Search bioRxiv⌕ Search

Biology subjects

Moore, M.

Publications and source records attributed to Moore, M..

At least 37 records · Page 2Linked to original sources

Migration strategies of a high-latitude breeding songbird (Setophaga coronata coronata) revealed using multi-sensor geolocators and stable isotopes

Seasonal migration allows animals to use habitat where conditions are unfavorable for part of the year but may constrain breeding ranges due to the costs of longer migrations as ranges expand poleward. In species with large ranges, high latitude breeding populations may employ different migratory strategies allowing them to persist far from other core non-breeding areas. The myrtle warbler (Setophaga coronata coronata) has two disjunct non-breeding ranges in North and Central America-one along the Gulf Coast and the other on the Pacific. Previous work indirectly linked birds breeding in Alaska with the Pacific non-breeding area, suggesting that high latitude populations evolved a shorter migration route. We directly tested this hypothesis using geolocators measuring both light and atmospheric pressure to track Alaskan myrtle warbler migration in fine detail and inferred non-breeding areas using hydrogen isotopes for a larger sample of birds breeding in Alaska, British Columbia, and Alberta. We found, contrary to expectations, that all geolocator-tracked birds and most birds with stable isotope data migrated to the southeastern United States, while only a small subset of birds ([~]5%) likely wintered on the Pacific Coast. We additionally demonstrate the advantages of pressure geolocation for characterizing migratory behavior at a fine scale.

animal behavior and cognition↗

Pharmacological inhibition of Fms-like kinase 3 (FLT3) promotes neuronal maturation and suppresses seizure in a mouse model

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase predominantly expressed in blood and brain cells. While the FLT3 signaling pathway has been extensively studied in blood cell development and leukemia, its role in the brain remains largely unexplored. Through our groups previous high-throughput drug screening work unexpectedly found that several small molecule FLT3 inhibitors (FLT3i), including KW-2449 and Sunitinib, enhance expression of the gene encoding chloride transporter KCC2 in neurons. KCC2 is crucial for brain development and function, and its dysregulation is linked to many brain diseases. These findings suggest previously unrecognized roles of FLT3 signaling in brain health and disease that have yet to be systematically studied. In this study, we utilized a functional genomics approach to investigate the transcriptomic changes induced by pharmacological inhibition of the FLT3 pathway in brain cells, including cultured primary mouse neurons, a human stem cell-derived neuronal model of Rett syndrome (RTT), and human stem cell-derived microglia cultures. Our results show that treating human or mouse neurons with FLT3i drugs significantly upregulates genes crucial for brain development while downregulating genes linked to neuroinflammation. In contrast, FLT3i treatment of human microglia, which do not express FLT3, has no effect on their gene expression, highlighting the cell type-specific roles of FLT3 signaling in the brain. To further understand how FLT3 signaling regulates the expression of neuronal maturation genes such as KCC2, we conducted a curated CRISPR screen that identified a number of transcription factors involved in FLT3i-mediated KCC2 activation in neurons. The mRNA and protein levels of several neurodevelopmental disorder (NDD) risk genes are significantly upregulated in FLT3i-treated neurons, indicating potential therapeutic applications of FLT3i in rescuing underexpression and/or haploinsufficiency of disease-associated genes. In our in vivo studies, we evaluated the efficacy of the FLT3i drug KW-2449 in mice, demonstrating that it can effectively cross the blood-brain barrier, induce KCC2 protein expression for up to 24 hours after a single injection, and reduces seizure activity in a chemoconvulsant-induced mouse model of temporal lobe epilepsy. Collectively, our findings uncover previously unrecognized roles of neuron-specific FLT3 signaling in promoting neuronal maturation and reducing neuroinflammation. These results suggest that FLT3 kinase signaling regulates a transcriptional program vital for brain development and function, position it as a promising therapeutic target for NDD treatment.

neuroscience↗

PGR5 promotes energy-dependent non-photochemical quenching to enable efficient C4 photosynthesis under fluctuating light

PROTON GRADIENT REGULATION 5 (PGR5) is essential for generating proton motive force across thylakoid membranes in C3 plants and supporting photoprotection under fluctuating light conditions. It is proposed that this function is achieved by regulating cyclic electron flow around Photosystem I. During the evolutionary transition from C3 to C4 photosynthesis, the leaf abundance of PGR5 has increased, coinciding with a rise in the cyclic electron flow rate. To investigate the contribution of PGR5 to photoprotection in C4 photosynthesis, we generated model C4 monocot Setaria viridis with null pgr5 alleles. We show that plants lacking PGR5 struggle to establish proton motive force and energy-dependent non-photochemical quenching (qE) at higher irradiances during instantaneous measurements. This leads to a progressive decline in maximum Photosystem I activity when leaves are exposed to repeated cycles of high irradiance. Additionally, plants without PGR5 exhibit severely reduced growth and photosynthesis compared to wild type plants when grown under fluctuating daylight but not under constant daylight. In the absence of PGR5, a slower-relaxing, zeaxanthin-dependent form of non-photochemical quenching supports growth under fluctuating light, albeit at the cost of reduced photochemical efficiency and assimilation rate. Our findings underscore the role of PGR5 in enabling efficient C4 photosynthesis under fluctuating light by establishing proton motive force for the rapid upregulation of qE and preventing photodamage to the electron transport machinery. This study highlights the importance of various non-photochemical quenching mechanisms for C4 photosynthesis and emphasises the role of PGR5 in the evolution of C4 plants.

plant biology↗

Uridine Phosphorylase-1 supports metastasis of mammary cancer by altering immune and extracellular matrix landscapes of the lung

Understanding the mechanisms that facilitate early events in metastatic seeding is key to developing therapeutic approaches to reduce metastasis - the leading cause of cancer-related death. Using whole animal screens in genetically engineered mouse models of cancer we have identified circulating metabolites associated with metastasis. Specifically, we highlight the pyrimidine uracil as a prominent metastasis-associated metabolite. Uracil is generated by neutrophils expressing the enzyme uridine phosphorylase-1 (UPP1), and neutrophil specific Upp1 expression is increased in cancer. Altered UPP1 activity influences expression of adhesion molecules on the surface of neutrophils, leading to decreased neutrophil motility in the pre-metastatic lung. Furthermore, we find that UPP1-expressing neutrophils suppress T-cell proliferation, and the UPP1 product uracil can increase fibronectin deposition in the extracellular microenvironment. Consistently, knockout or inhibition of UPP1 in mice with mammary tumours increases the number of T-cells and reduces fibronectin content in the lung and decreases the proportion of mice that develop lung metastasis. These data indicate that UPP1 influences neutrophil behaviour and extracellular matrix deposition in the lung and suggest that pharmacological targeting of this pathway could be an effective strategy to reduce metastasis.

cancer biology↗

White adipose tissue remodeling in Little Brown Myotis (Myotis lucifugus) with white-nose syndrome

White-nose syndrome (WNS) is a fungal wildlife disease of bats that has caused precipitous declines in certain Nearctic bat species. A key driver of mortality is premature exhaustion of fat reserves, primarily white adipose tissue (WAT), that bats rely on to meet their metabolic needs during winter. However, the pathophysiological and metabolic effects of WNS have remained ill-defined. To elucidate metabolic mechanisms associated with WNS mortality, we infected a WNS susceptible species, the Little Brown Myotis (Myotis lucifugus), with Pseudogymnoascus destructans (Pd) and collected WAT biopsies for histology and targeted lipidomics. These results were compared to the WNS-resistant Big Brown Bat (Eptesicus fuscus). A similar distribution in broad lipid class was observed in both species, with [~]60% of total WAT consisting of triacylglycerides (TAGs). We found several baseline differences in WAT chemical composition between species. M. lucifugus WAT had significantly higher levels of measured TAGs ([~]30%). Higher lipid levels in E. fuscus WAT were primarily sphingomyelins and glycerophosphoethanolamines (PEs), along with glycerophospholipids (GPs) dominated by unsaturated or monounsaturated moieties and n-6 (18:2, 20:2, 20:3, 20:4) fatty acids. These differences between M. lucifugus and E. fuscus may indicate dietary differences that lead to differential "fuel" reserves that are available during torpor. Following Pd-infection, we found that perturbation to WAT reserves occurs in M. lucifugus, but not in the resistant E. fuscus. A total of 36 GPs (primarily PEs) were higher in Pd-infected M. lucifugus, indicating perturbation to the WAT structural component. In addition to changes in lipid chemistry, smaller adipocyte sizes and increased extracellular matrix deposition was observed in Pd-infected M. lucifugus. This is the first study to describe WAT lipidomic composition of bats with different susceptibilities to WNS and highlights that recovery from WNS may require repair from adipose remodeling in addition to replenishing depot fat during spring emergence.

biochemistry↗

Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments

Altered cellular metabolism has been associated with acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumour resection to generate isogenic cells from primary tumours and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism leading to increased intracellular levels of specific ceramides. The combination of these two metabolic adaptations alters small extracellular vesicle (sEV) production to drive generation of an invasive microenvironment. Indeed, micrometastatic cells shut-down Rab27-dependent production of sEVs and, instead, switch-on neutral sphingomyelinase-2 (nSM2)-dependent sEV release. sEVs released in a nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing sEV release. SummaryBreast cancer cells isolated from lung micrometastases have altered metabolism which influences extracellular vesicle production to generate invasive microenvironments.

cancer biology↗

Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer

Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNAs in >42,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) is detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contain a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs are not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific.

cancer biology↗

Machine learning identifies cell-free DNA 5-hydroxymethylation biomarkers that detect occult colorectal cancer in PLCO Screening Trial subjects

BackgroundColorectal cancer (CRC) is a leading cause of cancer-related mortality, and CRC detection through screening improves survival rates. A promising avenue to improve patient screening compliance is the development of minimally-invasive liquid biopsy assays that target CRC biomarkers on circulating cell-free DNA (cfDNA) in peripheral plasma. In this report, we identify cfDNA biomarker candidate genes bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that diagnose occult CRC up to 36 months prior to clinical diagnosis using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial samples. MethodsArchived PLCO Trial plasma samples containing cfDNA were obtained from the National Cancer Institute (NCI) biorepositories. Study subjects included those who were diagnosed with CRC within 36 months of blood collection (i.e., case, n = 201) and those who were not diagnosed with any cancer during an average of 16.3 years of follow-up (i.e., controls, n = 402). Following the extraction of 3 - 8 ng cfDNA from less than 300 microliters plasma, we employed the sensitive 5hmC-Seal chemical labeling approach, followed by next-generation sequencing (NGS). We then conducted association studies and machine-learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio. ResultsDespite the technical challenges associated with the PLCO samples (e.g., limited plasma volumes, low cfDNA amounts, and long archival times), robust genome-wide 5hmC profiles were successfully obtained from these samples. Association analyses using the Cox proportional hazards models suggested several epigenetic pathways relevant to CRC development distinguishing cases from controls. A weighted Cox model, comprised of 32-associated gene bodies, showed predictive detection value for CRC as early as 24-36 months prior to overt tumor presentation, and a trend for increased predictive power was observed for blood samples collected closer to CRC diagnosis. Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and self-reported race/ethnicity, and significantly outperformed risk factors such as age and obesity according to BMI (body mass index). Additionally, further improvement of predictive performance was achieved by combining the 5hmC-based model and risk factors for CRC. ConclusionsAn assay of 5hmC epigenetic signals on cfDNA revealed candidate biomarkers with the potential to predict CRC occurrence despite the absence of clinical symptoms or the availability of effective predictors. Developing a minimally-invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient survival through higher compliance screening and earlier intervention. Future investigation to expand this strategy to prospectively collected samples is warranted.

genomics↗

Loss of TIM4-Dependent Efferocytosis in Kupffer CellsPromotes Liver Fibrosis in Nonalcoholic Steatohepatitis

Background and aimsHepatocyte apoptosis is a key feature of non-alcoholic steatohepatitis (NASH), but the fate of apoptotic hepatocytes in NASH is poorly understood. Herein we explore the hypothesis that impaired TIM4-mediated clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in NASH and drives the progression to liver fibrosis. MethodsKupffer cell (KC)-TIM4 expression and efferocytosis were assayed in normal and NASH liver from humans and diet-induced NASH mice. The engulfment of human and mouse apoptotic hepatocytes by primary human and mouse liver KCs was assayed ex vivo. Causation was assessed in NASH mice using anti-TIM4 antibodies, KC-TIM4-knockout, or inducible KC-TIM4 expression, with analyses focused on efferocytosis of apoptotic hepatocytes by liver macrophages and liver fibrosis. ResultsIn human and mouse NASH liver, apoptotic hepatocytes accumulated and was associated with the loss of the KC efferocytosis receptor TIM4. Anti-TIM4 inhibited the engulfment of apoptotic hepatocytes by primary human and mouse liver KCs ex vivo, and anti-TIM4 administration to early NASH mice worsened liver macrophage efferocytosis and accelerated the progression to fibrotic NASH. A similar result was obtained by genetically deleting TIM4 in KCs in NASH mice. Most importantly, genetic restoration of macrophage TIM4 in NASH mice enhanced the clearance of apoptotic hepatocytes by liver macrophages and decreased liver fibrosis. ConclusionsThe loss of macrophage TIM4 that occurs during NASH progression impairs the clearance of apoptotic hepatocytes by liver macrophages, which subsequently promotes the progression to fibrotic NASH. This pathogenic sequence of events can be prevented by restoring macrophage TIM4, suggesting that future therapeutic approaches designed to boost TIM4 expression in liver macrophages could represent a novel strategy to prevent fibrotic NASH progression. Lay summaryNonalcoholic steatohepatitis (NASH) is emerging as the leading cause of liver disease, but the processes leading to liver fibrosis in NASH, which determines clinical outcome, are incompletely understood. Our study provides evidence impaired clearance of dead liver cells by liver macrophages in NASH, which is due to loss of a macrophage receptor called TIM4, contributes to liver fibrosis. Knowledge of this process may suggest new ways to bolster the clearance of dead liver cells in NASH and thereby prevent the progression to liver fibrosis and subsequent liver disease.

pathology↗

Conserved cold tolerance of Rhagoletis species from different host fruits, elevations in Colorado, USA

Understanding and characterizing how insects tolerate low temperatures is important for predicting their overwintering survival and subsequent geographic spread. This study characterized the cold tolerance of two members of the Rhagoletis genus in Colorado, U.S.A. Pupae were collected from infested fruit in late summer and early fall. For the first time, we show that the rosehip fly Rhagoletis basiola is freeze-avoidant; overwintering pupae could supercool to temperatures as low as -26{degrees}C and survive. Interestingly, the temperature at which ice forms (supercooling point; SCP) did not vary between R. basiola at high (c. 2900 m above sea level) and lower (c. 1650 m a.s.l.) elevations. We also report the apple maggot Rhagoletis pomonella infesting an unusual host fruit, the Dolgo crabapple, in close proximity to infested hawthorn trees. R. pomonella infesting hawthorn fruits and crabapples had similar SCPs, and survived temperatures as low as -21{degrees}C. Pupae from both host fruits also survived prolonged exposure (2 weeks or more) to mild low temperatures (0 to -5{degrees}C). Further study into the mechanisms underlying the impressive and conserved cold tolerance of R. pomonella and R. basiola is an interesting avenue for future research.

zoology↗

eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers

Dysregulated translation is a hallmark of cancer. Targeting the translational machinery represents a therapeutic avenue which is being actively explored. eIF4A inhibitors target both eIF4A1, which promotes translation as part of the eIF4F complex, and eIF4A2, which can repress translation via the CCR4-NOT complex. While high eIF4A1 expression is associated with poor patient outcome, the role of eIF4A2 in cancer remains unclear. Furthermore, the on-target toxicity of targeting specific eIF4A paralogues in healthy tissue is under-explored. We show that while loss of either paralogue is tolerated in the wild-type intestine, eIF4A1 is specifically required to support the translational demands of oncogenic Wnt signalling. Intestinal tumourigenesis is suppressed in colorectal cancer models following loss of eIF4A1 but accelerated following loss of eIF4A2, while eIF4A inhibition with eFT226 mimics loss of eIF4A1 in these models.

cancer biology↗

Loss of ATP-sensitive channel expression and function decreases opioid sensitivity in a mouse model of type 2 diabetes

During diabetes, {beta}-cell dysfunction due to loss of potassium channels sensitive to ATP, known as KATP channels occurs progressively over time contributing to hyperglycemia. KATP channels are additionally present in the central and peripheral nervous systems and are downstream targets of opioid receptor signaling. The aim of this study is to investigate if KATP channel expression or activity in the nervous system changes in diabetic mice and if morphine antinociception changes in mice fed a high fat diet (HFD) for 16 weeks compared to controls. Mechanical thresholds were also monitored before and after administration of glyburide or nateglinide, KATP channel antagonists, for four weeks. HFD mice have decreased antinociception to systemic morphine, which is exacerbated after systemic treatment with glyburide or nateglinide. HFD mice also have lower rotarod scores, decreased mobility in an open field test, and lower burrowing behavior compared to their control diet counterparts, which is unaffected by KATP channel antagonist delivery. Expression of KATP channel subunits, Kcnj11 (Kir6.2) and Abcc8 (SUR1), were decreased in the peripheral and central nervous system in HFD mice, which is significantly correlated with baseline paw withdrawal thresholds. Upregulation of SUR1 through an adenovirus delivered intrathecally increased morphine antinociception in HFD mice, whereas Kir6.2 upregulation improved morphine antinociception only marginally. Perspective: This article presents the potential link between KATP channel function and neuropathy during diabetes. There is a need for increased knowledge in how diabetes affects structural and molecular changes in the nervous system to lead to the progression of chronic pain and sensory issues.

neuroscience↗

The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation

Increased protein synthesis supports growth of established tumours. However, how mRNA translation contributes to early tumorigenesis remains unclear. Here we show that following oncogene activation, hepatocytes enter a non-proliferative/senescent-like phase characterized by 5{beta}1 integrin-dependent deposition of fibronectin-rich extracellular matrix (ECM) niches. These niches then promote exit from oncogene-induced senescence to permit progression to proliferating hepatocellular carcinoma (HCC). Removal of eIF4A2, a negative regulator of mRNA translation, boosts the synthesis of membrane/secretory proteins which drives a compensatory increase in the turnover/degradation of membrane proteins including 5{beta}1 integrin. This increased membrane protein degradation, in turn, compromises generation of ECM-rich tumour initiation niches, senescence-exit and progression to proliferating HCC. Consistently, pharmacological inhibition of mRNA translation following eIF4A2 loss restores ECM deposition and reinstates HCC progression. Thus, although inhibition of protein synthesis may be an effective way to reduce tumour biomass and the growth of established tumours, our results highlight how agents which reduce mRNA translation, if administered during early tumorigenesis, may awaken senescent cells and promote tumour progression.

cancer biology↗

The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells

Type I conventional dendritic cells (cDC1s) are essential for the generation of protective cytotoxic T lymphocyte (CTL) responses against many types of viruses and tumours. They do so by internalizing antigens from virally infected or tumour cells and presenting them to CD8+ T cells in a process known as cross-presentation (XP). Despite the obvious biological importance of XP, the molecular mechanism(s) driving this process remain unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein 7C (APOL7C) is upregulated in response to innate immune stimuli and is recruited to phagosomes. Strikingly, the association of APOL7C with phagosomes leads to phagosomal rupture, which in turn allows for the escape of engulfed protein antigens to the cytosol where they can be processed via the endogenous major histocompatibility complex (MHC) class I antigen processing pathway. We show that APOL7C recruitment to phagosomes is voltage-dependent and occurs in response to NADPH oxidase-induced depolarization of the phagosomal membrane. Our data indicate the presence of dedicated pore-forming apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDC1s to facilitate MHC class I presentation of exogenous antigen and to regulate adaptive immunity.

cell biology↗

Integrative dissection of gene regulatory elements at base resolution

Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here we combine epigenetic perturbations, base editing, and deep learning models to dissect regulatory sequences within the exemplar immune locus encoding CD69. Focusing on a differentially accessible and acetylated upstream enhancer, we find that the complementary strategies converge on a [~]170 base interval as critical for CD69 induction in stimulated Jurkat T cells. We pinpoint individual cytosine to thymine base edits that markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. The most potent base edits may be explained by their effect on binding competition between the transcriptional activator GATA3 and the repressor BHLHE40. Systematic analysis of GATA and bHLH/Ebox motifs suggests that interplay between these factors plays a general role in rapid T cell transcriptional responses. Our study provides a framework for parsing gene regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants. HighlightsO_LIBase editing screens and deep learning pinpoint sequences and single bases affecting immune gene expression C_LIO_LIAn artificial C-to-T variant in a regulatory element suppresses CD69 expression by altering the balance of transcription factor binding C_LIO_LICompetition between GATA3 and BHLHE40 regulates inducible immune genes and T cell states C_LI

molecular biology↗

Special Nuclear Layer Contacts Among Starburst Amacrine Cells in the Mouse Retina

We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.

neuroscience↗

Dynamics of mRNA fate during light stress and recovery: from transcription to stability and translation

Transcript stability is an important determinant of its abundance and, consequently, translation. However, it is unclear the extent to which it is modulated between environmental conditions. We previously hypothesised that recovery-induced transcript destabilisation facilitated a phenomenon of rapid recovery gene down-regulation (RRGD) in Arabidopsis thaliana following stress, based on mathematical calculations to account for ongoing transcription. Here, we test this hypothesis, and investigate processes regulating transcript abundance and fate, by quantifying changes in transcription, stability, and translation before, during, and after light stress. We adapt syringe infiltration to apply a transcriptional inhibitor to soil-grown plants in combination with stress. Compared to measurements in juvenile plants and cell culture, we find reduced stability in a range of transcripts. We also observe transcript destabilisation during light stress, followed by stabilisation upon recovery. Alongside fast transcriptional shut-off in recovery, this destabilisation appears to facilitate RRGD. Translation was dynamic over the course of light stress and recovery, with substantial transcript-specific increases in ribosome-association, independent of changes in total transcript abundance, observed after 30 minutes of light stress. Taken together, we provide evidence for the combinatorial regulation of transcription, stability, and translation that occurs to facilitate responses to light stress and recovery.

plant biology↗

Affective enhancement of episodic memory is associated with widespread patterns of intrinsic functional connectivity across the adult lifespan

Subjectively arousing experiences tend to be better remembered than neutral ones. While numerous task-related neuroimaging studies have revealed the neural mechanisms associated with this phenomenon, it remains unclear how variability in the extent to which individuals show superior memory for subjectively arousing stimuli is associated with the intrinsic functional organization of their brains. Here, we addressed this issue using functional magnetic resonance imaging data collected at rest from a sample drawn from the Cambridge Centre for Ageing Neuroscience cohort (N = 269, 18-86 years). Specifically, we performed multi-voxel pattern analysis of intrinsic functional connectivity, an unbiased, data-driven approach to examine whole-brain voxel-wise connectivity patterns. This technique allowed us to reveal the most important features from the high-dimensional, whole-brain connectivity structure without a priori hypotheses about the topography and direction of functional connectivity differences. Behaviorally, both item and associative memory accuracy were enhanced for trials with affectively arousing (positive or negative) stimuli than those with neutral ones. Whole-brain multi-voxel pattern analysis of functional connectivity revealed that the affective enhancement of memory was associated with intrinsic connectivity patterns of spatially distributed brain regions belonging to several functional networks in the cerebral cortex. Post hoc seed-based brain-behavior regression analysis and principal component analysis of the resulting correlation maps showed that these connectivity patterns were in turn primarily characterized by the involvement of heteromodal association (dorsal attention, salience, and default mode) networks as well as select subcortical structures (striatum, thalamus, and cerebellum). Collectively, these findings suggest that the affective enhancement of episodic memory may be characterized as a whole-brain phenomenon, possibly supported by intrinsic functional interactions across several networks and structures in the brain.

neuroscience↗