Biology subjects

Guo, L.

Publications and source records attributed to Guo, L..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

An end-to-end approach for protein folding by integrating Cryo-EM maps and sequence evolution

Protein structure modeling is an important but challenging task. Recent breakthroughs in Cryo-EM technology have led to rapid accumulation of Cryo-EM density maps, which facilitate scientists to determine protein structures but it remains time-consuming. Fortunately, artificial intelligence has great potential in automating this process. In this study, we present SMARTFold, a deep learning protein structure prediction model combining sequence alignment features and Cryo-EM density map features. First, using density map, we sample representative points along the predicted high confidence areas of protein backbone. Then we extract geometric features of these points and integrate these features with sequence alignment features in our proposed protein folding model. Extensive experiments confirm that our model performs best on both single-chain and multi-chain benchmark dataset compared with state-of-the-art methods, which makes it a reliable tool for protein atomic structure determination from Cryo-EM maps.

bioinformatics↗

bioRxiv2023

Human RAMP1-overexpressing mice are resistant to migraine therapies for motion sensitivity: a mouse model of vestibular migraine

Both enhanced motion-induced nausea and increased static imbalance are observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 which enhances CGRP signaling in the nervous system, and compared to non-affected littermate controls. Behavioral surrogates such as the motion- induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Nausea readouts revealed that the nestin/hRAMP1 mouse exhibit an increased sensitivity to CGRPs effects at lower doses compared to unaffected controls. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male unaffected controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced or endogenous alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing nausea and sway in this hypersensitive CGRP mouse model. This study suggests that the hypersensitive nestin/hRAMP1 mouse may serve as a model for difficult to treat cases of migraine that exhibit increased motion sensitivity.

neuroscience↗

bioRxiv2023

A Spatiotemporal and Machine-Learning Platform Accelerates the Manufacturing of hPSC-derived Esophageal Mucosa

Human pluripotent stem cell-derived tissue engineering offers great promise in designer cell-based personalized therapeutics. To harness such potential, a broader approach requires a deeper understanding of tissue-level interactions. We previously developed a manufacturing system for the ectoderm-derived skin epithelium for cell replacement therapy. However, it remains challenging to manufacture the endoderm-derived esophageal epithelium, despite both possessing similar stratified structure. Here we employ single cell and spatial technologies to generate a spatiotemporal multi-omics cell atlas for human esophageal development. We illuminate the cellular diversity, dynamics and signal communications for the developing esophageal epithelium and stroma. Using the machine-learning based Manatee, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of the Manatee predictions leads to a clinically-compatible system for manufacturing human esophageal mucosa. Our approach creates a versatile platform to accelerate human tissue manufacturing for future cell replacement therapies to treat human genetic defects and wounds.

developmental biology↗

bioRxiv2023

Designing efficient randstrobes for sequence similarity analyses

Substrings of length k, commonly referred to as k-mers, play a vital role in sequence analysis, reducing the search space by providing anchors between queries and references. However, k-mers are limited to exact matches between sequences. This has led to alternative constructs, such as spaced k-mers, that can match across substitutions. We recently introduced a class of new constructs, strobemers, that can match across substitutions and smaller insertions and deletions. Randstrobes, the most sensitive strobemer proposed in [18], has been incorporated into several bioinformatics applications such as read classification, short read mapping, and read overlap detection. Randstrobes are constructed by linking together k-mers in a pseudo-random fashion and depend on a hash function, a link function, and a comparator for their construction. Recently, we showed that the more random this linking appears (measured in entropy), the more efficient the seeds for sequence similarity analysis. The level of pseudo-randomness will depend on the hashing, linking, and comparison operators. However, no study has investigated the efficacy of the underlying operators to produce randstrobes. In this study, we propose several new construction methods. One of our proposed methods is based on a Binary Search Tree (BST), which lowers the time complexity and practical runtime to other methods for some parametrizations. To our knowledge, we are also the first to describe and study the types of biases that occur during construction. We designed three metrics to measure the bias. Using these new evaluation metrics, we uncovered biases and limitations in previous methods and showed that our proposed methods have favorable speed and sampling uniformity to previously proposed methods. Lastly, guided by our results, we change the seed construction in strobealign, a short-read mapper, and find that the results change substantially. Also, we suggest combining the two versions to improve accuracy for the shortest reads in our evaluated datasets. Our evaluation highlights sampling biases that can occur and provides guidance on which operators to use when implementing randstrobes.

bioinformatics↗

bioRxiv2023

Mapping Cell-to-cell Interactions from Spatially Resolved Transcriptomics Data

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacias power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate in PDL1/PD1 signaling in tumors. We demonstrated that a CD8+ T cell/PDL1 effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between {gamma}{delta} T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

bioinformatics↗

bioRxiv2023

The Discovery and Characterization of 1,4-Dihydroxy-2-naphthoic Acid Prenyltransferase Involved in the Biosynthesis of Anthraquinones in Rubia cordifolia

Anthraquinones constitute the largest group of natural quinones, which are used as safe natural dyes and have many pharmaceutical applications. In plants, anthraquinones are biosynthesized through two main routes: the polyketide pathway and the shikimate pathway. The shikimate pathway primarily forms alizarin-type anthraquinones, and the prenylation of 1,4-dihydroxy-2-naphthoic acid is the first pathway-specific step. However, the prenyltransferase responsible for this key step remains uncharacterized. In this study, the cell suspension culture of Rubia cordifolia, a plant rich in alizarin-type anthraquinones, was used in target prenyltransferase mining. The microsomal protein prepared from the cell suspension culture prenylated 1,4-dihydroxy-2-naphthoic acid to form 2-carboxyl-3-prenyl-1,4-naphthoquinone and 3-prenyl-1,4-naphthoquinone. Then a candidate gene belonging to UbiA superfamily, RcDT1, was discovered to account for the prenylation activity. Substrate specificity studies revealed that the recombinant RcDT1 recognized naphthoic acids primarily, followed by 4-hydroxyl benzoic acids. The prenylation activities of R. cordifolia microsomes and the recombinant RcDT1 were both strongly inhibited by 1,2- and 1,4-dihydroxynaphthalene. The plastid localization and root-specific expression further confirmed the participation of RcDT1 in anthraquinone biosynthesis. The phylogenetic analyses of RcDT1 and its rubiaceous homologs indicated that DHNA-prenylation activity evolved convergently in Rubiaceae via recruitment from the ubiquinone biosynthetic pathway. The discovery and evolutionary studies of RcDT1 provide useful guidance for identifying additional and evolutionarily varied prenyltransferases which enable entry into quinones derived from shikimate pathway. Moreover, these findings will have profound implications for understanding the biosynthetic process of the anthraquinone/naphthoquinone ring derived from shikimate pathway.

plant biology↗

bioRxiv2023

The impact of Parkinson's disease on striatal network connectivity and cortico-striatal drive: an in-silico study

Striatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behaviour, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinsons disease (PD), both morphological and electrophysiological striatal neuronal features have been shown to be altered in rodent models. Our goal with this in-silico study is twofold: a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single neuron level, and b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary we predict that the richness of the connectivity motifs in the striatal network is significantly decreased during PD, while at the same time a substantial enhancement of the effective glutamatergic drive to striatum is present. AUTHOR SUMMARYThis in-silico study predicts the impact that the single cell neuronal morphological alterations will have on the striatal microcircuit connectivity. We find that the richness in the topological striatal motifs is significantly reduced in Parkinsons disease, highlighting that just measuring the pairwise connectivity between neurons gives an incomplete description of network connectivity. Moreover, we predict how the resulting electrophysiological changes of SPN excitability together with their reduced number of dendritic branches affect their response to the glutamatergic drive from cortex and thalamus. We find that the effective glutamatergic drive is likely significantly increased in PD, in accordance with the hyperglutamatergic hypothesis.

neuroscience↗

bioRxiv2023

Autoantibodies against eukaryotic translation elongation factor 1 delta (EEF1D) in two patients with autoimmune cerebellar ataxia

To report a novel autoantibody against eukaryotic translation elongation factor 1 delta (EEF1D) in two patients with autoimmune cerebellar ataxia (ACA). The patients on one center with cerebellar ataxia of unknown cause, who were tested positive with tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections and negative for comprehensive anti-neural autoantibodies panel, were investigated for novel autoantibody identification. Tissue-immunoprecipitation (TIP) combined with mass spectrometric (MS) analysis was used to identify the target antigen. The EEF1D protein was identified from complex precipitated by serum and cerebrospinal fluid (CSF) of one patient, while the specific binding of autoantibodies and EEF1D were confirmed by subsequent neutralization experiment, recombinant cell-based indirect immunofluorescence assay (CBA) and western blot. In consequently test using CBA, another anti-EEF1D positive ACA patient was identified and confirmed by western blot. All enrolled 30 health doners and 15 connective tissue diseases patients without neurological disorders were anti-EEF1D negative. The two anti-EEF1D positive patients presented similar clinical manifestations, their outcomes supported the effectiveness of immunotherapy, but the cerebellar atrophy occurred before treatment may be irreversible. Symptoms of one patient worsened again after the weaning of pulse corticosteroid therapy. The identification of anti-EEF1D autoantibody provides a new potential biomarker for early diagnosis and recurrence prevention of ACA.

immunology↗

bioRxiv2023

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

biochemistry↗

bioRxiv2023

Electrostatic modulation of signaling at cell membrane: Waveform- and time-dependent electric control of ERK dynamics

Different exogenous electric fields (EF) can guide cell migration, disrupt proliferation, and program cell development. Studies have shown that many of these processes were initiated at the cell membrane, but the mechanism has been unclear, especially for conventionally non-excitable cells. In this study, we focus on the electrostatic aspects of EF coupling with the cell membrane by eliminating Faradaic processes with dielectric-coated microelectrodes, and show that the ERK signaling pathway of epithelial cells (MCF10A) can be both inhibited and activated by AC EF with different amplitude thresholds, peaking times and refractory periods. Interestingly, the ERK responses were sensitive to the waveform and timing of EF stimulation pulses, depicting the characteristics of electrostatic and dissipative interactions. Blocker tests and correlated changes of active Ras on the cell membrane with ERK signals indicated that both EGFR and Ras were involved in the rich ERK dynamics induced by EF. We propose that the frequency-dependent dielectric relaxation process could be an important mechanism to couple EF energy to the cell membrane region and modulate membrane protein-initiated signaling pathways, which can be further explored to precisely control cell behavior and fate with high temporal and spatial resolution.

biophysics↗

bioRxiv2023

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between progressive HIV infection and cocaine use disorder is likely bidirectional, with cocaine use having direct effects on immune function while HIV infection can alter addiction-related behavior. To better characterized the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of progressive HIV infection on cocaine-related behaviors in a cocaine conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection did not impact the formation of a cocaine CPP, but did result in resistance to extinction of the CPP. No effects of HIV on yohimbine-primed reinstatement or cocaine seeking under conflict were observed. These behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human markers. Among other targets, this included HIV-induced reductions in mouse IL-1 and G-CSF and human TNF and cocaine-induced alterations in human TNF and mouse GM-CSF such that cocaine exposure increases both cytokines only in the absence of HIV infection. Together these data provide new insights into the unique neurobehavioral processes underlying HIV infection and cocaine use disorders, and further how they interact to effect immune responses.

neuroscience↗

bioRxiv2023

TRAFfic signals: High-throughput CAR discovery in NK cells reveals novel TRAF-binding endodomains that drive enhanced persistence and cytotoxicity

Natural killer (NK) cells are a promising alternative therapeutic platform to CAR T cells given their favorable safety profile and potent killing ability. However, CAR NK cells suffer from limited persistence in vivo, which is, in part, thought to be the consequence of limited cytokine signaling. To address this challenge, we developed an innovative high-throughput screening strategy to identify CAR endodomains that could drive enhanced persistence while maintaining potent cytotoxicity. We uncovered a family of TRAF-binding endodomains that outperform benchmarks in primary NK cells along dimensions of persistence and cytotoxicity, even in low IL-2 conditions. This work highlights the importance of cell-type-specific cell therapy engineering and unlocks a wide range of high-throughput molecular engineering avenues in NK cells.

immunology↗

bioRxiv2023

Species -Shared and -Unique Gyral Peaks on Human and Macaque Brains

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, we defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. In this study, we identified shared and unique gyral peaks in human and macaque, and investigated the similarities and differences in the spatial distribution, anatomical morphology, and functional connectivity of them.

neuroscience↗

bioRxiv2023

Structural basis for auto-inhibition and activation of a short prokaryotic Argonaute associated TIR-APAZ defense system

Short prokaryotic Ago accounts for most prokaryotic Argonaute (pAgo) and is involved in defending bacteria against invading nucleic acids. Short prokaryotic Ago associated with APAZ-TIR (SPARTA) has been shown to oligomerize and deplete NAD+ upon guide-mediated target DNA recognition. However, the molecular basis of SPARTA inhibition and activation remains unknown. Here we determine the cryo-EM structures of Crenotalea thermophila SPARTA in its inhibited, transient, as well as activated states. The SPARTA is auto-inhibited by its acidic tail, which occupies the guide-target binding channel. Guide mediated target binding expels this acidic tail and triggers substantial conformational changes to expose Ago-Ago dimerization interface. As a result, SPARTA assembles into an active TIR-APAZ4/short Ago4 octamer, where the four TIR domains are rearranged and packed to form NADase active sites. Together with biochemical evidence, our results provide a panoramic vision explaining SPARTA auto-inhibition and activation, and expand understanding of pAgo mediated bacterial defense systems.

biochemistry↗

bioRxiv2023

Polygenic Risk Score Associates with Atherosclerotic Plaque Characteristics at Autopsy

BackgroundPolygenic risk scores (PRS) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. MethodsFrom 4,327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner (OCME) for sudden death between 1994 and 2015, 2,455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas (TCFA), and thrombotic CAD. ResultsAfter exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age 48.8{+/-}14.7; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater %stenosis (80.3%{+/-}27.0% vs. 50.4%{+/-}38.7%; adjusted p<0.001) and a higher frequency of calcification (69.6% vs. 35.8%; adjusted p=0.004) and TCFAs (26.7% vs. 9.5%; adjusted p=0.007). Even after adjustment for traditional CAD risk factors subjects within the highest PRS quintile had higher odds of severe atherosclerosis (i.e., [≥]75% stenosis; adjusted OR 3.77; 95%CI 2.10-6.78; p<0.001) and plaque rupture (adjusted OR 4.05; 95%CI 2.26-7.24; p<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged 50 years and younger (adjusted OR 4.08; 95%CI 2.01-8.30; p<0.001). No associations were observed with plaque erosion. ConclusionsThis is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects. HighlightsO_LIIn this autopsy study including 954 subjects within the CVPath Sudden Death Registry, high PRS correlated with plaque burden and atherosclerosis severity. C_LIO_LIThe PRS showed differential associations with plaque rupture and plaque erosion, suggesting different etiologies to these two causes of thrombotic CAD. C_LIO_LIPRS may be useful for risk stratification, particularly in the young. Further examination of individual risk loci and their association with plaque morphology may help understand molecular mechanisms of atherosclerosis, potentially revealing new therapy targets of CAD. C_LI Graphic AbstractA polygenic risk score, generated from 291 known CAD risk loci, was assessed in 954 subjects within the CVPath Sudden Death Registry. Histopathologic examination of the coronary arteries was performed in all subjects. Subjects in the highest PRS quintile exhibited more severe atherosclerosis as compared to subjects in the lowest quintile, with a greater plaque burden, more calcification, and a higher frequency of plaque rupture.

genetics↗

bioRxiv2023

Fus3 interacts with Gal83, revealing the MAPK crosstalk to Snf1/AMPK to regulate secondary metabolic substrates in filamentous fungi

The pheromone MAPK is essential for the vital activities of fungi and is widely identified in filamentous fungi of agricultural, medical, and industrial relevance. The targets have rarely been reported and it is difficult to understand the mechanism of pheromone MAPK signaling pathway. Aflatoxins (AFs), highly carcinogenic natural products, are produced by the secondary metabolism of fungi, such as Aspergillus flavus. Our previous studies demonstrated that Fus3 regulates AFs by modulating substrate levels in Aspergillus flavus, but no mechanism explain that in fungi. Here we show Gal83, a new target of Fus3, and identified the pheromone Fus3-MAPK signaling pathway regulates the Snf1/AMPK energy-sensing pathway to modulate aflatoxins synthesis substrates. In the screening for target proteins of Fus3, the Snf1/AMPK complexes {beta} subunit was identified by using tandem affinity purification and multi-omics, which physically interacted with Fus3 in vivo and vitro and received phosphorylation from Fus3. While neither aflatoxin transcript levels were down-regulated in gal83-mutant and fus3-mutant strains, significant decreases in aflatoxin B1, aflatoxin synthetic substrates levels and gene expression levels of primary metabolic enzymes were shown that both the Fus3-MAPK and Snf1/AMPK pathways could response energy signal. In conclusion, all the evidence unlocks a novel pathway of Fus3-MAPK to regulate AFs synthesis substrates by cross-talking to the Snf1/AMPK complexes. ImportanceAflatoxin poses a great threat to human and animal health and the economy, thus the mechanisms regulating aflatoxin synthesis have been of great interest. We have previously demonstrated that MAPK regulates aflatoxin biosynthesis significantly, but the regulatory mechanism of Fus3-MAPK is not clear. Here we found that Pheromone Fus3-MAPK responds to energy and transmits to Snf1/AMPK through phosphorylation, which regulates the level of secondary metabolic substrates in Aspergillus flavus, as a novel pathway of Fus3-MAPK. Fus3 interacts stably with Gal83 and colocalizes in the cytoplasm and nucleus, directly regulating the levels of aflatoxin synthetic substrates. These data advance our understanding of the regulation of aflatoxin by pheromone MAPK, and the mechanism of pheromone MAPK and Snf1/AMPK crosstalk regulation is confirmed. Overall, this has a positive effect on both fungal regulatory mechanisms and aflatoxin prevention and control.

microbiology↗

bioRxiv2023

Regeneration leads to global tissue rejuvenation in aging sexual planarians

An ability to delay aging--or to reverse the negative effects of aging--could prevent age-related disease and greatly enhance quality of life in old age. However, whether it is possible to globally reverse the physiological effects of aging in order to extend healthspan is unknown. The freshwater planarian Schmidtea mediterranea has been considered "immortal" due to its exceptional tissue regeneration capabilities. Here, we report that a sexually reproducing lineage of S. mediterranea exhibits age-associated physiological decline 12 months after birth. Age-associated changes include alterations in sensory organs, loss of neurons and muscle, loss of fertility, and impaired motility, but no reduction in stem cells at the age of 3 years. Differential gene expression analysis, comparing young and old planarian cells, furthermore revealed cell-type-specific changes in transcription as well as changes in classical aging pathways (e.g., insulin signaling). Remarkably, amputation followed by regeneration of lost tissues led to a global reversal of these age-associated changes. Older individuals that underwent regeneration showed restored youthful patterns of gene expression, stem cell states, tissue composition and rejuvenation of whole-animal physiology. Our work reveals a naturally evolved solution to age reversal in planaria that may provide insights into anti-aging strategies in humans.

developmental biology↗

bioRxiv2023

Integrating Image and Molecular Profiles for Spatial Transcriptomics Analysis

The spatially resolved transcriptomics (SRT) field has revolutionized our ability to comprehensively leverage image and molecular profiles to elucidate spatial organization of cellular microenvironments. Current clustering analysis of SRT data primarily relies on molecular information and fails to fully exploit the morphological features present in histology images, leading to compromised accuracy and interpretability. To overcome these limitations, we have developed a multi-stage statistical method called iIMPACT. It includes a finite mixture model to identify and define histology-based spatial domains based on AI-reconstructed histology images and spatial context of gene expression measurements, and a negative binomial regression model to detect domain-specific spatially variable genes. Through multiple case studies, we demonstrate iIMPACT outperformed existing methods, confirmed by ground truth biological knowledge. These findings underscore the accuracy and interpretability of iIMPACT as a new clustering approach, providing valuable insights into the cellular spatial organization and landscape of functional genes within spatial transcriptomics data.

bioinformatics↗