Biology subjects

Xie, L.

Publications and source records attributed to Xie, L..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Delineation of Single-cell Altas Provides New Insights for Development of Coronary Artery Lesions in Kawasaki Disease: Bad and Good Signaling Molecules

BackgroundKawasaki Disease (KD) is a vasculitis syndrome featured with a high and persistent fever and mainly affects children under 5 years of age. It is the leading cause of acquired heart disease in the form of coronary artery lesions (CALs) for children in developed countries. Most KD can be relieved with the high-dosage Intravenous immunoglobulin (IVIG) therapy, but a small proportion develop CALs after IVIG treatment. MethodsWe performed the single-cell RNA sequencing for the peripheral blood mononuclear cells (PBMCs) from three KD non-CAL patients whose samples were acquired before and after IVIG treatment and three KD CAL patients whose samples were acquired only after IVIG treatment. Cell-to-cell communication patterns were also analyzed in KD CAL and non-CAL patients ResultsOverall cell expression feature analyses show immunoglobulin and adaptive immunity related genes are upregulated in KD CAL patients while B cell activation related genes are downregulated in them. Pseudo-time analyses demonstrate that both KD non-CAL patients before treatment and KD CAL patients after treatment have a dysregulated B cell developmental trajectory while the former has a mixed T and B lineage and the latter has a mixed monocyte and B lineage. The early elevated expression of SPI1 could partly explain the dysregulated B cell development in KD CAL patients. Cell communication analyses propose a disorder cell communication pattern in KD non-CAL patients before treatment and some persistent bad cell-to-cell signals in KD CAL patients after treatment. There are four signaling molecules, APP, CCL, and MCH-II, whose expression is significantly increased in the CD14 and CD16 monocytes of KD CAL patients, where the expression of RESISTIN is significantly increased in those KD non-CAL patients. ConclusionsOur results suggest that APP, CCL, and MCH-II might be the bad signals for indicating the possible development of CAL while RESISTIN is a good one for protecting from CAL.

immunology↗

bioRxiv2024

Classifying Irritable Bowel Syndrome Using Spatio-Temporal Graph Convolution Networks on Brain fMRI Data

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and changes in stool consistency or frequency. Recent studies have explored the link between IBS and various cognitive deficits using functional MRI. Despite these efforts, an effective diagnostic or predictive model for IBS remains elusive. This shortfall is twofold: firstly, the sample sizes in these studies are typically small, and secondly, the machine learning or deep learning models currently in use fail to adequately detect the subtle and dynamic pathological changes present in fMRI data for IBS. In this study, we extracted rs-fMRI of 79 subjects with IBS and 79 healthy controls, then put them into spatio-temporal graph convolution network (ST-GCN) for classification. We also incorporated a novel interpretability module into this model to identify potential regions of interest (ROI) associated with IBS. Our model outperformed other state-of-the-art ML and DL methods with the highest average accuracy of 83.51% on our dataset. Furthermore, based on the results of our interpretability module, the Inferior Parietal Lobule (IPL.R), Inferior Frontal Orbital part (ORBinf.R), Postcentral Gyrus (PCG.R), Middle Frontal Orbital part (ORBmid.R), and Superior Medial Frontal Orbital part (ORBsupmed.L) were identified as top 5 important brain regions for distinguishing IBS patients from the control group, which are consistent with the brain regions identified in previous literature reviews. We also conducted an external data-driven experiment to further validate the effectiveness of the interpretability module. The results indicate that the selected regions significantly impact IBS.

bioengineering↗

bioRxiv2024

Physical-aware model accuracy estimation for protein complex using deep learning method

With the breakthrough of AlphaFold2 on monomers, the research focus of structure prediction has shifted to protein complexes, driving the continued development of new methods for multimer structure prediction. Therefore, it is crucial to accurately estimate quality scores for the multimer model independent of the used prediction methods. In this work, we propose a physical-aware deep learning method, DeepUMQA-PA, to evaluate the residue-wise quality of protein complex models. For the input complex model, the residue-based contact area and orientation features were first constructed using Voronoi tessellation, representing the potential physical interactions and hydrophobic properties. Then, the relationship between local residues and the overall complex topology as well as the inter-residue evolutionary information are characterized by geometry-based features, protein language model embedding representation, and knowledge-based statistical potential features. Finally, these features are fed into a fused network architecture employing equivalent graph neural network and ResNet network to estimate residue-wise model accuracy. Experimental results on the CASP15 test set demonstrate that our method outperforms the state-of-the-art method DeepUMQA3 by 3.69% and 3.49% on Pearson and Spearman, respectively. Notably, our method achieved 16.8% and 15.5% improvement in Pearson and Spearman, respectively, for the evaluation of nanobody-antigens. In addition, DeepUMQA-PA achieved better MAE scores than AlphaFold-Multimer and AlphaFold3 self-assessment methods on 43% and 50% of the targets, respectively. All these results suggest that physical-aware information based on the area and orientation of atom-atom and atom-solvent contacts has the potential to capture sequence-structure-quality relationships of proteins, especially in the case of flexible proteins. The DeepUMQA-PA server is freely available at http://zhanglab-bioinf.com/DeepUMQA-PA/.

bioinformatics↗

bioRxiv2024

BT-11 repurposing potential for Alzheimer's disease and insights into its mode of actions

Neuroinflammation is a key pathological hallmark of Alzheimers disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model. BT-11 reduced hippocampal-dependent spatial memory deficits, A{beta} plaque load and neuronal loss in males, and mitigated microglia numbers in females. BT-11 treatment led to hippocampal transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potential different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, showing a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data suggest that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology by potentially modulating G-protein signaling and oligodendrocyte function. Our studies contribute to the field of novel immunomodulatory AD therapeutics, and merit further research on the role of LANCL2 in this disease.

neuroscience↗

bioRxiv2024

Soluble guanylyl cyclase, the NO-receptor, regulates endothelium-dependent vascular relaxation via its transnitrosation activity.

We previously demonstrated that the NO-receptor soluble guanylyl cyclase (GC1) has the ability to transnitrosate other proteins in a reaction that involves, in some cases, oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was established in vitro and we identified by mass spectrometry and mutational analysis Cys 610 (C610) of GC1 -subunit as a major donor of S-nitrosothiols (SNO). To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI C610S) under basal or angiotensin II (Ang II)-treated conditions. Despite similar GC1 expression and NO-stimulated cGMP-forming activity, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 and SNO-RhoA in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure despite an intact NO-cGMP axis, pressure myography and in vivo intravital microscopy were conducted to analyze the vascular resistance tone. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant deficiency in acetylcholine-induced vasorelaxation while smooth muscle relaxation in response to NO remained unchanged. These findings indicate that the C610S mutation uncoupled the two NO signaling pathways involved in the endothelium and smooth muscle vasorelaxation and suggest that GC1-dependent S-nitrosation is a key player in endothelium-derived hyperpolarization.

biochemistry↗

bioRxiv2024

GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation

Neuropathic pain, a major health problem affecting 7-10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK+) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here, we show that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal neurons was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK+ neurons reversed CCI-induced neuropathic pain. Furthermore, GPR30 in spinal CCK+ neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Moreover, GPR30 was expressed in spinal CCK+ neurons that received direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons was required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK+ neurons and S1-SDH postsynaptic neurons is pivotal for neuropathic pain, thereby representing a promising therapeutic target for neuropathic pain.

neuroscience↗

bioRxiv2024

LRRC8 complexes are adenosine nucleotide release channels regulating platelet activation and arterial thrombosis

Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in Leucine-Rich Repeat Containing 8 (LRRC8) protein subunits that form the Volume-Regulated Anion Channel (VRAC) which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume, adhesion, and agonist-stimulated activation, aggregation, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y1 and P2Y12 receptors. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo. These studies identify the mechanoresponsive LRRC8 channel complex as an ATP/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.

cell biology↗

bioRxiv2024

Dynamic BMP signaling regulates sclerotome induction and lineage diversification in zebrafish

The sclerotome is an embryonic structure that gives rise to various supportive tissues, including the axial skeleton and connective tissues. Despite its significance, the mechanisms underlying sclerotome induction and diversification during embryonic development remain poorly understood. Sclerotome progenitors exhibit transient bmp4 expression and an active response to BMP signaling. Using BMP gain- and loss-of-function tools, we demonstrate that BMP signaling is both necessary and sufficient for sclerotome induction. Furthermore, through mosaic expression of a dominant-negative tool, we show that BMP signaling induces sclerotome fate in a cell-autonomous manner. Interestingly, different populations of sclerotome-derived cells have distinct BMP signaling requirements. Sclerotome-derived notochord-associated cells in the trunk lack BMP response, and sustained BMP signaling inhibits their differentiation into tenocytes. By contrast, sclerotome-derived fin mesenchymal cells in the fin fold require high levels of BMP signaling for proper morphogenesis. Our findings suggest that dynamic regulation of BMP signaling is crucial for the induction of the sclerotome and the subsequent diversification of sclerotome-derived lineages in zebrafish.

developmental biology↗

bioRxiv2024

Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism

The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo, LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.

cell biology↗

bioRxiv2024

Epigenomic, transcriptomic and proteomic characterizations of reference samples

A variety of newly developed next-generation sequencing technologies are making their way rapidly into the research and clinical applications, for which accuracy and cross-lab reproducibility are critical, and reference standards are much needed. Our previous multicenter studies under the SEQC-2 umbrella using a breast cancer cell line with paired B-cell line have produced a large amount of different genomic data including whole genome sequencing (Illumina, PacBio, Nanopore), HiC, and scRNA-seq with detailed analyses on somatic mutations, single-nucleotide variations (SNVs), and structural variations (SVs). However, there is still a lack of well-characterized reference materials which include epigenomic and proteomic data. Here we further performed ATAC-seq, Methyl-seq, RNA-seq, and proteomic analyses and provided a comprehensive catalog of the epigenomic landscape, which overlapped with the transcriptomes and proteomes for the two cell lines. We identified >7,700 peptide isoforms, where the majority (95%) of the genes had a single peptide isoform. Protein expression of the transcripts overlapping CGIs were much higher than the protein expression of the non-CGI transcripts in both cell lines. We further demonstrated the evidence that certain SNVs were incorporated into mutated peptides. We observed that open chromatin regions had low methylation which were largely regulated by CG density, where CG-rich regions had more accessible chromatin, low methylation, and higher gene and protein expression. The CG-poor regions had higher repressive epigenetic regulations (higher DNA methylation) and less open chromatin, resulting in a cell line specific methylation and gene expression patterns. Our studies provide well-defined reference materials consisting of two cell lines with genomic, epigenomic, transcriptomic, scRNA-seq and proteomic characterizations which can serve as standards for validating and benchmarking not only on various omics assays, but also on bioinformatics methods. It will be a valuable resource for both research and clinical communities.

genomics↗

bioRxiv2024

MLL1 directs gut-associated antibody responses to helminth and bacterial infections

Soil-transmitted helminths are one of the most common infections globally, yet how to promote effective gut-associated humoral responses is not well understood. We identify the histone methyltransferase MLL1 as a key target to promote IgA-driven responses. Mll1 was increased in germinal center B cells in gut-associated lymphoid tissues, and Mll1-deficiency led to changes in the histone modification H3K4me3 on key B cell and immune-regulatory genes. Correspondingly, MLL1-deficient B cells had defective germinal centers and IgG1 in response to the helminth Trichuris muris. Yet, Mll1f/fCd23cre/+ mice expelled worms more rapidly compared to control mice. Accelerated worm clearance correlated with elevated IgA+ plasma cells, as well as both serum and fecal IgA. RNA-sequencing identified CCR9 as a key MLL1-regulated molecule. As such, Mll1f/fCd23cre/+ mice infected with T. muris had increased IgA+CCR9+ PC localized in the large intestine. Regulation of IgA by MLL1 was confirmed beyond T. muris infection. In vitro cultures confirmed Mll1-deficiency increased IgA+ plasma cells in a B cell-intrinsic manner, and IgA production was also increased in Mll1f/fCd23cre/+ mice infected with the bacterium C. rodentium. This study reveals MLL1 as a key target to promote IgA responses to gut-associated infections.

immunology↗

bioRxiv2024

Genetic diversity and evolution of rice centromeres

AbstractUnderstanding the mechanisms driving centromere evolution is crucial for deciphering eukaryotic evolution and speciation processes. Despite their widely recognized characteristics of conserved function in cell division, the centromeres have showed high diversity in composition and structure between species. The mechanism underlying this paradox remain poorly understood. Here, we assembled 67 high-quality rice genomes from Oryza AA group, encompassing both Asian and African rice species, and conducted an extensive analysis of over 800 nearly complete centromeres. Through de novo annotation of satellite sequences and employing a progressive compression strategy, we quantified the local homogenization and multi-layer nested structures of rice centromeres and found that genetic innovations in rice centromeres primarily arise from internal structural variations and retrotransposon insertions, along with a certain number of non-canonical satellite repeats (sati). Despite these rapid structural alterations, the single-base substitution rate in rice centromeres appears relatively lower compared to the chromosome arms. Contrary to the KARMA model for Arabidopsis centromere evolution, our model (RICE) suggests that centrophilic LTRs contribute to the decline of progenitor centromeres composed of satellite repeats, and facilitate the formation of evolutionary neo-centromeres, which are enriched with extended CENH3 binding regions beyond the native satellite arrays in plant genomes. In summary, this study provides novel insights into genomic divergence and reproductive barriers among rice species and subspecies, and advances our understanding of plant centromere evolution.

genetics↗

bioRxiv2024

The divergence of DHN-derived melanin pathways in Metarhizium robertsii

The important role of dihydroxynaphthalene-(DHN) melanin in enhancing fungal stress resistance and its importance in fungal development and pathogenicity are well-established. This melanin also aids biocontrol fungi in surviving in the environment and effectively infecting insects. However, the biosynthetic origin of melanin in the biocontrol agents, Metarhizium spp., has remained elusive due to the complexity resulting from the divergence of two DHN-like biosynthetic pathways. Through the heterologous expression of biosynthetic enzymes from these two pathways in bakers yeast Saccharomyces cerevisiae, we have confirmed the presence of DHN biosynthesis in M. roberstii, and discovered a novel naphthopyrone intermediate that can produce a different type of pigment. These two pigment biosynthetic pathways differ in terms of polyketide intermediate structures and subsequent modification steps. Stress resistance studies using recombinant yeast cells have demonstrated that both DHN and its intermediates confer resistance against UV light prior to polymerization; a similar result was observed for its naphthopyrone counterpart. This study contributes to the understanding of the intricate and diverse biosynthetic mechanisms of fungal melanin and has the potential to enhance the application efficiency of biocontrol fungi such as Metarhizium spp. in agriculture.

microbiology↗

bioRxiv2024

Olfactory cortical outputs recruit and shape distinct brain-wide spatiotemporal networks

Odor information is transmitted from the olfactory bulb to several primary olfactory cortical regions in parallel, including the anterior olfactory nucleus (AON) and piriform cortex (Pir). However, the specific roles of the olfactory bulb and cortical outputs in wider interactions with other interconnected regions throughout the brain remain unclear due to the lack of suitable in vivo techniques. Furthermore, emerging associations between olfactory-related dysfunctions and neurological disorders underscore the need for examining olfactory networks at the systems level. Using optogenetics, fMRI, and computational modeling, we interrogated the spatiotemporal properties of brain-wide neural interactions in olfactory networks. We observed distinct downstream recruitment patterns. Specifically, stimulation of excitatory projection neurons in OB predominantly activates primary olfactory network regions, while stimulation of OB afferents in AON and Pir primarily orthodromically activates hippocampal/striatal and limbic networks, respectively. Temporally, repeated OB or AON stimulation diminishes neural activity propagation brain-wide in contrast to Pir stimulation. Dynamic causal modeling analysis reveals a robust inhibitory effect of AON outputs on striatal and limbic network regions. In addition, experiments in aged rat models show decreased brain-wide activation following OB stimulation, particularly in the primary olfactory and limbic networks. Modeling analysis identifies a dysfunctional AON to Pir connection, indicating the impairment of this primary olfactory cortical circuit that disrupts the downstream long-range propagation. Our study delineates the spatiotemporal properties of olfactory neural activity propagation in brain-wide networks for the first time and distinguishes the roles of primary olfactory cortical, AON and Pir, outputs in shaping neural interactions at the systems level.

neuroscience↗

bioRxiv2024

CUTS RNA Biosensor for the Real-Time Detection of TDP-43 Loss-of-Function

Mounting evidence implicates TDP-43 dysfunction and the accumulation of pathological cryptic exons across multiple neurodegenerative diseases, underscoring the need for accessible tools to detect and quantify TDP-43 loss-of-function (LOF). These tools are crucial for assessing potential disease contributors and exploring therapeutic candidates in TDP-43 proteinopathies. Here, we develop a sensitive and accurate real-time sensor for TDP-43 LOF: the CUTS (CFTR UNC13A TDP-43 Loss-of-Function) system. This system combines UG-rich sequences and previously reported cryptic exons regulated by TDP-43 with a reporter, enabling the tracking of TDP-43 LOF through live microscopy and RNA/protein-based assays. We show that CUTS effectively detects TDP-43 loss of function arising from mislocalization, impaired RNA binding, and pathological aggregation. Our results show the sensitivity and accuracy of the CUTS system in detecting and quantifying TDP-43 LOF, opening avenues to explore unknown TDP-43 interactions that regulate its function. In addition, by replacing the fluorescent tag in the CUTS system with the coding sequence for TDP-43, we show significant recovery of its function under TDP-43 LOF conditions, highlighting the potential utility of CUTS for self-regulating gene therapy applications. In summary, CUTS represents a platform for evaluating TDP-43 LOF in real-time and gene-replacement therapies in neurodegenerative diseases associated with TDP-43 dysfunction. HighlightsO_LICUTS is a cryptic exon RNA biosensor enabling real-time detection of TDP-43 loss of splicing function. C_LIO_LICUTS exhibits a linear relationship with a reduction in TDP-43 protein. C_LIO_LICUTS can deliver an autoregulated gene payload in response to TDP-43 loss-of-function. C_LIO_LITDP-43 homotypic phase transitions and cell stress induce loss of splicing function detected via CUTS. C_LI

molecular biology↗

bioRxiv2024

Pandemic Vibrio parahaemolyticus wave succession by gene loss

While spontaneous mutation and gene acquisition are well-established drivers of pathogen adaptation, the role of gene loss remains underexplored. Here, we investigated the emergence and diversification of the pandemic clone (PC) of Vibrio parahaemolyticus through large-scale phylogenomic analysis of 8,684 global isolates. The PC rapidly acquired multiple marker genes and genomic islands, subsequently diverging into successive sublineages mediating independent waves of cross-country transmission, as also observed in V. cholerae. Wave succession in the last two decades was driven by loss of putrescine utilization (Puu) genes, conferring phenotypic advantages for environmental adaptation (enhanced biofilm formation) and human transmission (increased cell adhesion/intestinal colonization, reduced virulence), consistent with the virulence trade-off hypothesis. We identified Puu-gene loss in multiple bacterial genera, with effects on biofilm and adhesion replicated in V. cholerae and Escherichia coli, suggesting convergent evolution and universal phenotypic effects. Our results highlight the indispensable role of gene loss in bacterial pathogen adaptation.

microbiology↗

bioRxiv2024

The maternal vGluT2 and embryonic mGluR3 signaling relay system controls offspring wing dimorphism in pea aphid

Transgenerational phenotypic plasticity (TPP) refers to the phenomenon that environmental conditions experienced by one generation can influence the phenotype of subsequent generations to adapt to the environment without modification of their DNA sequences. Aphid wing dimorphism is a textbook example of TPP by which a maternal aphid perceives the environmental cues to decide the wing morph of her offspring. However, the signaling mechanism from mother to daughter remains unclear. In this study, we showed that the population density and physical contact caused high proportion of winged offspring in the pea aphid Acyrthosiphon pisum. Its vesicular glutamate transporter 2 (ApvGluT2) and metabotropic glutamate receptor 3 (ApmGluR3) were identified by tissue-specific RNA-seq as differentially expressed genes in the head and embryo respectively between solitary and more densely housed maternal aphids. Elevated expression of brain ApvGluT2 and embryonic ApmGluR3 led to increases in the winged proportion. Knockdown of either gene inhibited phosphorylation of ApFoxO in embryos. Furthermore, EMSA showed that dephosphorylated ApFoxO directly bound to the promotor of hedgehog (ApHh), a morphogen gene for wing development, to repress its transcription in stage 20 embryos, causing a lower winged proportion. Our results demonstrated that brain vGluT2 and embryonic mGluR3 coordinately relayed the maternal physical contact signals and control wing development in offspring, showcasing a novel regulatory mechanism underlying physical contact-dependent, transgenerational wing dimorphism in aphids.

zoology↗

bioRxiv2024

Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality

ObjectivesVolumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimers disease. However, poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. MethodMRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimers Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. ResultsThe multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. ConclusionThe multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

bioengineering↗