Biology subjects

Hao, X.

Publications and source records attributed to Hao, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

FLASH radiotherapy using high-energy X-rays: validation of the FLASH effect triggered by a compact single high-energy X-ray source device

PurposeThis preclinical study aimed to verify the FLASH effect of compact single high-energy X-ray source (CHEXs) and to explore whether three irradiations with single-gantry rotation two 30 s pauses can generate FLASH effect in mice. Materials and methodsThe absolute dose and pulsed beam of the CHEXs were measured using an EBTXD radiochromic film and fast current transformer. Healthy C57BL/6J female mice and a subcutaneous tumor model were irradiated under different conditions: sham (control), FLASH-RT (FLASH1: delivering the total dose in 1 fraction; FLASH3: delivering the total dose with two 30 second pauses to simulate a three-field delivery where the gantry rotation is occurring within 30 seconds), and conventional dose rate radiotherapy (CONV-RT). Various total doses were administered to the corresponding normal tissues (whole thorax, 30 Gy; whole abdomen, 12 Gy; and skin, 36 Gy) and tumors (CT26, 16.5 Gy; and LLC, 18 Gy). Survival status, normal tissue damage, and tumor growth suppression were recorded in each group. ResultsThe average dose rate of the CHEXs exceeded 40 Gy/s. For whole-thorax and skin irradiation, both FLASH1 and FLASH3 demonstrated protective effects. For whole-abdomen irradiation, FLASH1 exhibited a superior protective effect. No significant differences in tumor growth responses were observed between the FLASH1, FLASH3, and CONV-RT groups (P>0.05). ConclusionThis study confirmed that the FLASH effect could be triggered using CHEXs FLASH radiotherapy, and demonstrated that three irradiations with single gantry rotation two 30 s pauses can trigger the FLASH effect, indicating the potential benefit of CHEXs 3D conformal radiotherapy. Our findings indicate that further clinical trials on CHEXs are warranted.

cancer biology↗

bioRxiv2024

Strong Protection by Bazedoxifene Against Chemically-Induced Ferroptotic Neuronal Death In Vitro and In Vivo

Ferroptosis is a form of regulated cell death characterized by excessive iron-dependent lipid peroxidation. Ferroptosis can be induced in cultured cells by exposure to certain chemicals (e.g., erastin and RSL3). Recently it was shown that protein disulfide isomerase (PDI) is a mediator of chemically-induced ferroptosis and also a target for ferroptosis protection. In this study, we find that bazedoxifene (BAZ), a selective estrogen receptor modulator with reported neuroprotective actions in humans, can inhibit PDI function and also strongly protect against chemically-induced ferroptosis in cultured neuronal cells. We find that BAZ can directly bind to PDI in vitro and in intact neuronal cells, and also can inhibit PDIs catalytic activity. Computational modeling analysis reveals that BAZ forms a hydrogen bond with PDI-His256. Inhibition of PDI by BAZ markedly reduces nNOS and iNOS dimerization and NO accumulation, which have recently been shown to play a crucial role in mediating chemically-induced ferroptosis. In addition, the direct antioxidant activity of BAZ may also partially contribute to its protective effect against chemically-induced ferroptosis. Behavioral analysis shows that mice treated with BAZ are strongly protected against kainic acid-induced memory deficits and hippocampal neuronal damage in vivo. In conclusion, the results of this study demonstrate that BAZ is an inhibitor of PDI and can strongly prevent chemically-induced ferroptosis in hippocampal neurons both in vitro and in vivo. These observations offer a novel, estrogen receptor-independent mechanism for the recently-reported neuroprotective actions of BAZ in humans. SIGNIFICANCE STATEMENTFerroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. Recent evidence has shown that protein disulfide isomerase (PDI) is an important mediator of chemically-induced ferroptosis and also a new target for ferroptosis protection. We find that bazedoxifene is an inhibitor of PDI, which can strongly protect against chemically-induced ferroptotic neuronal death in vitro and in vivo. Additionally, the molecular mechanism of PDI{square}bazedoxifene binding interaction is defined. This work provides evidence for an estrogen receptor-independent, PDI-mediated mechanism of neuroprotection by bazedoxifene.

neuroscience↗

bioRxiv2024

Protective Effect of 2-Hydroxyestrone and2-Hydroxyestradiol Against Chemically-Induced Hepatotoxicity In Vitro and In Vivo

Ferroptosis is a form of regulated cell death closely associated with glutathione depletion and accumulation of reactive lipid peroxides. In the present study, we seek to determine whether 2-hydroxyestrone (2-OH-E1) and 2-hydroxyestradiol (2-OH-E2), two major metabolites of endogenous estrone and 17{beta}-estradiol formed in liver by cytochrome P450 enzymes, can strongly protect against erastin- and RSL3-induced ferroptosis in hepatoma cells (H-4-II-E and HuH-7) in vitro and acetaminophen-induced mouse liver injury in vivo. We find that 2-OH-E1 and 2-OH-E2 can protect, in a dose-dependent manner, H-4-II-E hepatoma cells against erastin/RSL3-induced ferroptosis. Similar protective effect of 2-OH-E1 and 2-OH-E2 against RSL3-induced ferroptosis is also observed in HuH-7 hepatoma cells. These two estrogen metabolites strongly reduce the levels of erastin- and/or RSL3-induced accumulation of cellular NO, ROS and lipid-ROS. Mechanistically, 2-OH-E1 and 2-OH-E2 protect cells against chemically-induced ferroptosis mainly by binding to cellular protein disulfide isomerase (PDI), and then inhibit its catalytic activity and reduce PDI-catalyzed formation of iNOS dimer, thereby abrogating cellular NO, ROS and lipid-ROS accumulation. Animal studies show that 2-OH-E1 and 2-OH-E2 can also exert a strong protection against acetaminophen-induced liver injury in mice. Interestingly, while estrone and 17{beta}-estradiol display a very weak protective effect in cultured hepatoma cells, they exert a similarly-strong protective effect as 2-OH-E1 and 2-OH-E2 in vivo, suggesting that the metabolic conversion of estrone and 17{beta}-estradiol to 2-OH-E1 and 2-OH-E2 contributes importantly to their hepatoprotective effect. The results of this study reveal that 2-OH-E1 and 2-OH-E2 are important endogenous factors for protection against chemically-induced liver injury in vivo.

pharmacology and toxicology↗

bioRxiv2024

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ER) and exhibit active ER signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ER expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ER+ macrophages in the metastatic niche and functionally tied ER signaling in macrophages to T cell exclusion during metastatic colonization. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/593016v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1cd65b6org.highwire.dtl.DTLVardef@1d099e2org.highwire.dtl.DTLVardef@26cd91org.highwire.dtl.DTLVardef@181f5f3_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics. C_LIO_LIMetastatic niches are typically enriched with macrophages and depleted of T cells. C_LIO_LIDirect interaction with cancer cells induces ER expression in niche macrophages. C_LIO_LIKnockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization. C_LI

cancer biology↗

bioRxiv2024

Single cell profiling of bone metastasis ecosystems from multiple cancer types reveals convergent and divergent mechanisms of bone colonization.

Bone represents congenial soil for metastatic seeds and is frequently affected by metastasis of multiple cancer types. The histological and molecular characteristics of bone metastases (BMs) are diverse but poorly understood. Herein, we performed single-cell RNA-seq on 34 BMs from 6 cancer types and identified 3 ecosystem archetypes characterized by enrichment of macrophages/osteoclasts (M{varphi}-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes (Mono), respectively. Breast cancer BMs are mostly the M{varphi}-OC archetype driven by the osteolytic vicious cycle, whereas kidney cancers BMs mainly belong to the Treg-Tex archetype that lacks osteoclasts. Lung cancers BMs evenly distributed across all archetypes. Further analyses revealed parallel mechanisms of immunosuppression and bone remodeling. Elevated estrogen signaling distinguishes macrophages in the M{varphi}-OC subtype, which was investigated in a companion study. Together, we elucidated that divergent mechanisms toward bone colonization and that BMs of different origins can adopt the same mechanism through convergent evolution or adaptation. HIGHLIGHTSO_LIAnalyses of bone metastases from 6 cancer types revealed three immune archetypes. C_LIO_LIArchetypes diverge on immune trajectories, and features of tumor and stromal cells. C_LIO_LIDominant cell type in each archetype undergoes convergent evolution. C_LIO_LIRegulatory networks converge on osteoclasts and Tregs to drive archetype formation. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/593027v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@82cef6org.highwire.dtl.DTLVardef@1e1b021org.highwire.dtl.DTLVardef@1f2881eorg.highwire.dtl.DTLVardef@1c6874a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Negative Selection Allows DNA Mismatch Repair-Deficient Mouse Fibroblasts In Vitro to Tolerate High Levels of Somatic Mutations

Substantial numbers of somatic mutations have been found to accumulate with age in different human tissues. Clonal cellular amplification of some of these mutations can cause cancer and other diseases. However, it is as yet unclear if and to what extent an increased burden of random mutations can affect cellular function without clonal amplification. We tested this in cell culture, which avoids the limitation that an increased mutation burden in vivo typically leads to cancer. We performed single-cell whole-genome sequencing of primary fibroblasts from DNA mismatch repair (MMR) deficient Msh2-/- mice and littermate control animals after long-term passaging. Apart from analyzing somatic mutation burden we analyzed clonality, mutational signatures, and hotspots in the genome, characterizing the complete landscape of somatic mutagenesis in normal and MMR-deficient mouse primary fibroblasts during passaging. While growth rate of Msh2-/-fibroblasts was not significantly different from the controls, the number of de novo single-nucleotide variants (SNVs) increased linearly up until at least 30,000 SNVs per cell, with the frequency of small insertions and deletions (INDELs) plateauing in the Msh2-/- fibroblasts to about 10,000 INDELS per cell. We provide evidence for negative selection and large-scale mutation-driven population changes, including significant clonal expansion of preexisting mutations and widespread cell-strain-specific hotspots. Overall, our results provide evidence that increased somatic mutation burden drives significant cell evolutionary changes in a dynamic cell culture system without significant effects on growth. Since similar selection processes against mutations preventing organ and tissue dysfunction during aging are difficult to envision, these results suggest that increased somatic mutation burden can play a causal role in aging and diseases other than cancer.

genomics↗

bioRxiv2024

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC. SummaryIn neutrophil-enriched triple-negative breast cancer (TNBC) models, CREB binding protein (CBP)/P300 bromodomain (BRD) inhibition reduces tumor growth and systemic neutrophil accumulation while stimulating an antitumor immune response. This improves standard-of-care therapies, suggesting a potential therapeutic benefit of CBP/P300 BRD inhibitors for neutrophil-enriched TNBC.

cancer biology↗

bioRxiv2024

Brain age prediction and deviations from normative trajectories in the neonatal connectome

Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brains maturity relative to normative data. The difference between the individuals predicted and chronological age--or brain age gap (BAG)--represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We used resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predicted PMA for term and preterm infants. Predicted ages from each modality were correlated. At the network level, nearly all canonical brain networks--even putatively later developing ones--generated accurate PMA prediction. Additionally, BAGs were associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period.

neuroscience↗

bioRxiv2024

Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T

Familial dilated cardiomyopathy (DCM) is frequently caused by autosomal dominant point mutations in genes involved in diverse cellular processes, including sarcomeric contraction. While patient studies have defined the genetic landscape of DCM, genetics are not currently used in patient care, and patients receive similar treatments regardless of the underlying mutation. It has been suggested that a precision medicine approach based on the molecular mechanism of the underlying mutation could improve outcomes; however, realizing this approach has been challenging due to difficulties linking genotype and phenotype and then leveraging this information to identify therapeutic approaches. Here, we used multiscale experimental and computational approaches to test whether knowledge of molecular mechanism could be harnessed to connect genotype, phenotype, and drug response for a DCM mutation in troponin T, deletion of K210. Previously, we showed that at the molecular scale, the mutation reduces thin filament activation. Here, we used computational modeling of this molecular defect to predict that the mutant will reduce cellular and tissue contractility, and we validated this prediction in human cardiomyocytes and engineered heart tissues. We then used our knowledge of molecular mechanism to computationally model the effects of a small molecule that can activate the thin filament. We demonstrate experimentally that the modeling correctly predicts that the small molecule can partially rescue systolic dysfunction at the expense of diastolic function. Taken together, our results demonstrate how molecular mechanism can be harnessed to connect genotype and phenotype and inspire strategies to optimize mechanism-based therapeutics for DCM. Significance statementDilated cardiomyopathy (DCM), a leading cause of heart failure, is characterized by the inability of the heart to perfuse the body at normal filling pressures. There are multiple causes of DCM, including point mutations in sarcomeric proteins, but most patients receive similar courses of treatment, regardless of the underlying cause of the DCM. Many patients remain unserved by current therapies, and there is a need for new approaches. Here, we use multiscale experimental and computational approaches to demonstrate how knowledge of molecular mechanism can be harnessed to accurately predict the effects of a patient-specific mutation and responses to presumptive therapeutics. Our approach lays the foundation for a precision medicine approach to DCM.

biophysics↗

bioRxiv2024

Endo-reduplication in mouse liver after conditional mutation of ORC2 and combined mutation of ORC1 and ORC2

The six subunit ORC is essential for initiation of DNA replication in eukaryotes. Cancer cell-lines in culture can survive and replicate DNA replication after genetic inactivation of individual ORC subunits, ORC1, ORC2 or ORC5. In primary cells, ORC1 was dispensable in the mouse liver for endo-reduplication, but this could be explained by the ORC1 homolog, CDC6, substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2, which does not have a homolog. Although mouse embryo fibroblasts require ORC2 for proliferation, mouse hepatocytes synthesize DNA in cell culture and endo-reduplicate in vivo without ORC2. Mouse livers endo-reduplicate after simultaneous deletion of ORC1 and ORC2 both during normal development and after partial hepatectomy. Since endo-reduplication initiates DNA synthesis like normal S phase replication these results unequivocally indicate that primary cells, like cancer cell lines, can load MCM2-7 and initiate replication without ORC.

genetics↗

bioRxiv2024

A brain-to-text framework of decoding natural tonal sentences

Speech brain-computer interfaces (BCIs) directly translate brain activity into speech sound and text, yet decoding tonal languages like Mandarin Chinese poses a significant, unexplored challenge. Despite successful cases in non-tonal languages, the complexities of Mandarin, with its distinct syllabic structures and pivotal lexical information conveyed through tonal nuances, present challenges in BCI decoding. Here we designed a brain-to-text framework to decode Mandarin tonal sentences from invasive neural recordings. Our modular approach dissects speech onset, base syllables, and lexical tones, integrating them with contextual information through Bayesian likelihood and the Viterbi decoder. The results demonstrate accurate tone and syllable decoding under variances in continuous naturalistic speech production, surpassing previous intracranial Mandarin tonal syllable decoders in decoding accuracy. We also verified the robustness of our decoding framework and showed that the model hyperparameters can be generalized across participants of varied gender, age, education backgrounds, pronunciation behaviors, and coverage of electrodes. Our pilot study shed lights on the feasibility of more generalizable brain-to-text decoding of natural tonal sentences from patients with high heterogeneities.

neuroscience↗

bioRxiv2023

Accurate 3D SMLM localization via Vectorial In-situ PSF Retrieval and Aberration Assessment

In single-molecule localization microscopy (SMLM), achieving precise localization hinges on obtaining an authentic point spread function (PSF) influenced by system and sample-induced aberrations. Here, we introduce VISPR (Vectorial in-situ PSF retrieval) retrieving precise 3D PSF models considering both system and sample-induced aberrations under SMLM conditions. By employing the theory of vectorial PSF model and maximum likelihood estimation (MLE) phase retrieval, VISPR is capable of reconstructing an accurate 3D PSF model achieving the theoretically minimum uncertainty and accurately reflecting three-dimensional information of single molecules. This capability empowers accurate 3D super-resolution reconstruction in 3D SMLM. Additionally, VISPR applies to low signal-to-noise ratio circumstances and is adept at retrieving high-frequency details of the experimental PSF across an extensive depth range--a challenging feat for alternative approaches. As an effective tool, VISPR enables the quantitative assessment of aberrations induced by the system and sample environment. From the simulations and experiments, we verified the superiority and effectiveness of VISPR. It is essential to highlight that VISPR applies to various SMLM microscope modalities.

molecular biology↗

bioRxiv2023

Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids

Due to proteostasis stress induced by aging or disease, misfolded proteins can form toxic intermediate species of aggregates and eventually mature into less toxic inclusion bodies (IBs). Here, using a yeast imaging-based screen, we identified 84 potential synphilin-1 (SY1) IB regulators and isolated the conserved sphingolipid metabolic components in the most enriched groups. Furthermore, we show that, in both yeast cells and mammalian cells, SY1 IBs are associated with mitochondria. Pharmacological inhibition of the sphingolipid metabolism pathway or knockout of its key genes results in a delayed IB maturation and increased SY1 cytotoxicity. We postulate that SY1 IB matures by association with the mitochondrion membrane, and that sphingolipids stimulate the maturation via their membrane-modulating function and thereby protecting cells from SY1 cytotoxicity. Our findings identify a conserved cellular component essential for IB maturation and suggest a mechanism by which cells may detoxify the pathogenic protein aggregates through forming mitochondrion-associated IBs.

cell biology↗

bioRxiv2023

Benchmarking nearest neighbor retrieval of zebra finch vocalizations across development

Vocalizations are highly specialized motor gestures that regulate social interactions. The reliable detection of vocalizations from raw streams of microphone data remains an open problem even in research on widely studied animals such as the zebra finch. A promising method for finding vocal samples from potentially few labelled examples (templates) is nearest neighbor retrieval, but this method has never been extensively tested on vocal segmentation tasks. We retrieve zebra finch vocalizations as neighbors of each other in the sound spectrogram space. Based on merely 50 templates, we find excellent retrieval performance in adults (F1 score of 0.93 {+/-} 0.07) but not in juveniles (F1 score of 0.64 {+/-} 0.18), presumably due to the larger vocal variability of the latter. The performance in juveniles improves when retrieval is based on fixed-size template slices (F1 score of 0.72 {+/-} 0.10) instead of entire templates. Among the several distance metrics we tested such as the cosine and the Euclidean distance, we find that the Spearman distance largely outperforms all others. We release our expert-curated dataset of more than 50000 zebra finch vocal segments, which will enable training of data-hungry machine-learning approaches.

animal behavior and cognition↗

bioRxiv2022

Experimental study of modified human tendon stem cells to promote graft ligamentation and tendon-bone healing after anterior cruciate ligament reconstruction

Restoring the normal structure and function of injured tendons is one of the biggest challenges faced by the Department of Orthopedics and Sports Medicine. Tendon-derived stem cells (TDSCs), a new type of pluripotent stem cells with multidirectional differentiation potential, are expected to be promising cell seeds for the treatment of tendon injury and tendon-bone healing in the future. In this study, tendon stem cells were successfully isolated from human tissues, which were positive for markers CD44, CD90, and CD105, and exhibited clonality and multilineage differentiation ability. Analysis of single-cell sequencing results and mass spectrometry identification results showed that there were differences in protein expression during CTGF-induced TDSC tendon differentiation. Reverse Co-IP, qPCR, WB, and immunofluorescence detection all confirmed that CTGF directly interacts with KIT, thereby mediating the transcription factor HES1 to regulate the Wnt/{beta}-catenin signaling pathway (GSK3{beta}, {beta}-catenin, TCF4). ChIP-qPCR and dual-luciferase reporter gene assays indicated that HES1 regulates stem cell differentiation by directly regulating the expression of GSK3{beta} in the Wnt/{beta}-catenin pathway. Rats were treated with TDSCs overexpressing the KIT gene after repair surgery. This method had a more ideal recovery effect than other methods through animal behavioral scores, mechanical properties testing, and HE staining tissue observation. This study found that the use of modified human tendon stem cells (hTDSC) could promote graft ligamentization and tendon-bone healing after ACL reconstruction, which could provide an effective way for faster and better recovery from tendon injury.

cell biology↗

bioRxiv2022

A Host-Harbored Metabolic Susceptibility of Coronavirus Enables Broad-Spectrum Targeting

Host-based antivirals could offer broad-spectrum therapeutics and prophylactics against the constantly-mutating viruses including the currently-ravaging coronavirus, yet must target cellular vulnerabilities of viruses without grossly endangering the host. Here we show that the master lipid regulator SREBP1 couples the phospholipid scramblase TMEM41B to constitute a host "metabolism-to-manufacture" cascade that maximizes membrane supplies to support coronaviral genome replication, harboring biosynthetic enzymes including Lipin1 as druggable viral-specific-essential (VSE) host genes. Moreover, pharmacological inhibition of Lipin1, by a moonlight function of the widely-prescribed beta-blocker Propranolol, metabolically uncouples the SREBP1-TMEM41B cascade and consequently exhibits broad-spectrum antiviral effects against coronaviruses, Zika virus, and Dengue virus. The data implicate a metabolism-based antiviral strategy that is well tolerated by the host, and a potential broad-spectrum medication against current and future coronavirus diseases.

cell biology↗

bioRxiv2022

A non-invasive, fast on/off 'Odourgenetic' Method to Manipulate Physiology

Manipulating molecular processes governing physiological functions has significant potential for clinical therapeutics and is an important approach to elucidate the cellular basis of physiological functions. Here, we designed a Odourgenetic system co-expressed Drosophila odorant receptor system (DORs) consisting of OR35a and OR83b, which were exclusively activated by their odor ligand, 2-pentanone. Applying 2-pentanone to DOR-expressing cells or tissues induced calcium influx and membrane depolarization. By inhalation of 2-pentanone, we successfully applied DORs to manipulate behaviour, control insulin secretion and regulate blood glucose and manipulate muscle contraction and associated limb movement. Because 2-pentanone rapidly enters the blood upon inhalation and leaves the body by exhalation, this odorant can be used with DORs to manipulate cellular function, and the manipulation can be terminated at any time. Such feature approach significantly improves the safety and controllability of DORs used in the clinic. Thus, the present study developed a non-invasive, controllable, fast on/off method to manipulate cellular activity and behaviour on a time scale of minutes.

cell biology↗

bioRxiv2022

A novel method revealing animal evolutionary relationships based on milk Mid-infrared

Mid-infrared spectra (MIRS) can effectively reflect the chemical bonds in milk, which has been widely used in dairy herd improvement. However, the relationship between MIRS and animal evolution remains largely unclear. This study firstly found great differences in MIRS and the components of milk by analyzing MIRS information of 12 different mammal species. A five-level discriminant model of evolutionary level based on MIRS was established with a test set kappa coefficient >0.97. In addition, a regression model of genetic distance was also established to estimate the genetic distance of different animal species with a correlation coefficient of R >0.94. These results showed that this method could be used for accurate mammalian evolutionary relationship assessment. We further clarified the potential relationship between MIRS and genes, such as PPP3CA and SCD that could change MIRS by regulating specific milk components. In conclusion, we expand the application of MIRS in animal species identification and evolution research and provide new perspectives for the research on the formation mechanism of different animal milk special components.

evolutionary biology↗