Biology subjects

Xiao, Y.

Publications and source records attributed to Xiao, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2023

A population-averaged structural connectomic brain atlas of 422 HCP-Aging subjects

Population-averaged brain atlases, that are represented in a standard space with anatomical labels, are instrumental tools in neurosurgical planning and the study of neurodegenerative conditions. Traditional brain atlases are primarily derived from anatomical scans and contain limited information regarding the axonal organization of the white matter. With the advance of diffusion MRI that allows the modelling of fiber orientation distribution (FOD) in the brain tissue, there is an increasing interest for a population-averaged FOD template, especially based on a large healthy aging cohort, to offer structural connectivity information for connectomic surgery and analysis of neurodegeneration. The dataset described in this article contains a set of multi-contrast structural connectomic MRI atlases, including T1w, T2w, and FOD templates, along with the associated whole brain tractograms. The templates were made using multi-contrast group-wise registration based on 3T MRIs of 422 Human Connectome Project in Aging (HCP-A) subjects. To enhance the usability, probabilistic tissue maps and segmentation of 22 subcortical structures are provided. Finally, the subthalamic nucleus shown in the atlas is parcellated into sensorimotor, limbic, and associative sub-regions based on their structural connectivity to facilitate the analysis and planning of deep brain stimulation procedures. The dataset is available on the OSF Repository: https://osf.io/p7syt. Specifications table O_TBL View this table: org.highwire.dtl.DTLVardef@59fb82org.highwire.dtl.DTLVardef@18f1f44org.highwire.dtl.DTLVardef@14de18dorg.highwire.dtl.DTLVardef@1318a8org.highwire.dtl.DTLVardef@1b7bea8_HPS_FORMAT_FIGEXP M_TBL C_TBL Value of the dataO_LIThese publicly available templates were created using 422 HCP-Aging subjects, representing averaged anatomical and structural connectivity features of the healthy aging brain. C_LIO_LIMatching T1w, T2w, and fiber orientation distribution (FOD) templates are provided, together with the associated tractograms that contain 20K and 2 million streamlines. C_LIO_LISegmentation of 22 subcortical structures and probabilistic tissue maps are provided to enhance the usability of the templates. C_LIO_LIParcellation of the subthalamic nucleus, based on structural connectivity of the included cohort at 0.3 x 0.3 x 0.3 mm3 resolution, is provided. C_LI

bioengineering↗

bioRxiv2023

A NanoDam toolkit for tissue-specific transcription factor profiling in C. elegans

During development of multicellular organisms, cells must execute precise molecular decisions to achieve cell fate specification and differentiation. These decisions are orchestrated by networks of transcription factors (TFs) which act to regulate gene expression of specific cohorts of genes to ultimately confer identity. Depending on the cellular context, TF expression can vary dramatically both spatially and temporally. These differences in expression patterns can result in tissue-specific differences in TF binding to downstream targets. To identify targets on a tissue-specific basis, Targeted DamID (TaDa) has been recently introduced to generate TF binding profiles in various models including C. elegans. However, TaDa suffers from portability such that a new promoter-TF fusion transgene must be constructed for every new experimental condition of interest. Here, we adapt NanoDam for usage in C. elegans, which relies on endogenous TF-GFP knock-ins, a plethora of which have already been generated by the community. We report that NanoDam single copy transgenes consisting of lowly expressed, tissue-specific GFP nanobody-Dam fusions, when combined with endogenous GFP-tagged alleles of TFs, results in robust, tissue-specific profiling. Using an endogenous GFP-tagged allele of EGL-43/EVI1, we performed NanoDam profiling of two disparate tissue types, the anchor cell (AC) and dopaminergic neurons, and identify targets unique to each and shared by both cell types. We also identify two GATA TFs, ELT-6 and EGL-18, as novel regulators of AC invasion. Together, we demonstrate that NanoDam is capable of profiling endogenous GFP-tagged TFs to identify novel downstream targets in specific cell types of C. elegans.

genetics↗

bioRxiv2023

Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides

CBASS is a common anti-phage immune system that uses cyclic oligonucleotide signals to activate effectors and limit phage replication. In turn, phages encode anti-CBASS (Acb) proteins. We recently uncovered a widespread phage anti-CBASS protein Acb2 that acts as a "sponge" by forming a hexamer complex with three cGAMP molecules. Here, we identified that Acb2 binds and sequesters many CBASS and cGAS-produced cyclic dinucleotides in vitro and inhibits cGAMP-mediated STING activity in human cells. Surprisingly, Acb2 also binds CBASS cyclic trinucleotides 333-cyclic AMP-AMP-AMP (cA3) and 333-cAAG with high affinity. Structural characterization identified a distinct binding pocket within the Acb2 hexamer that binds two cyclic trinucleotide molecules and another binding pocket that binds to cyclic dinucleotides. Binding in one pocket does not allosterically alter the other, such that one Acb2 hexamer can simultaneously bind two cyclic trinucleotides and three cyclic dinucleotides. Phage-encoded Acb2 provides protection from Type III-C CBASS that uses cA3 signaling molecules in vivo and blocks cA3-mediated activation of the endonuclease effector in vitro. Altogether, Acb2 sequesters nearly all known CBASS signaling molecules through two distinct binding pockets and therefore serves as a broad-spectrum inhibitor of cGAS-based immunity.

microbiology↗

bioRxiv2023

Predicting Parkinson's disease progression using MRI-based white matter radiomic biomarker and machine learning: a reproducibility and replicability study

BackgroundThe availability of reliable biomarkers of Parkinsons disease (PD) progression is critical to the understanding of the disease and development of treatment options. Magnetic Resonance Imaging (MRI) provides a promising source of PD biomarkers, however, neuroimaging results have been shown to be markedly sensitive to analytical conditions and population sampling, which motivates investigations of their robustness. This study is part of a project to investigate the replicability of 11 structural MRI measures of PD identified in a recent review. ObjectiveThis paper attempts to reproduce (similar data, similar analysis) and replicate (variations in data and analysis) the design of the machine learning (ML) model described in [1] to predict PD progression from T1-weighted MRIs. MethodsWe used the Parkinsons Progression Markers Initiative dataset (PPMI, ppmi-info.org) used in [1] and we followed as closely as possible the original methods. We also investigated slight methodological variations in cohort selection, feature extraction, ML model design, and evaluation techniques. ResultsThe Area under the ROC Curve (AUC) achieved by our model closely reproducing the original study remained lower than 0.5. Across all tested models, we obtained a peak AUC of 0.685, which is better than chance performance but remained lower than the AUC value of 0.795 reported in [1]. ConclusionWe managed to train a model that predicts disease progression with a performance better than chance on a cohort extracted from the PPMI dataset, using methods adapted from [1]. However, the performance of this model remains substantially lower than the one reported in [1]. Our difficulties to reproduce or replicate the original work are likely explained by the relatively low sample size in the original study. We provide recommendations on how to improve the reproducibility of MRI-based ML models of PD in the future.

neuroscience↗

bioRxiv2023

RNA-binding protein YBX1 promotes Type H vessels dependent bone formation in an m5C-dependent manner

RNA Binding Proteins (RBPs) interact with RNA and ubiquitously regulating RNA transcripts during their life cycle. Previous works showed that RBPs play fundamental roles in the progression of angiogenesis-related diseases. However, the role of RBPs in skeletal endothelium-dependent bone formation and osteogenesis is unclear. Here, we show that RBP-Ybx1 was strongly reduced in bone vasculature from ovariectomy-induced osteoporotic mice. Endothelial cell-specific deletion of Ybx1 impaired CD31hiEMCNhi endothelium morphology and osteogenesis and resulted in low bone mass, while its overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss in OVX mice. Mechanistically, Ybx1 deletion disrupted CD31, EMCN and BMP4 stability in an m5C-dependent manner and blocked endothelial-derived BMP4 release, thereby inhibiting osteogenic differentiation of BMSCs. Administration of recombinant BMP4 protein promoted osteogenic differentiation of BMSCs and restored impaired bone formation in Ybx1i{Delta}EC mice. Finally, tail vein injection of CD31-modified PEG-PLGA carrying sciadopitysin, a natural Ybx1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels decline and improved the restoration of bone mass both in OVX and aging animals. These findings demonstrated the role of RBP-Ybx1 in angiogenesis-dependent bone formation and provided a novel therapeutic approach for ameliorating aging-related and postmenopausal osteoporosis.

molecular biology↗

bioRxiv2023

A parabrachial-hypothalamic parallel circuit governs cold defense in mice

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Remarkable advances have been made in understanding how neurocircuits centered in the hypothalamic preoptic area (POA), the brains thermoregulation center, control warm defense, whereas mechanisms by which the POA regulates cold defense remain unclear. Here, we confirmed that the pathway from the lateral parabrachial nucleus (LPB) to the POA, is critical for cold defense. Parallel to this pathway, we uncovered that a pathway from the LPB to the dorsomedial hypothalamus (DMH), namely the LPB[->]DMH pathway, is also essential for cold defense. Projection-specific blockings revealed that both pathways provide an equivalent and cumulative contribution to cold defense, forming a parallel circuit. Specifically, activation of the LPB[->]DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and physical activity. Further, we identified a subpopulation of somatostatin+ neurons in the LPB that target the DMH to promote BAT thermogenesis. Therefore, we reveal a parabrachial-hypothalamic parallel circuit in governing cold defense in mice. This not only enables resilience to hypothermia but also provides a scalable and robust network in heat production, reshaping our understanding of how neural circuits regulate essential homeostatic behaviors.

neuroscience↗

bioRxiv2023

Using macromolecular electron densities to improve the enrichment of active compounds in virtual screening

The quest for more effective virtual screening algorithms is hindered by the scarcity of training data, calling for innovative approaches. This study presents the first use of experimental electron density (ED) data for improving active compound enrichment in virtual screening, supported by EDs ability to reflect the time-averaged behavior of ligands and solvents in the binding pocket. Experimental ED-based grid matching score (ExptGMS) was developed to score compounds by measuring the degree of matching between their binding conformations and a series of multi-resolution experimental ED grids. The efficiency of ExptGMS was validated using both in-silico tests with the Directory of Useful Decoys-Enhanced dataset and wet-lab tests on Covid-19 3CLpro-inhibitors. ExptGMS improved the active compound enrichment in top-ranked molecules by approximately 20%. Furthermore, ExptGMS helped identify four new and active inhibitors of 3CLpro, with the top showing an IC50 value of 1.9 {micro}M. To facilitate the use of ExptGMS, we developed an online database containing experimental ED grids for over 17,000 proteins.

bioinformatics↗

bioRxiv2023

Integration of recognition, episodic, and associative memories during complex human behavior

The ability to transiently remember what happened where and when is a cornerstone of cognitive function. Forming and recalling working memories depends on detecting novelty, building associations to prior knowledge, and dynamically retrieving context-relevant information. Previous studies have scrutinized the neural machinery for individual components of recognition or associative memory under laboratory conditions, such as recalling elements from arbitrary lists of words or pictures. In this study, we implemented a well-known card- matching game that integrates multiple components of memory formation together in a naturalistic setting to investigate the dynamic neural processes underlying complex natural human memory. We recorded intracranial field potentials from 1,750 depth or subdural electrodes implanted in 20 patients with pharmacologically-intractable epilepsy while they were performing the task. We leveraged generalized linear models to simultaneously assess the relative contribution of neural responses to distinct task components. Neural activity in the gamma frequency band signaled novelty and graded degrees of familiarity, represented the strength and outcome of associative recall, and finally reflected visual feedback on a trial-by-trial basis. We introduce an attractor-based neural network model that provides a plausible first-order approximation to capture the behavioral and neurophysiological observations. The large-scale data and models enable dissociating and at the same time dynamically tracing the different cognitive components during fast, complex, and natural human memory behaviors.

neuroscience↗

bioRxiv2023

Duckweed evolution: from land back to water

Terrestialization is supposedly an important evolutionary process plant experience. However, directions of land back to water acquired little attention. Here we integrate multiproxy evidence to elucidate the evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in roots structure and stomatal function and decrease in lignocellulose content, accompanied by gradual contraction in relevant gene numbers and/or decline in transcription. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also related to the adaptation of duckweed to floating growth. This study reconstructs the evolution history of duckweeds from land back to water, reverse to that of early land plants. SummaryWith terrestrialization being the popularly acknowledged plant evolutionary process, little is known about the evolution of higher plant from land back to water. Here we integrate multiproxy evidence to elucidate the gradual reverse evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in the structure of roots, the function of stomata, and decrease in lignocellulose content, accompanied by gradient contraction in relevant gene numbers and/or decline in transcript expression. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also highly related to the adaptation of duckweed to floating growth. Our study combined with the fossil evidence reconstruct the evolution history of duckweeds from land back to water, reverse to that of early land plants. This study reconstructed the process of how a land plant returns to water, a reverse evolutionary approach which is different from what we studied in textbook about plant terrestrialization. This finding could be helpful for us to deeply and widely understand the adaptation of plant to the environment, and to expand and deepen the knowledge of evolution theory.

evolutionary biology↗

bioRxiv2023

Artificially cultivated duckweed: a high-efficiency starch producer

The increasing demand for starch has been a social struggle. We report a new technology that efficiently produces starch from duckweed. Although Landoltia punctata has a dramatic contraction of gene families, its starch content and productivity reached 72.2% (dry basis) and 10.4 g m-2 d-1 in 10 days, equivalent to a yield of 38.0 t ha-1 y-1 under nutrient limitation and CO2 elevation treatment. Meanwhile, we also examined the mechanism of duckweeds high starch accumulation. This is exhibited in the regulation of DNA methylation and transcription factors as well as the significantly up-regulated transcription levels and the increased enzyme activities of key genes in starch biosynthesis. Meantime, while nitrogen redistribution was enhanced, sucrose biosynthesis and transportation, and lignocellulose biosynthesis were all reduced. These alterations led to a reduction in lignocellulose and protein content and ultimately an increase in an accumulation of starch in the chloroplast. This work demonstrates duckweeds potential of being a highly efficient starch producer.

plant biology↗

bioRxiv2023

NRF2 deficiency promotes ferroptosis of astrocytes mediated by oxidative stress in Alzheimer's disease

Oxidative stress is involved in the pathogenesis of Alzheimers disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aim to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. Postmortem frontal cortex tissues from patients with AD and nondemented controls and brain tissue from the 3xTg AD mouse model and wild-type mice (10 months old) were used. Immunofluorescence staining for Nrf2, the ROS marker NADPH oxidase 4 (NOX4), and GFAP was performed. We further induced Nrf2 deficiency in mouse astrocytes by using RNAi and assessed the changes in ROS, ferroptosis, lipid peroxidation, and mitochondrial dysfunction by using western blotting and immunofluorescence staining. We found decreased expression of Nrf2 and upregulated expression of NOX4 in the frontal cortex from patients with AD and in the cortex of 3xTg mice compared to control mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes. In conclusion, these results suggest that Nrf2 promotes ferroptosis of astrocytes involving oxidative stress in AD.

neuroscience↗

bioRxiv2023

DNP-assisted solid-state NMR enables detection of proteins at nanomolar concentrations in fully protonated cellular environments

With the sensitivity enhancements conferred by dynamic nuclear polarization (DNP), magic angle spinning (MAS) solid state NMR spectroscopy experiments can attain the necessary sensitivity to detect very low concentrations of proteins. This potentially enables structural investigations of proteins at their endogenous levels in their biological contexts where their native stoichiometries with potential interactors is maintained. Yet, even with DNP, experiments are still sensitivity limited. Moreover, when an isotopically-enriched target protein is present at physiological levels, which typically range from low micromolar to nanomolar concentrations, the isotope content from the natural abundance isotopes in the cellular milieu can outnumber the isotope content of the target protein. Using isotopically enriched yeast prion protein, Sup35NM, diluted into natural abundance yeast lysates, we optimized sample composition we find that modest cryoprotectant concentrations and fully protonated environments support efficient DNP. We experimentally validated theoretical calculations of the limit of specificity for an isotopically enriched protein in natural abundance cellular milieu. We establish that, using pulse sequences that are selective for adjacent NMR-active nuclei, proteins can be specifically detected in cellular milieu at concentrations in the hundreds of nanomolar. Finally, we find that maintaining native stoichiometries of the protein of interest to the components of the cellular environment may be important for proteins that make specific interactions with cellular constituents.

biophysics↗

bioRxiv2023

Two teosintes made modern maize

Despite its global importance as a crop with broad economic, dietary, and cultural importance, the origins of maize and its closest wild relatives remained the topic of vigorous debate for nearly a century. Molecular analyses ultimately concluded that maize was domesticated once from a common ancestor with its closest extant relative, the lowland wild grass Zea mays ssp. parviglumis. But neither the current genetic model nor earlier models based on archaeological data account for the totality of available data, and recent work has highlighted the potential contribution of a second wild relative, the highland Zea mays ssp. mexicana. Here we present a detailed population genetic analysis of the contributions of both wild taxa to modern maize diversity using the largest sample of traditional maize varieties sequenced to date. We show that all modern maize can trace its origin to an ancient admixture event between domesticated ancient maize and Zea mays ssp. mexicana in the highlands of Mexico ca 5300 cal BP, some 4,000 years after domestication began. We show that variation in admixture is a key component of modern maize genetic and phenotypic diversity, both at the level of individual loci and as a factor driving a substantial component of additive genetic variation across a number of agronomic traits. Our results clarify the long-debated origin of modern maize, highlight the potential contributions of crop wild relatives to agronomic improvement, and raise new questions about the anthropogenic mechanisms underlying multiple waves of dispersal throughout the Americas. One-Sentence SummaryOur results clarify the long-debated origin of modern maize and highlight the contributions of crop wild relatives to the agronomic improvement of modern varieties.

evolutionary biology↗

bioRxiv2023

Gastrodin ameliorates synaptic impairment, reestablishes mitochondrial membrane potential and reduces oxidative stress in N2a/APP cells through the ERK1/2 and GSK-3beta pathways

Alzheimers disease (AD) is featured by abnormal {beta}-amyloid (A{beta}) deposition, neurofibrillary tangle formation, downstream mitochondrial dysfunction, oxidative stress, and synaptic loss. Gastrodin, a phenolic glycoside, has shown neuroprotective effect and used in the treatment of a range of brain diseases. Here we aim to assess the mechanisms and signaling pathways involved in the neuroprotective effect of gastrodin in murine neuroblastoma N2a cells expressing human Swedish mutant amyloid precursor protein (N2a/APP). The levels of pre- and postsynaptic proteins, amyloid precursor protein C-terminal fragments (APP-CTFs), levels of tau, glycogen synthase kinase-3 {beta} (GSK-3{beta}), extracellular regulated kinase (ERK), and c-Jun N-terminal Kinase (JNK) were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well as immunofluorescence staining for lipid peroxidation (4{square}hydroxynonenal) and DNA oxidation (8{square}hydroxy{square}2{square}deoxyguanosine), were performed. We found that gastrodin treatment increased the levels of presynaptic SNAP25, synaptophysin, and postsynaptic PSD95, reduced phosphorylated tau protein Ser396, and APP-CTFs in N2a/APP cells. In addition, gastrodin reduced the levels of reactive oxygen species generation, lipid peroxidation, and DNA oxidation, reestablished mitochondrial membrane potential. Upregulated levels of phosphorylated-GSK-3{beta}, reduced levels of phosphorylated-ERK, and phosphorylated-JNK were involved the protective effect of gastrodin. In conclusion, we demonstrated a neuroprotective effect of gastrodin in N2a/APP cell line.

neuroscience↗

bioRxiv2023

Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways

Alzheimers disease is characterized by abnormal {beta}-amyloid (A{beta}) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetins protective effect on the toxicity induced by the A{beta}42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with A{beta}42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 {beta} (GSK-3{beta}) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented A{beta}42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the A{beta}42 oligomer. Moreover, myricetin prevented the A{beta}42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3{beta} and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against A{beta}42 oligomer-induced toxicity.

neuroscience↗

bioRxiv2022

ClpP/ClpX deficiency impairs mitochondrial functions and mTORC1 signaling during spermatogenesis and meiosis

Caseinolytic protease proteolytic subunit (ClpP) and caseinolytic protease X (ClpX) are mitochondrial matrix peptidases that activate mitochondrial unfolded protein response to maintain protein homeostasis in the mitochondria. However, the role of ClpP and ClpX in spermatogenesis remains largely unknown. In this study, we demonstrated the importance of ClpP/ClpX for meiosis and spermatogenesis with two conditional knockout (cKO) mouse models. We found that ClpP/ClpX deficiency reduced mitochondrial functions and quantity in spermatocytes, affected energy supply during meiosis and attenuated zygotene-pachytene transformation of the male germ cells. The dysregulated spermatocytes finally underwent apoptosis resulting in decreased testicular size and vacuolar structures within the seminiferous tubules. We found mTORC1 pathway was over-activated after deletion of ClpP/ClpX in spermatocytes. Long-term inhibition of the mTORC1 signaling via rapamycin treatment in vivo partially rescue spermatogenesis. The data reveal the novel roles of ClpP and ClpX in regulating meiosis and spermatogenesis. One-Sentence SummaryClpP/ClpX is required for maintaining mitochondrial functions in spermatocytes during meiosis and spermatogenesis.

developmental biology↗

bioRxiv2022

Extracellular vesicle cargo metabolome changes in response to the mesenchymal stromal cell microenvironment and influences cell quiescence and activation in a human breast cancer cell model

Breast cancer is the leading cause of cancer mortality in women worldwide and commonly metastasizes to the bone marrow, drastically reducing patient prognosis and survival. In the bone marrow niche, metastatic cells can enter into a dormant state, thereby evading immune surveillance and treatment, and can be reactivated to enter a proliferative state due to poorly understood cues. Mesenchymal stromal cells (MSCs) maintain cells in this niche partly by secreting extracellular matrix and paracrine factors and by responding to regenerative cues. MSCs also produce extracellular vesicles (EVs) that carry a range of cargoes, some of which are implicated in cell signalling. Here, we investigate if the changing metabolic state of MSCs alters the cargoes they package into EVs, and how these changing cargoes act on dormant breast cancer cells (BCCs) using an in vitro BCC spheroid model and a scratch assay to create a regenerative demand on MSCs. Our findings show that EVs produced by standard MSCs contain glycolytic metabolites that maintain BCC dormancy. When MSCs are placed under a regenerative demand and increase their respiration to fuel differentiation, these metabolites disappear from the EV cargo and their absence encourages rapid growth in the BCC spheroids. This work implicates EVs in cancer cell dormancy in the bone marrow niche and indicates that pressures on the niche, such as regeneration, can be a driver of BCC activation.

cell biology↗

bioRxiv2022

Bright and sensitive red voltage indicators for imaging action potentials in brain slices and pancreatic islets

As fast developing tools for observing cellular membrane potential, red-emitting genetically encoded voltage indicators (GEVIs) reduce auto-fluorescence background, allow multiplexed recordings, and enable all-optical electrophysiology, but have been limited by either insensitivity or dimness. Here, we report a pair of red GEVIs, Cepheid1b/s, with improved sensitivity, brightness, and photostability. Cepheid1 indicators faithfully report cellular excitability in pancreatic islets and neural activity in acute brain slices.

neuroscience↗