regulated via the menstrual cycle through CCR5 signaling
Authors: Swaims-Kohlmeier Alison , Wein Alexander N. , Hardnett Felica P. , Sheth Anandi N. , Li Zheng-Rong Tiger , Williams M. Elliot , Radzio-Basu Jessica , Zheng HaoQiang , Dinh Chuong , Haddad Lisa B. , Collins Elizabeth M.B. , Lobby Jenna L. , Kost Kirsten , Hayward Sarah L. , Ofotokun Igho , Antia Rustom , Scharer Christopher D. , Lowen Anice C. , Garcia-Lerma J. Gerardo , Kohlmeier Jacob E. 
Published: October 2022

AbstractDespite their importance for immunity against sexually transmitted infections (STIs), the composition of the female reproductive tract (FRT) memory CD4 T cell population in response to changes in the local tissue environment during the menstrual cycle remains poorly defined. Here we show that across humans, non-human primates (NHP), and mice, FRT CD4 T cells comprise distinct subsets corresponding to migratory memory (TMM) and resident memory (TRM) cells. TMM display tissue-itinerant trafficking characteristics, restricted FRT tissue distribution, with distinct transcriptional properties and effector responses to infection. CD4 T cell subset fluctuations synchronized with cycle-driven proinflammatory changes within the local tissue environment and oral administration of a CCR5 antagonist inhibited cycle phase-specific migratory T cell surveillance. This study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of memory T cell defense at the site of STI exposure.SummaryThe menstrual cycle regulates memory T cell surveillance.
Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function
Authors: Braverman Erica L. , McQuaid Margaret A. , Monlish Darlene A. , Dobbs Andrea K. , Ramsey Manda J , Ramgopal Archana , Brown Harrison , Byersdorfer Craig A. 
Published: October 2022

ABSTRACTT cell-based cellular therapies benefit from a product with reduced differentiation and enhanced oxidative metabolism. Methods to achieve this balance without negatively impacting T cell expansion or impairing T cell function have proven elusive. AMP-activated protein kinase (AMPK) is a cellular energy sensor which promotes mitochondrial health and improves oxidative metabolism. We hypothesized that increasing AMPK activity in human T cells would augment their oxidative capacity, creating an ideal product for adoptive cellular therapies. Lentiviral transduction of the regulatory AMPKγ2 subunit stably enhanced intrinsic AMPK signaling and promoted mitochondrial respiration with increased basal oxygen consumption rates (OCR), higher maximal OCR, and augmented spare respiratory capacity. These changes were accompanied by increased mitochondrial density and elevated expression of proteins involved in mitochondrial fusion. AMPKγ2-transduction also increased T cell glycolytic activity. This combination of metabolic reprogramming enhanced in vitro T cell expansion while promoting memory T cell yield. Finally, when activated under decreasing glucose conditions, AMPKγ2-transduced T cells maintained higher levels of both proliferation and inflammatory cytokine production. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPKγ2 can improve the expansion and function of human T cells for subsequent use in adoptive cellular therapies.Key pointsLentiviral Transduction of AMPKγ2 increases oxidative metabolism in human T cellsAMPKγ2 transduction enhances in vitro proliferation without inducing exhaustionAMPKγ2-transduced T cells function better under low glucose conditions
Biophysical characterisation of the structure of a SARS-CoV-2 self-amplifying - RNA (saRNA) vaccine
Authors: Myatt Daniel P , Wharram Lewis , Graham Charlotte , Liddell John , Branton Harvey , Pizzey Claire , Cowieson Nathan , Rambo Robert , Shattock Robin J 
Published: October 2022

AbstractThe current SARS-Covid-2 pandemic has led to an acceleration of messenger – ribonucleic acid (mRNA) vaccine technology. The development of production processes for these large mRNA molecules, especially self-amplifying mRNA (saRNA) has required concomitant development of analytical characterisation techniques. Characterising the purity, shape and structure of these biomolecules is key to their successful performance as drug products. This paper describes the biophysical characterisation of the Imperial College London Self-amplifying viral RNA vaccine (IMP-1) developed for SARS-CoV-2. A variety of analytical techniques have been used to characterise the IMP-1 RNA molecule. In this paper we use UV spectroscopy, dynamic light scattering (DLS), size-exclusion chromatography small angle scattering (SEC-SAXS) and circular dichroism (CD) to determine key biophysical attributes of IMP-1. Each technique provides important information about the concentration, size, shape, structure and purity of the molecule.Statement of significanceThis paper is highly significant as it provides a prescient biophysical characterisation of an efficacious Sars-Cov-2 vaccine self-amplifying (sa)RNA molecule. RNA vaccines have been a major scientific breakthrough of the Covid-19 pandemic. saRNA is a further development of conventional mRNA vaccines, amplifying the RNA of interest in the cell, allowing the vaccine to be administered at lower dosages. These new biologics are distinct from previous biologics and have required distinct analytical characterisation. The analytics described herein provide detailed information on the size, shape, and structure of the RNA molecule. This paper is therefore an important step in characterising large saRNA biological relevant molecules.