Biology subjects

Sun, H.

Publications and source records attributed to Sun, H..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Evolution of chronic lymphocytic leukemia after allogeneic stem cell transplant

Allogeneic stem cell transplant (alloSCT) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) can result in cure in some patients. Analogous to chemotherapy and targeted therapy, we hypothesized that allogeneic cellular immunotherapies, including alloSCT and donor lymphocyte infusion (DLI), would impact malignant evolution through the application of selective immunologic pressure with reciprocal changes in the T cell compartment. We tested a cohort of 24 patients treated with HLA-matched alloSCT +/- DLI, two mediators of the graft versus leukemia (GVL) effect. Comparison of pre-alloSCT samples revealed that a key difference between responders (n=13) and non-responders (n=11) is the cellularity of leukemic cells. We further mapped mutational trajectories of tumor cells by whole exome sequencing (WES) of sort-purified CLL in 11 post-transplant relapsed patients and found evidence of subclonal leukemic evolution in 8/11 patients after nonmyeloablative human leukocyte antigen (HLA)-matched alloSCT. Different patterns of CLL evolution were observed, and these changes included putative CLL drivers in every case. To investigate the presence of immune-related variants in patients, we collected 19 T cell co-culture CRISPR datasets and identified the top positive and negative regulators of cancer cells response to T-cell-dependent killing. We found that most mutations linked to T-cell killing emerged after allo-SCT treatment, suggesting that selective pressures from the GVL effect may drive the evolution of these mutations. Together, these data identify cellular homogeneity as a key biomarker for susceptibility to GVL-driven immunity in CLL and illustrate how the leukemic cells further evolve to evade immunosurveillance. SIGNIFICANCEThe impact of allogeneic stem cell transplant (alloSCT) on subclonal leukemia evolution remains poorly understood. By performing whole exome sequencing (WES) on pre- and post-alloSCT patient samples, we reveal different patterns of CLL evolution and potential immune-related driver genes influencing CLL relapse and refractory disease post-alloSCT.

cancer biology↗

bioRxiv2025

ca-circSCN8A promotes HPASMCs ferroptosis via LLPS initiated R-Loop

BACKGROUNDFerroptosis has been implicated in pulmonary hypertension. Chromatin-associated RNAs are linked to ferroptosis. However, their role in pulmonary vascular ferroptosis in PH is unexplored. METHODSBioinformatics, Sanger sequencing, RNase R and others were employed to identify differentially higher expression of ca-circSCN8A. Functional gain and loss assays were employed to unveil the role of ca-circSCN8A in hypoxia-induced redox-dependent ferroptosis in HPASMCs and PH mice model. Interaction between ca-circSCN8A and FUS was detected via RNA immunoprecipitation and pull-down assays. FRAP, CHIRP-qPCR, MDA, GSH and GSSG were conducted to explore the potential molecular mechanism. RESULTSca-circSCN8A was firstly identified and confirmed to be upregulated in PH. Upregulation of ca-circSCN8A can promote hypoxia induced ferroptosis in HPASMCs. Under hypoxic conditions, ca-circSCN8A promoted the lactylation of FUS by recruiting EP300, leading to formation of LLPS of ca-circSCN8A/FUS/EP300. LLPS maintained the stability of the R-Loop formed by ca-circSCN8A and ferroptosis related-gene SLC7A11 promoter that inhibit the transcription of the SLC7A11 gene, further result in the disruption of the redox balance and causes ferroptosis in HPASMCs. CONCLUSIONSca-circSCN8A recruits EP300 to promote the lactylation of FUS, thereby promoting LLPS formation of ca-circSCN8A/EP300/FUS. Further, the LLPS motivates ca-circSCN8A to form R-loop with its non-host SLC7A11 and participating in the regulation of hypoxic induced HPASMCs redox-dependent ferroptosis. This is the first confirmation that circRNAs forming R-loops with non-host genes regulated by LLPS. Our findings indicated that ca-circSCN8A plays an important role in ferroptosis of hypoxic induced HPASMCs and may be a potential target for the treatment of PH.

molecular biology↗

bioRxiv2025

Fusobacteria nucleatum determines the expression of amphetamine-induced behavioral responses through an epigenetic phenomenon.

Amphetamines (AMPHs) are psychostimulants commonly used for the treatment of neuropsychiatric disorders. They are also misused (AMPH use disorder; AUD), with devastating outcomes. Recent studies have implicated dysbiosis in the pathogenesis of AUD. However, the mechanistic roles of microbes in AUD are unknown. Fusobacterium nucleatum (Fn) is a bacterium that increases in abundance in both rats and humans upon AMPH exposure. Fn releases short-chain fatty acids (SCFAs), bacterial byproducts thought to play a fundamental role in the gut-brain axis as well as the pathogenesis of AUD. We demonstrate that in gnotobiotic Drosophila melanogaster, colonization with Fn or dietary supplementation of the SCFA butyrate, a potent inhibitor of histone deacetylases (HDACs), enhances the psychomotor and rewarding properties of AMPH as well as its ability to promote male sexual motivation. Furthermore, solely HDAC1 RNAi targeted inhibition recapitulates these enhancements, pointing to a specific process underlying this Fn phenomenon. Of note is that the expression of these AMPH behaviors is determined by the increase in extracellular dopamine (DA) levels that result from AMPH-induced reversal of DA transporter (DAT) function, termed non-vesicular DA release (NVDR). The magnitude of AMPH-induced NVDR is dictated, at least in part, by DAT expression levels. Consistent with our behavioral data, we show that Fn, butyrate, and HDAC1 inhibition enhance NVDR by elevating DAT expression. Thus, the participation of Fn in AUD stems from its ability to release butyrate and inhibit HDAC1. These data offer a microbial target and probiotic interventions for AUD treatment.

neuroscience↗

bioRxiv2025

Atomistic Mechanism of Non-Canonical Voltage Gating in TREK K2P Channels

Two-pore-domain K+ (K2P) channels are essential regulators of cellular excitability and respond to various external stimuli that also include membrane potential for most K2P channels. Voltage gating is particularly pronounced in members of the TREK/TRAAK subfamily. This voltage sensitivity was surprising, as K2P channels lack a classical voltage sensing domain. Prior studies have attributed this non-canonical voltage sensing mechanism to the unique ion-flux gating properties of the K2P selectivity filter (SF), where inward currents induce fast inactivation, while depolarization activates the SF. Here, we performed large-scale molecular dynamics (MD) simulations across various voltages to gain an atomistic understanding of ion-flux gating in TREK channels. Our analysis revealed an asymmetric stability difference in the SF, enabling water influx into the filter due to conformational flexibility on the extracellular side. Inward flux inactivation occurs when water entry halts ion permeation, followed by the unbinding of three K+ ions, consistent with gating charge analysis. Additionally, MD simulations of TREK-2 mutants and the TWIK-1 channel, which exhibited increased SF flexibility, showed augmented SF water occupancy, aligning with their electrophysiological phenotypes. Key experimental evidence of this mechanism was provided by electrophysiology measurements, which showed that high extracellular sucrose slowed ion-flux inactivation by reducing water entry into the SF. These findings uncover the atomistic mechanism of voltage gating in TREK K2P channels and pave the way for exploring non-canonical voltage gating mechanisms in other ion channels.

biophysics↗

bioRxiv2024

Atomistic Mechanism of Cation Permeation and Pore Voltage Sensitivity in Cyclic Nucleotide-Gated CNGA1 Ion Channel

Mammalian cyclic nucleotide-gated (CNG) ion channels play a fundamental role in signal transduction within the visual and olfactory sensory cells, converting external stimuli into electrical signals. Here, using large-scale atomistic molecular dynamics (MD) simulations under transmembrane voltages, we uncover the atomistic mechanism of monovalent cation permeation in the homotetrameric CNGA1 channel, involving hydrated cations in the selectivity filter. We propose that hydration fluctuations in the central gate region, driven by pore flexibility, are the underlying mechanism for excess single-channel conductance noise and characteristic single-channel flickering. Furthermore, we suggest an atomistic mechanism for intrinsic voltage sensitivity in the channel pore, mediated by allosteric coupling between the selectivity filter and the central cavity gate. Our study provides atomistic insights into non-selective cation permeation and voltage sensitivity of the CNGA1 channel pore that could not be resolved by static structural analysis alone.

biophysics↗

bioRxiv2024

Discovery of Novel and Selective GPR17 Antagonists as Pharmacological Tools for Developing New Therapeutic Strategies in Diabetes and Obesity

G protein coupled receptors (GPCRs) are promising targets for diabetes and obesity therapy due to their roles in metabolism and excellent potential for pharmacological manipulation. We previously reported that Gpr17 ablation in the brain-gut axis leads to improved metabolic homeostasis, suggesting GPR17 antagonism could be developed for diabetes and obesity treatment. Here, we performed high throughput screening (HTS) and identified two new GPR17 antagonists (compound 978 and 527). Both compounds antagonized downstream Gi/o, Gq and {beta}-arrestin signaling with high selectivity for GPR17, but not the closely related purinergic and cysteinyl leukotriene receptors. The molecular mechanisms of antagonism were revealed through Schild analysis, structure-activity relationship (SAR) studies and homology modelling. Compound 978 and its analog (793) attenuated GPR17 signaling and promoted glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. In summary, we identified selective GPR17 antagonists through HTS, which represent promising pharmacological tools for developing new therapeutic strategies in diabetes and obesity. SignificanceOur work highlights the therapeutic potential of GPR17 antagonism in the treatment of diabetes and obesity by leveraging its role in metabolic regulation. In previous studies, we have shown that Gpr17 ablation improves metabolic homeostasis, and here we expanded our research by identifying two novel small molecule antagonists of GPR17 through high-throughput screening. The compounds inhibited multiple downstream signaling pathways of GPR17 with high selectivity over other closely related receptors. Of particular significance, compound 978 and its analogs not only attenuated GPR17 signaling but also increased glucagon-like peptide-1 (GLP-1) secretion, a critical hormone for glucose homeostasis and appetite regulation. These findings shed new light into the molecular mechanisms of GPR17 antagonism and introduce valuable pharmacological tools for further exploration of therapeutic strategies in diabetes and obesity.

pharmacology and toxicology↗

bioRxiv2024

Atomistic Mechanisms of Calcium Permeation Modulated by Q/R Editing and Selectivity Filter Mutations in GluA2 AMPA Receptors

GluA2 is a key subunit of AMPA receptor ion channels that is abundantly expressed in the vertebrate brain. Post-transcriptional Q/R editing of GluA2 renders AMPARs nearly impermeable to calcium ions, which is crucial for their normal function. Although previous studies have characterized conductivity and selectivity differences between edited and unedited GluA2 variants and heteromeric receptors incorporating GluA2, the atomistic mechanism remains largely unknown. In this study, we investigate ion permeation in the context of multiple Ca2+ binding sites along the pore predicted from MD simulations, considering both mutations and co-permeating monovalent ions. Patch clamp electrophysiology recordings confirmed a binding site at the intracellular mouth of the selectivity filter that confers selectivity for calcium over monovalent ions. A patient mutation at the same site has been previously shown to cause neurodevelopmental abnormalities. Furthermore, MD simulations of GluA2 with different arginine copy number at the Q/R site show that Ca2+ conduction is blocked in the presence of two arginines, whereas K+ is only blocked by four arginines, in explaining the results from decades of electrophysiological work. Finally, MD simulations revealed that Ca2+ reduces K+ conduction by preferentially occupying the intracellular SF binding site, whereas Na+ does not. This result is consistent with electrophysiological results from the D590 mutants, and suggests that divalent binding in the selectivity filter is a major determinant of AMPAR conductance.

biophysics↗

bioRxiv2024

Heterogeneous endocrine cell composition defines human islet functional phenotypes

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers, enabling the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes, analyzed using this pipeline, highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While and {beta} cell composition influenced insulin and glucagon secretory traits, the abundance of {delta} cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and {beta} cell replacement therapy.

physiology↗

bioRxiv2024

Heat Acclimation in Mice Requires Preoptic BDNF Neurons and Postsynaptic Potentiation

Heat acclimation (HA) is a key adaptive response in mammals to repeated heat exposure, essential for fitness and survival1-3. HA improves cardiovascular function, thermal comfort, and exercise capacity4, 5. However, the lack of a genetically tractable model has hindered understanding of the molecular and neural mechanisms underlying HA. Here, we show that 10 days of daily 38{degrees}C exposure lowers core body temperature (Tcore) and reduces anxiety during subsequent heat exposures in mice. HA increases brain-derived neurotrophic factor (BDNF) expression in the medial preoptic area (MPO). BDNF-expressing MPO neurons (MPOBDNF) show increased intrinsic heat sensitivity after HA. These neurons orchestrate downstream targets in the dorsomedial hypothalamus (DMH) and rostral raphe pallidus (rRPa) to mediate HA effects. BDNF, acting through its receptor tropomyosin-related kinase B (TrkB) in the DMH, facilitates the anxiolytic effect of HA by enhancing excitatory synaptic connections between MPOBDNF and DMH neurons. This study provides new insights into HA mechanisms, setting the stage for future research on heat stress reduction and exercise optimization.

neuroscience↗

bioRxiv2024

Structural insights into the opening mechanism of C1C2 channelrhodopsin

Channelrhodopsins, light-gated cation channels, enable precise control of neural cell depolarization or hyperpolarization with light in the field of optogenetics. This study integrates time-resolved serial crystallography and atomistic molecular dynamics (MD) simulations to resolve the structural changes during C1C2 channelrhodopsin activation. Our observations reveal that within the crystal environment, C1C2 predominantly remains in a light-activated state with characteristics of the M390 intermediate. Here, rearrangement of retinal within its binding pocket partially opens the central gate towards the extracellular vestibule. These structural changes initiate channel opening but were insufficient to allow K+ flow. Adjusting protonation states to represent the subsequent N520 intermediate in our MD simulations induced further conformational changes, including rearrangements of transmembrane helices 2 and 7, that opened the putative ion- translocation pathway. This allows spontaneous but low cation but not anion conduction, that matches experiments. Our findings provide critical structural insights into key intermediates of the channel opening mechanism, enhancing our understanding of ion conduction and selectivity in channelrhodopsins at an atomistic level.

biophysics↗

bioRxiv2024

High-resolution imaging atlas reveals context-dependent role of pancreatic sympathetic innervation in diabetic mice

Gaining a better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in islets of adult WT and diabetic mice. Our data shows that more than [~]30% /{beta}-cells are innervated by sympathetic nerves in both WT and diabetic mice. Also, sympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. Besides, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db/db mice, but decreases in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our comprehension of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation. HighlightsPancreatic sympathetic innervation plays an important role in glucose homeostasis. In our study, we systematically investigate sympathetic innervation in the islets of WT and diabetic mice. O_LI45.9% -cells and 31.8% {beta}-cells are innervated by sympathetic nerves in 10-week-old WT mice. C_LIO_LISympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. C_LIO_LIUnlike the core-mantle structure observed in WT and DIO mice, -cells and {beta}-cells are intermixed in db/db mice. C_LIO_LIPancreatic sympathetic denervation elicits varied responses across diabetic models, where it improves glucose tolerance and insulin sensitivity in db/db mice, yet it increases insulin sensitivity but reduces glucose tolerance in DIO mice. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/623708v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@183be78org.highwire.dtl.DTLVardef@4dc76borg.highwire.dtl.DTLVardef@5f5ca0org.highwire.dtl.DTLVardef@ba3cc7_HPS_FORMAT_FIGEXP M_FIG Summary of morphological and physiological phenotypes in diabetic mice. All data are normalized to that of WT-10 mice. The numbers of "+" refer to their relative numbers. {uparrow} or {downarrow} refers to increase or decrease, ns refers to "not significant". "-" refers to the experiment has not been carried out. C_FIG

neuroscience↗

bioRxiv2024

Target-specific design of drug-like PPI inhibitors via hot-spot-guided generative deep learning

Protein-protein interactions (PPIs) are vital therapeutic targets. However, the large and flat PPI interfaces pose challenges for the development of small-molecule inhibitors. Traditional computer-aided drug design approaches typically rely on pre-existing libraries or expert knowledge, limiting the exploration of novel chemical spaces needed for effective PPI inhibition. To overcome these limitations, we introduce Hot2Mol, a deep learning framework for the de novo design of drug-like, target-specific PPI inhibitors. Hot2Mol generates small molecules by mimicking the pharmacophoric features of hot-spot residues, enabling precise targeting of PPI interfaces without the need for bioactive ligands. The framework integrates three key components: a conditional transformer for pharmacophore-guided, drug-likeness-constrained molecular generation; an E(n)-equivariant graph neural network for accurate alignment with PPI hot-spot pharmacophores; and a variational autoencoder for generating novel and diverse molecular structures. Experimental evaluations demonstrate that Hot2Mol outperforms baseline models across multiple metrics, including docking affinities, drug-likenesses, synthetic accessibility, validity, uniqueness, and novelty. Furthermore, molecular dynamics simulations confirm the good binding stability of the generated molecules. Case studies underscore Hot2Mols ability to design high-affinity and selective PPI inhibitors, demonstrating its potential to accelerate rational PPI drug discovery.

bioinformatics↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗

bioRxiv2024

Semi-supervised Contrastive Learning for Bioactivity Prediction using Cell Painting Image Data

Morphological profiling has recently demonstrated remarkable potential for identifying the biological activities of small molecules. Alongside the fully supervised and self-supervised machine learning methods recently proposed for bioactivity prediction from Cell Painting image data, we introduce here a semi-supervised contrastive (SemiSupCon) learning approach. This approach combines the strengths of using biological annotations in supervised contrastive learning and leveraging large unannotated image datasets with self-supervised contrastive learning. SemiSupCon enhances downstream prediction performance of classifying MeSH pharmacological classifications from PubChem, as well as mode of action and biological target annotations from the Drug Repurposing Hub across two publicly available Cell Painting datasets. Notably, our approach has effectively predicted the biological activities of several unannotated compounds, and these findings were validated through literature searches. This demonstrates that our approach can potentially expedite the exploration of biological activity based on Cell Painting image data with minimal human intervention.

bioinformatics↗

bioRxiv2024

The Nematostella Wnt/β-catenin destruction complex provides insight into the evolution of the regulation of a major metazoan signal transduction pathway

The genesis of signaling pathways likely drove metazoan evolution, but the origins of these pathways and how they acquired signaling activity is poorly understood. Here, we studied functional evolution of the Wnt/{beta}-catenin (cWnt) pathway destruction-complex (DC) that regulates {beta}-catenin signaling. Bilaterian DC function requires {beta}-catenin binding to Axin and APC proteins, and Axin-APC heterodimerization. However, bioinformatic analyses predicted that Axin and APC-like homologs in early-branching non-bilaterians lack important previously defined bilaterian {beta}-catenin binding domains, questioning if they have functional cWnt-DCs. We demonstrate that both Axin and APC proteins in the cnidarian Nematostella vectensis (a representative of the sister taxon to bilaterians) can regulate cWnt signaling indicating an active cWnt-DC. Using in vitro analyses, we show that NvAxin binds Nv{beta}-catenin weakly despite lacking the conserved bilaterian Axin {beta}-catenin-binding motif ({beta}catBM). Using AlphaFold3, we identified two predicted {beta}catBM-like sequences in NvAxin, one within the Axin-RGS domain and another towards the C-terminus. Similar analysis of placozoan, poriferan, and ctenophore Axin identified single {beta}catBM-like sequences located within Axin-RGS. We show that ctenophore Axin and {beta}-catenin do not interact and changing a conserved leucine on NvAxin-{beta}catBM-like motifs to resemble the ctenophore sequence abolished NvAxin-Nv{beta}-catenin interactions. We propose that an ancestral Axin-RGS sequence acquired low-affinity {beta}-catenin binding early in metazoan evolution, followed by motif duplication in the cnidarian-bilaterian ancestor. In bilaterians, the duplicated {beta}catBM evolved higher-affinity for {beta}-catenin, while the ancestral sequence was lost. Our results demonstrate how phylogenetic insights, AI tools and functional assays can be used to reconstruct the evolution of complex signaling pathways.

developmental biology↗

bioRxiv2024

Human-mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome

Murine models of Alzheimers disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome (n > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including A{beta}-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

biochemistry↗

bioRxiv2024

Intrinsic Diversity in Primary Cilia Revealed Through Spatial Proteomics

Primary cilia are a critical organelle found on most human cells, and their dysfunction is linked to hereditary ciliopathies with a wide phenotypic spectrum. Despite their significance, the specific roles of cilia in different cell types remain poorly understood due to limitations in analyzing ciliary protein composition. We employed antibody-based spatial proteomics to expand the Human Protein Atlas to primary cilia. Our analysis identified the subciliary locations of 715 proteins across three cell lines, examining 128,156 individual cilia. We found that 69% of the ciliary proteome is cell-type specific, and 78% exhibited single-cilia heterogeneity. Our findings portray cilia as sensors tuning their proteome to effectively sense the environment and compute cellular responses. We identified 91 novel cilia proteins and found a genetic candidate variant in CREB3 in one clinical case with features overlapping ciliopathy phenotypes. This open, spatial cilia atlas advances research on cilia and ciliopathies.

cell biology↗

bioRxiv2024

Proteomic analysis of papillary thyroid carcinoma in the context of Hashimoto's thyroiditis

ObjectiveTo analyze the proteomic characteristics of papillary thyroid carcinoma in the context of Hashimotos thyroiditis by mass spectrometry and screen the corresponding differential proteins. MethodsPostoperative paraffin specimens of 3 patients with Hashimotos thyroiditis combined with papillary thyroid carcinoma and 3 patients with Hashimotos thyroiditis and benign nodules were collected. The differential proteins were obtained by qualitative and quantitative analysis using Q ExactiveTM mass spectrometer. Functional enrichment cluster analysis and protein interaction analysis were then performed on these differential proteins. Finally, key proteins were screened out and immunohistochemical verification was performed. Results72 up-regulated differentially expressed proteins and 21 down-regulated differentially expressed proteins were screened out. THBS2 and COL12A1 were further identified by bioinformatics analysis. After immunohistochemical verification, it was concluded that COL12A1 can be used as a specific tumor marker. ConclusionThere are differentially expressed proteins between the Hashimotos thyroiditis combined with papillary thyroid carcinoma group and the Hashimotos thyroiditis combined with benign nodules group. The up-regulated expression of COL12A1 can become an auxiliary diagnostic marker for papillary thyroid carcinoma with Hashimotos thyroiditis.

genomics↗