Biology subjects

Song, X.

Publications and source records attributed to Song, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2022

Variations of photosynthetic N-use efficiency through plant phylogeny in relation to mesophyll cell wall thickness

Leaf photosynthetic nitrogen-use efficiency (PNUE) diversified significantly among C3 species. However, morpho-physiological mechanisms and interrelationships forming PNUE remain unclear on the evolutionary time scale. In this study, we compiled a novel extensive matrix of morpho-anatomical and physiological traits of leaf in 679 C3 species ranging from bryophytes to angiosperms to understand the intricacy of interrelationships underlying the variations in PNUE. We found that LMA, mesophyll cell wall thickness (Tcwm), Rubisco N allocation fraction (PR), and mesophyll conductance (gm) together interpreted 83% of variations in PNUE, with PR and gm accounting for 65% of those variations. However, the PR effects were species-dependent on gm; that is, the contribution of PR on PNUE was extensively significant in high-gm species in comparison to low-gm species. Standard major analysis (SMA) and path analysis suggested a weak correlation between PNUE and LMA, whereas the SMA correlation for PNUE-Tcwm was strong. The PR was inversely proportional to Tcwm, which was similar to the relationship between gm and Tcwm (p-value < 0.01), so that the internal CO2 drawdown from intercellular airspace to carboxylaton sites was relatively conservative over a wide range of Tcwm. Collectively, the coordination of changes in PR and gm connecting Tcwm suggested the complex physiological mechanisms mediated by Tcwm modulating PNUE across contrasting plant groups.

plant biology↗

bioRxiv2022

A small-molecule lycorine derivative reveals Na+/K+-ATPase α3 as an anti-obesity target

Obesity remains a severe global public health challenge, with contemporary therapeutic approaches primarily focusing on appetite suppression. Here, we discovered HLY72, a lycorine-derived small molecule that potently counteracts obesity in mice at doses without affecting food intake, by promoting sympathetic activation-mediated lipolysis and thermogenesis in adipose tissues. Mass spectrometry identified Na+/K+-ATPase (NKA) 3, the brain-specific isoform, as HLY72s target. Only blood-brain barrier-permeable NKA inhibitors reproduce HLY72s anti-obesity effects, and resistance to HLY72 treatment occurs specifically in NKA 3 (not 1) knockin mice harboring a HLY72-binding mutation. Similar to the chemical inhibition by HLY72, genetic inhibition of NKA 3 also effectively protects mice from diet-induced obesity. These findings point NKA 3 as a potent anti-obesity drug target and highlight HLY72s potential in treating and preventing obesity independent of appetite control.

physiology↗

bioRxiv2022

Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance

Cancer cells derived from secondary tumors can form new distant metastases more efficiently as compared to their primary tumor counterparts. This is partially due to the unfavorable microenvironments encountered by metastasizing cancer cells that result in the survival of a more metastatic phenotype from the original population. However, it is unclear how cancer cells may acquire such metastatic competency after overcoming deleterious mechanical stresses. Here, by forcing cancer cells to flow through small capillary-sized constrictions, we demonstrate that mechanical deformation can select a tumor cell subpopulation that exhibits resilience to mechanical squeezing-induced cell death. Transcriptomic profiling reveals up-regulated proliferation and DNA damage response pathways in this subpopulation, which are further translated into a more proliferative and chemotherapy-resistant phenotype. Our results highlight a potential link between the microenvironmental physical barriers and the enhanced malignancy of metastasizing cancer cells which may potentially be utilized for novel therapeutic strategies in preventing the metastatic spread of cancer cells.

cancer biology↗

bioRxiv2022

Integrative analysis of the MD Anderson Prostate Cancer Patient-Derived Xenograft Series (MDA PCa PDX)

Progress in understanding prostate cancer (PCa) metastasis and therapy resistance has been hampered by the lack of models, representative of the clinical spectrum and biologic complexity of the disease. Our laboratory is home to one of the largest worldwide repositories of PCa patient-derived xenografts (PDXs), the MDA PCa PDX series, a collection of clinically annotated PDXs reflecting the full spectrum of potentially lethal disease, that includes tumors that are not end stage and not castration-resistant PCa. We performed whole genome sequencing, targeted sequencing and RNA sequencing of 46 MDA PCa PDX models derived from biopsy and surgical specimens from 39 patients, selected in order to reflect the clinicopathological PCa subtypes (data available in cBioPortal). MDA PCa PDXs genomic characterization shows that the cohort recapitulates the mutational landscape found in PCa, highlighting the clinical relevance of these models. Interestingly and consistently with the clinic, certain models lack the typical PCa driver alterations, thus providing a suitable tool for discovery of novel drivers. Our cohort also includes PDXs derived from different areas of the same tumor and longitudinal samples, allowing to study disease heterogeneity and progression. Finally, we have developed a procedure to grow organoids from PDXs, thus providing a powerful in vitro platform that supports hypothesis generation, and testing of clinically relevant observations. Genomic and transcriptomic characterization of MDA PCa PDXs together with the ability to grow them as organoids for in vitro experimentation, provides a unique resource to address the existing clinical gap in PCa, helping to better understand mechanisms of response and resistance. One Sentence SummaryMDA PCa PDX series is a dynamic resource capturing the molecular landscape of prostate cancer; a platform for discovery and personalized medicine

cancer biology↗

bioRxiv2022

KDM4A promotes NEPC progression through regulation of MYC expression

Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation of MYC. We showed that MYC is hyper-activated in human and mouse NEPC. KDM4A KD led to suppression of MYC signaling. MYC KD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC. SignificanceNeuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer subtype that is resistant to potent androgen receptor pathway inhibitors (ARPIs) and currently lacks effective therapeutic options. Histone lysine demethylase KDM4A is an important epigenetic regulator of gene expression in development and cancer. In this study, we show that KDM4A is highly expressed in NEPC and is required for NEPC proliferation, anchorage-independent growth, and in vivo growth, which is in part mediated through the regulation of MYC expression. Importantly, we demonstrate that inhibition of KDM4A significantly impairs NEPC growth in preclinical models. Thus, our findings provide valuable insights into the molecular mechanisms underlying NEPC progression and offer a rationale for clinical trials with KDM4 inhibitor in NEPC patients.

cancer biology↗

bioRxiv2022

FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression. One Sentence SummaryCalcium channel RyR2 dictates Treg adhesion-based suppression

immunology↗

bioRxiv2022

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

immunology↗

bioRxiv2022

Expanding adult tubular microvessels on stiff substrates with endothelial cells and pericytes from the same tissue

Microvessels are essential for tissue engineering and regeneration. In current methods, endothelial cells are usually cultured in commercially available media and form a monolayer of cell sheets on stiff substrates and a tubular structure when cultured with soft hydrogels. To mimic the microvessels in vivo, researchers usually coculture the endothelial cells and pericytes from different adult tissues or derived from pluripotent stem cells in a three-dimensional hydrogel. However, there is a challenge for these models to reflect tissue-specific characteristics due to the vascular heterogeneity throughout the body. Here, we established a culture model for expanding adult tubular microvessels on stiff substrates with endothelial cells and pericytes derived from the same tissue. We isolated microvessels from adult rat subcutaneous soft connective tissue and cultured them on regular plastic dishes. We performed a series of screenings and formulated a custom-made medium (Medium-X), containing mainly antioxidants and three small molecules, Chir99021, A83-01, and Y27632. Medium-X significantly promoted adult microvessel growth while maintaining their characteristic tubular morphology up to 8 weeks in vitro, contrary to the monolayer of endothelial cell sheets in the commercially available medium EGM2MV. Transcriptomic analysis showed that Medium-X maintained the tubular morphology of microvessels by promoting angiogenesis and vascular remodeling while suppressing oxidation and lipid metabolic pathways. The model presented in this study can be applied to other organs for expanding organ-specific microvessels for tissue engineering and vascular regeneration.

bioengineering↗

bioRxiv2022

Population genomics unravels the Holocene history of Triticum-Aegilops species

Deep knowledge of crop biodiversity is essential to improve global food security. Despite bread wheat serving as a keystone crop worldwide, the population history of bread wheat and its wild relatives (a.k.a. wheats) remains elusive. By analyzing whole-genome sequences of 795 wheats, we found that bread wheat originated southwest of the Caspian Sea [~]11,700 years ago and underwent a slow speciation process, lasting [~]3,300 years due to persistent gene flow from wild relatives. Soon after, bread wheat spread across Eurasia and reached Europe, South Asia, and East Asia [~]7,000 to [~]5,000 years ago, shaping a diversified but occasionally convergent adaptive landscape of bread wheat in novel environments. Opposite to cultivated wheat, wild wheat populations have declined by [~]82% in the past [~]2,000 years due to the food choice shift of humans, and likely continue to drop because of the changing climate. These findings will guide future efforts in protecting and utilizing wheat biodiversity to improve global food security.

genetics↗

bioRxiv2022

Effects of seasonal changes on the carbon dynamics in mixed coniferous forests

We characterized seasonal changes in the residual rate and mass-loss rate of litter, as well as the carbon release dynamics of litter and soil, in mixed coniferous forests in the Xiaoxinganling region by conducting a controlled freeze-thaw experiment. The carbon release rate and mass-loss rate of litter at two levels of decomposition (undecomposed and semi-decomposed) were measured during four seasons: the unfrozen season, freeze-thaw season, frozen season, and thaw season. The temperature was higher, the mass-loss rate was faster, and the overall mass-loss rate of litter was higher in the unfrozen season than in the other three seasons; litter organic carbon increased and soil organic carbon increased due to the strong carbon sequestration capacity of plants. The temperature fluctuated above and below 0{degrees}C during the freeze-thaw season, which results in the physical breakage of the undecomposed litter and increases in the mass-loss rate. This leads to increases in the organic carbon of undecomposed litter and decreases in the soil organic carbon of undecomposed litter; the opposite patterns were observed for changes in the organic carbon of semidecomposed litter and soil organic carbon. There was noticeable mass loss of litter during the frozen season, and the rate of mass loss of litter during the thaw season was the lowest. Litter organic carbon decreased and soil organic carbon increased in both seasons. The organic carbon of undecomposed litter was highest in the thaw season, followed by the freeze-thaw season, frozen season, and unfrozen season. The organic carbon of semi-decomposed litter was highest in the frozen season, followed by the thaw season, freeze-thaw season, unfrozen season to freeze-thaw season, frozen season, thaw season, and unfrozen season. After freeze-thaw treatment, the organic carbon in deadfall soil was highest in the unfrozen season, freeze-thaw season, frozen season, thaw season to unfrozen season, frozen season, thaw season, and freeze-thaw season. The findings of this study provide new insights into the material cycling process under freeze-thawing, as well as information on the effect of seasonal freeze-thaws on the forest carbon cycle.

ecology↗

bioRxiv2022

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology ("Stereo-seq"), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with [~]600 genes per cell for 10 m-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for [~]1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

cell biology↗

bioRxiv2022

MiXcan: a Framework for Cell-Type-Specific Transcriptome-Wide Association Studies with an Application to Breast Cancer

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study (TWAS) approaches predict gene expression at the tissue level from genotype data, without considering cell-type heterogeneity, and test associations of the predicted tissue-level gene expression with disease. Here we develop MiXcan, a new TWAS approach that predicts cell-type-specific gene expression levels, identifies disease-associated genes via combination of cell-type-specific association signals for multiple cell types, and provides insight into the disease-critical cell type. We conducted the first cell-type-specific TWAS of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-specific TWAS can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.

bioinformatics↗

bioRxiv2022

TFIIB-related factor 1 is a nucleolar protein that promotes RNA polymerase I-directed transcription and tumour cell growth

RNA polymerase I (Pol I) products play pivotal roles in ribosomal assembly, protein synthesis and cell growth. Dysregulation of Pol I product synthesis closely correlates with tumourigenesis. However, the factors and pathways governing Pol I-dependent transcription remain to be identified. Here, we report that TFIIB-related factor 1 (BRF1), a subunit of TFIIIB required for Pol III-mediated transcription, is a nucleolar protein and modulates the rRNA synthesis directed by Pol I. We show that BRF1 can be co-localized with nucleolar protein markers in several human cell types. BRF1 expression positively correlates with Pol I product levels and tumour cell growth in vitro and in vivo. Mechanistically, BRF1 binds to the Pol I transcription machinery factors and is recruited to the rDNA promoter with them. Alteration of BRF1 expression affected the recruitment of Pol I transcription machinery at the rDNA promoter, the rDNA promoter activity and expression of TBP and TAF1A, indicating that BRF1 modulates Pol I-direct transcription by controlling the expression of selective factor 1 subunits. Collectively, we demonstrate that BRF1 acts as a positive factor to regulate Pol I-directed transcription, suggesting that BRF1 can concurrently modulate Pol I and Pol III transcription and acts as a key coordinator between them.

molecular biology↗

bioRxiv2022

Comprehensive Epitope Mapping of Broad Sarbecovirus Neutralizing Antibodies

Omicron sub-lineage BA.2 has rapidly surged globally, accounting for over 60% of recent SARS-CoV-2 infections. Newly acquired RBD mutations and high transmission advantage over BA.1 urge the investigation of BA.2s immune evasion capability. Here, we show that BA.2 causes strong neutralization resistance, comparable to BA.1, in vaccinated individuals plasma. However, BA.2 displays more severe antibody evasion in BA.1 convalescents, and most prominently, in vaccinated SARS convalescents plasma, suggesting a substantial antigenicity difference between BA.2 and BA.1. To specify, we determined the escaping mutation profiles1,2 of 714 SARS-CoV-2 RBD neutralizing antibodies, including 241 broad sarbecovirus neutralizing antibodies isolated from SARS convalescents, and measured their neutralization efficacy against BA.1, BA.1.1, BA.2. Importantly, BA.2 specifically induces large-scale escape of BA.1/BA.1.1-effective broad sarbecovirus neutralizing antibodies via novel mutations T376A, D405N, and R408S. These sites were highly conserved across sarbecoviruses, suggesting that Omicron BA.2 arose from immune pressure selection instead of zoonotic spillover. Moreover, BA.2 reduces the efficacy of S309 (Sotrovimab)3,4 and broad sarbecovirus neutralizing antibodies targeting the similar epitope region, including BD55-5840. Structural comparisons of BD55-5840 in complexes with BA.1 and BA.2 spike suggest that BA.2 could hinder antibody binding through S371F-induced N343-glycan displacement. Intriguingly, the absence of G446S mutation in BA.2 enabled a proportion of 440-449 linear epitope targeting antibodies to retain neutralizing efficacy, including COV2-2130 (Cilgavimab)5. Together, we showed that BA.2 exhibits distinct antigenicity compared to BA.1 and provided a comprehensive profile of SARS-CoV-2 antibody escaping mutations. Our study offers critical insights into the humoral immune evading mechanism of current and future variants.

immunology↗

bioRxiv2022

Emodin Combined with Multiple Low-frequency Low-intensity Ultrasound to Relieve Osteomyelitis Through Sonoantimicrobial Chemotherapy

Treatment of osteomyelitis is still challenging as conventional antibiotic therapy is limited by the emergence of resistant strains and the formation of biofilms. Sonoantimicrobial chemotherapy (SACT) is a novel therapy of low-frequency and low-intensity ultrasound (LFLIU) combined with sonosensitizer. Therefore, in our study, a sonosensitizer named emodin (EM) was proposed to be combined with LFLIU to relieve acute osteomyelitis caused by Methicillin-resistant Staphylococcus aureus (MRSA) through synergistic antibacterial and anti-biofilm effects. The efficiency of different intensities of ultrasound, single (S-LFLIU, 15 min) and multiple ultrasound (M-LFLIU, 5 min every 4 h, three times) against bacteria and biofilm was compared, contributing to develop the best treatment regimen. Our results demonstrated that EM plus S-LFLIU or M-LFLIU (EM+S-LFLIU or EM+M-LFLIU) have significant synergetic bactericidal and anti-biofilm effects and EM+M-LFLIU exhibits superior performance in anti-biofilm. Furthermore, it was suggested that EM+M-LFLIU could produce a large amount of reactive oxygen species (ROS), destroy the integrity of bacterial membrane and wall, down-regulate the expression of oxidative stress, membrane wall synthesis, bacterial virulence and other related genes (agrB, PBP3, sgtB, GMK, zwf, msrA). In vivo study, micro-CT, H&E staining, ELISA assay and bacterial quantification of bone tissue indicated that EM+M-LFLIU could also relieve osteomyelitis of MRSA infection. Our work proffers an original treating bacterial osteomyelitis approach that weakens drug-resistant bacterial and suppresses biofilm formation through SACT, which may provide new prospects for clinical treatment.

microbiology↗

bioRxiv2022

Dissecting Mutational Allosteric Effects in Alkaline Phosphatases Associated with Different Hypophosphatasia Phenotypes: An Integrative Computational Investigation

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization, is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach for large-scale analysis of ALPL mutations - from nonpathogenic to severe HPPs is proposed. Allosteric molecular signatures of ALPL mutations were determined using an integrated pipeline of synergistic approaches including sequence and energetic-based analysis, structural topology network modeling and elastic network models. Statistical analysis of molecular features computed for the ALPL mutations showed a significant difference between the control and mild and severe HPP phenotypes, and the developed machine learning model suggested that the topological network parameters could serve as is a robust indicator for severe mutations. Molecular dynamics simulations coupled with protein structure network was employed to analyze the effect of single-residue variation on conformational dynamics of TNSALP dimers, and we found that severe disease-associated mutations have a significantly greater effect on allosteric communications. The results of this study suggested that ALPL mutations associated with mild and severe HPPs tend to have different effects on protein stability on local scale and long-range communications caused by network rewiring. By linking disease phenotypes with allosteric molecular signatures, the proposed integrative computational approach elucidates the complex sequence-structure-allostery relationships of ALPL mutations and dissects the role of allosteric effects in the pathogenesis of HPPs. Author SummaryThe understanding of mutational genotype- disease phenotype relationship is a fundamental step for enabling precision medicine. It remains a challenging task to assess the molecular principle of the genotype- phenotype relationship. By focusing on Hypophosphatasia, a rare inherited disorder, as an example, we performed comprehensive analysis of single-amino-acid mutations in the encoded protein of Tissue Nonspecific Alkaline Phosphatase associated in terms of their sequence, structure, and dynamics properties. We further developed a machine learning -based method to classify different disease phenotypes, and the interpretability of the classification model was addressed by the structural-functional analysis of network topological important mutations. Our results highlighted the allosteric propensity of severe mutations, and show the potential allosteric principle of genotype- phenotype relationship.

biophysics↗

bioRxiv2022

Human genetic variations reveal Chromosomal Instability aiding Variants (CIVa) in kinetochore-microtubule associated proteins

The vast majority of Chromosomal Instability (CIN) promoting mutations remain unknown. We assess the prevalence of Chromosomal Instability aiding Variants (CIVa) by collating Loss-of-Function (LoF) variants predicted in 135 chromosome segregation genes from over 150,000 humans, including consanguineous individuals. Surprisingly, we observe heterozygous and homozygous CIVa in Astrin and SKA3 genes that encode evolutionarily conserved microtubule-associated proteins essential for chromosome segregation. By combining high-resolution microscopy and controlled protein expression, we show the naturally occurring Astrin variant, p.Q1012*, as potentially harmful because it fails to localise normally, delays anaphase onset, induces chromosome misalignment and promotes chromosome missegregation. We show that N-terminal frameshift variants in Astrin and SKA3 are likely to generate shorter isoforms that do not compromise chromosome segregation revealing resilient mechanisms to cope with harmful variants. This study provides a framework to predict and stratify naturally occurring CIVa, an important step towards precision medicine for CIN syndromes.

cell biology↗

bioRxiv2021

Muscle systems and motility of early animals highlighted by cnidarians from the basal Cambrian

Although fossil evidence suggest that various animal groups were able to move actively through their environment in the early stages of their evolution, virtually no direct information is available on the nature of their muscle systems. The origin of jellyfish swimming, for example, is of great concern to biologists. Exceptionally preserved muscles are described here in benthic peridermal olivooid medusozoans from the basal Cambrian of China (Kuanchuanpu Formation, ca. 535 Ma) that have direct equivalent in modern medusozoans. They consist of circular fibers distributed over the bell surface (subumbrella) and most probably have a myoepithelial origin. This is the oldest record of a muscle system in cnidarians and more generally in animals. This basic system was probably co-opted by younger early Cambrian jellyfish to develop capacities for the jet-propelled swimming within the water column. Additional lines of fossil evidence obtained from ecdysozoans (worms and panarthropods) show that the muscle systems of early animals underwent a rapid diversification through the early Cambrian and increased their capacity to colonize a wide range of habitats both within the water column and sediment at a critical time of their evolutionary radiation.

evolutionary biology↗