Biology subjects

Schroeder, A.

Publications and source records attributed to Schroeder, A..

28 records · Page 2Linked to original sources

bioRxiv2022

Control of neocortical memory by long-range inhibition in layer 1

Mounting evidence identifies layer 1 (L1) as a central site of memory in sensory neocortex. While this work revealed plasticity in several excitatory brain-wide afferent systems, the existence, connectivity and memory-related signaling of long-range inhibitory input to L1 remains elusive. We report that inhibitory afferents from zona incerta project specifically to auditory cortex L1, where they connect selectively to interneurons to disinhibit the cortical circuit and facilitate behavioral memory. Chronic calcium imaging of these synapses identifies a balanced form of plasticity that develops rapidly during threat learning and is characterized by the de novo appearance of negative stimulus responses which transmit most information. Our results therefore pinpoint malleability of long-range (dis)inhibitory afferents to L1 as a key factor for the exquisite computational flexibility of this unique layer.

neuroscience↗

bioRxiv2021

DNase treatment improves viral enrichment in agricultural soil viromes

The small genomes of most viruses make it difficult to fully capture viral diversity in metagenomes dominated by DNA from cellular organisms. Viral size-fraction metagenomics (viromics) protocols facilitate enrichment of viral DNA from environmental samples, and these protocols typically include a DNase treatment of the post-0.2 m viromic fraction to remove contaminating free DNA prior to virion lysis. However, DNase may also remove desirable viral genomic DNA (e.g., contained in virions compromised due to frozen storage or laboratory processing), suggesting that DNase-untreated viromes might be useful in some cases. In order to understand how virome preparation with and without DNase treatment influences the resultant data, here we compared 15 soil viromes (7 DNase-treated, 8 untreated) from 8 samples collected from agricultural fields prior to tomato planting. DNase-treated viromes yielded significantly more assembled viral contigs, contained significantly less non-viral microbial DNA, and recovered more viral populations (vOTUs) through read mapping. However, DNase-treated and untreated viromes were statistically indistinguishable, in terms of ecological patterns across viral communities. Although results suggest that DNase treatment is preferable where possible, in comparison to previously reported total metagenomes from the same samples, both DNase-treated and untreated viromes were significantly enriched in viral signatures by all metrics compared, including a ~225 times greater proportion of viral reads in untreated viromes compared to total metagenomes. Thus, even without DNase treatment, viromics was preferable to total metagenomics for capturing viral diversity in these soils, suggesting that preparation of DNase-untreated viromes can be worthwhile when DNase treatment is not possible. ImportanceViromics is becoming an increasingly popular method for characterizing soil viral communities. DNase treatment of the viral size fraction prior to DNA extraction is meant to reduce contaminating free DNA and is a common step within viromics protocols to ensure sequences are of viral origin. However, some samples may not be amendable to DNase treatment due to viral particles being compromised either in storage (i.e. frozen) or during other sample processing. To date, the effect of DNase treatment on the recovery of viruses and downstream ecological interpretations of soil viral communities is not thoroughly understood. This work sheds light on these questions and indicates that while DNase treatment of soil viromes improves recovery of viral populations, this improvement is modest in comparison to the gains made by viromics over total soil metagenomics. Further, DNase treatment may not be necessary to observe the ecological patterns structuring soil viral communities.

microbiology↗

bioRxiv2021

Bioluminescent Synthetic Cells Communicate with Natural Cells and Self-Activate Light-Responsive Proteins

Development of regulated cellular processes and signaling methods in synthetic cells is essential for their integration with living materials. Light is an attractive tool to achieve this, but the limited penetration depth into tissue of visible light restricts its usability for in-vivo applications. Here, we describe the synthesis and application of blue-light-generating synthetic cells using bioluminescence, dismissing the need for an external light source. First, the lipid membrane and internal composition of light-producing synthetic cells were optimized to enable high-intensity emission. Next, we show these cells capacity for triggering bioprocesses in natural cells by initiating asexual sporulation of dark-grown mycelial cells of the fungus Trichoderma atroviride in a quorum-sensing like mechanism. Finally, we demonstrate regulated transcription and membrane recruitment in synthetic cells using bioluminescent self-activating fusion proteins. These functionalities pave the way for deploying synthetic cells as embeddable microscale light sources that are capable of activating engineered processes inside tissues.

bioengineering↗

bioRxiv2021

Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases

Neurons within the tumor microenvironment promote cancer progression, thus their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer crosstalk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer-cell viability. In vivo, bupivacaine-loaded nanoparticles administered intravenously, suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

cancer biology↗

bioRxiv2020

Integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network

Recent advances in spatial transcriptomics technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and histology in spatial transcriptomics data analysis. Through graph convolution, SpaGCN aggregates gene expression of each spot from its neighboring spots, which enables the identification of spatial domains with coherent expression and histology. The subsequent domain guided differential expression analysis then detects genes with enriched expression patterns in the identified domains. Analyzing five spatially resolved transcriptomics datasets using SpaGCN, we show it can detect genes with much more enriched spatial expression patterns than existing methods. Furthermore, genes detected by SpaGCN are transferrable and can be utilized to study spatial variation of gene expression in other datasets. SpaGCN is computationally fast, making it a desirable tool for spatial transcriptomics studies.

bioinformatics↗

bioRxiv2020

Chemotherapeutic Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Fertility and Anticancer Activity

Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. This can have positive or negative effects. We demonstrate a 2-fold increase in nanoparticle accumulation in the ovaries during female mouse ovulation compared to the non-ovulatory stage following intravenous administration. Accumulation in the reproductive system is favored by nanoparticles smaller than 100 nm. Chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased short-term and long-term fertility when compared to the free drug. Breast cancer treated with nanomedicines during ovulation results in higher drug accumulation in the reproductive system rather than at the site of the tumor, reducing treatment efficacy. Conversely, ovarian cancer treatment was improved by enhanced nanoparticle accumulation in the ovaries during ovulation. Our findings suggest that the menstrual cycle should be considered when designing and implementing nanotherapeutics for females.

bioengineering↗

bioRxiv2020

Towards Building a Smart Kidney Atlas: Network-based integration of multimodal transcriptomic, proteomic, metabolomic and imaging data in the Kidney Precision Medicine Project

AO_SCPLOWBSTRACTC_SCPLOWKidney Precision Medicine Project (KPMP) is building a spatially-specified human tissue atlas at the single-cell resolution with molecular details of the kidney in health and disease. Here, we describe the construction of an integrated reference tissue map of cells, pathways and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 55 subjects. We use single-cell and -nucleus transcriptomics, subsegmental laser microdissection bulk transcriptomics and proteomics, near-single-cell proteomics, 3-D nondestructive and CODEX imaging, and spatial metabolomics data to hierarchically identify genes, pathways and cells. Integrated data from these different technologies coherently describe cell types/subtypes within different nephron segments and interstitium. These spatial profiles identify cell-level functional organization of the kidney tissue as indicative of their physiological functions and map different cell subtypes to genes, proteins, metabolites and pathways. Comparison of transcellular sodium reabsorption along the nephron to levels of mRNAs encoding the different sodium transporter genes indicate that mRNA levels are largely congruent with physiological activity.This reference atlas provides an initial framework for molecular classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

bioinformatics↗

bioRxiv2020

Evidence for non-methanogenic metabolisms in globally distributed archaeal clades basal to the Methanomassiliicoccales

Recent discoveries of mcr and mcr-like complexes in genomes from diverse archaeal lineages suggest that methane (and more broadly alkane) metabolism is an ancient pathway with complicated evolutionary histories. The conventional view is that methanogenesis is an ancestral metabolism of the archaeal class Thermoplasmata. Through comparative genomic analysis of 12 Thermoplasmata metagenome-assembled genomes (MAGs), we show that these microorganisms do not encode the genes required for methanogenesis, which suggests that this metabolism may have been laterally acquired by an ancestor of the order Methanomassiliicoccales. These MAGs include representatives from four orders basal to the Methanomassiliicoccales, including a high-quality MAG (95% complete) that likely represents a new order, Ca. Lunaplasma lacustris ord. nov. sp. nov. These MAGs are predicted to use diverse energy conservation pathways, such as heterotrophy, sulfur and hydrogen metabolism, denitrification, and fermentation. Two of these lineages are globally widespread among anoxic, sedimentary environments, with the exception of Ca. Lunaplasma lacustris, which has thus far only been detected in alpine caves and subarctic lake sediments. These findings advance our understanding of the metabolic potential, ecology, and global distribution of the Thermoplasmata and provide new insights into the evolutionary history of methanogenesis within the Thermoplasmata.

microbiology↗

bioRxiv2019

Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via its Ig4-5 domains. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.

neuroscience↗

bioRxiv2019

A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

scientific communication and education↗