Biology subjects

Jackman, S.

Publications and source records attributed to Jackman, S..

5 recordsLinked to original sources

bioRxiv2026

Mapping AMPA and NMDA receptors at mouse brain hippocampal synapses by cryo-ET

AMPA and NMDA receptors are fundamental to synaptic transmission through the detection of released neurotransmitter. These ion channels open in response to glutamate binding, resulting in depolarization of the postsynaptic membrane and influx of calcium. Receptor localization plays a key role in synaptic strength, and changes in receptor number and location underpin synaptic plasticity, learning and memory. Here we apply receptor subunit-specific antibody fragments and multiplexed gold nanoparticle conjugates, together with cryo-electron tomography (cryo-ET), to elucidate the in-situ molecular organization of AMPA and NMDA receptors at hippocampal synapses in adult mouse brain tissue. AMPA receptors are predominantly found in densely packed liquid-like clusters, with interspersed NMDA receptors and adjacent NMDA receptor clusters. By direct localization of individual receptors, we provide molecular-resolution insight into the distribution of AMPA and NMDA receptors across the synapse, at peri and extrasynaptic sites, and within endocytosed vesicles. Visualization of multiple presynaptic vesicle fusion events suggests that receptors are near, but not always directly adjacent to, transmitter release sites. By mapping AMPA and NMDA receptors, and glutamate release sites, we provide receptor-resolution insight into the structure and function of brain hippocampal synapses.

neuroscience↗

bioRxiv2026

Plac1 Ablation Disrupts Signaling Pathways Essential for Prenatal Development and Induces a Preeclampsia-Associated Transcriptomic Signature

Plac1 is an X-linked gene essential for placental and embryonic development. A knockout (KO) mouse model was used to define placental gene expression changes associated with Plac1 loss at E16.5 and E18.5 using gene expression microarray. Genes exhibiting at least a 1.5-fold change and FDR < 0.05 were considered significant. At E16.5, 717 genes were downregulated and 796 upregulated in KO placentas relative to wild type (WT), whereas at E18.5, 1121 genes were downregulated and 1151 upregulated. Subsets of highly and uniquely dysregulated genes were examined by gene-level curation alongside systems-level analyses, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity Pathway Analysis (IPA), applied to the full differentially expressed gene (DEG) datasets. Downregulated genes were enriched for Rho GTPase-mediated and actin cytoskeleton-based processes, as well as membrane-associated signaling pathways with established roles in placental and embryonic development, vascular function, and branching morphogenesis. Overlap with pathways and molecular features associated with preeclampsia was also observed. In contrast, upregulated genes reflected, in part, immune activation and oxidative stress responses. These findings represent an important exploratory, hypothesis-generating analysis and provide a biologically coherent framework for understanding how Plac1 loss may be associated with placental dysfunction and pregnancy-related disease.

developmental biology↗

bioRxiv2026

Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell-based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1-driven epithelial dysfunction as a potential therapeutic strategy.

cell biology↗

bioRxiv2022

Relationship between thyroid hormones and associated metabolites and gene expression bioindicators in the serum of Rana catesbeiana tadpoles and frogs during metamorphosis

Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3,5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28{+/-}10 and 2.3{+/-}0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.

developmental biology↗

bioRxiv2019

A robust benchmark for germline structural variant detection

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution, and comprehensiveness. Translating these methods to routine research and clinical practice requires robust benchmark sets. We developed the first benchmark set for identification of both false negative and false positive germline SVs, which complements recent efforts emphasizing increasingly comprehensive characterization of SVs. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle (GIAB) Consortium integrated 19 sequence-resolved variant calling methods, both alignment- and de novo assembly-based, from short-, linked-, and long-read sequencing, as well as optical and electronic mapping. The final benchmark set contains 12745 isolated, sequence-resolved insertion and deletion calls [≥]50 base pairs (bp) discovered by at least 2 technologies or 5 callsets, genotyped as heterozygous or homozygous variants by long reads. The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.66 Gbp and 9641 SVs supported by at least one diploid assembly. Support for SVs was assessed using svviz with short-, linked-, and long-read sequence data. In general, there was strong support from multiple technologies for the benchmark SVs, with 90 % of the Tier 1 SVs having support in reads from more than one technology. The Mendelian genotype error rate was 0.3 %, and genotype concordance with manual curation was >98.7 %. We demonstrate the utility of the benchmark set by showing it reliably identifies both false negatives and false positives in high-quality SV callsets from short-, linked-, and long-read sequencing and optical mapping.

genomics↗