Biology subjects

Xie, J.

Publications and source records attributed to Xie, J..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Developmental variability in cotton fiber cell wall properties linked to important agronomic traits

The economic value of cotton is based on its long, thin, strong, and twisted trichoblasts that emerge from the ovule epidermis. The mature dried fiber cell reflects the outcome of a rapid tapering of the nascent trichoblast, weeks of polarized diffuse growth, followed by a transition to persistent secondary cell wall synthesis. Highly conserved and dynamic microtubule and cellulose microfibril-based anisotropic growth control modules are central to all of these phases. In this paper, we developed novel quantitative phenotyping and computational modeling pipelines to analyze fiber growth behaviors at a daily resolution. We uncovered unexpected variability in growth rate, cell wall properties, and cell geometry across a critical window of fiber development. Finite element computational modeling of fiber growth was used to analyze the instability of cell diameter control and predict how spatial gradients of fiber and matrix material properties can interact to dictate the patterns of shape change. As an initial step toward gaining insight into the molecular orchestration of cellulose biosynthesis, expression profiles of a broad set of relevant genes were quantified across the same developmental timeline and correlated with fiber phenotypes. This analysis identified specific candidate genes that may serve as targets for fiber quality improvement.

plant biology↗

bioRxiv2024

A high-resolution model of gene expression during Gossypium hirsutum (cotton) fiber development

Cotton fiber development relies on complex and intricate biological processes to transform newly differentiated fiber initials into the mature, extravagantly elongated cellulosic cells that are the foundation of this economically important cash crop. Here we extend previous research into cotton fiber development by employing controlled conditions to minimize variability and utilizing time-series sampling and analyses to capture daily transcriptomic changes from early elongation through the early stages of secondary wall synthesis (6 to 24 days post anthesis; DPA). A majority of genes are expressed in fiber, largely partitioned into two major coexpression modules that represent genes whose expression generally increases or decreases during development. Differential gene expression reveals a massive transcriptomic shift between 16 and 17 DPA, corresponding to the onset of the transition phase that leads to secondary wall synthesis. Subtle gene expression changes are captured by the daily sampling, which are discussed in the context of fiber development. Coexpression and gene regulatory networks are constructed and associated with phenotypic aspects of fiber development, including turgor and cellulose production. Key genes are considered in the broader context of plant secondary wall synthesis, noting their known and putative roles in cotton fiber development. The analyses presented here highlight the importance of fine-scale temporal sampling on understanding developmental processes and offer insight into genes and regulatory networks that may be important in conferring the unique fiber phenotype.

cell biology↗

bioRxiv2024

Interspecies interaction reshapes the fitness landscape of evolved genotypes

Microbial interaction and their evolution is vital for shaping the structure and function of microbial communities. However, the mechanisms governing the directionality and stability of the evolution of interactions within microbial communities remain poorly understood. Here, we used a syntrophic two-species biofilm consortium composed of Bacillus velezensis SQR9 and Pseudomonas stutzeri XL272 that promotes plant growth through their metabolic interactions and investigated how the interactions within the consortium change over evolutionary timescale to characterize the phenotypic and genetic diversification. The focal species B. velezensis SQR9 rapidly diversified into diverse colony morphotypes, both in the presence and absence of its interactor, P. stutzeri XL272, with variable frequencies. These morphotypes displayed phenotypic differentiation among biofilm formation, planktonic growth, and spore formation. The evolved P. stutzeri altered the fitness landscape of B. velezensis morphotypes, allowing the weaker rough morphotype to outcompete the biofilm-enhanced slimy morphotype. Whole genome re-sequencing correlated these phenotypic changes with mutations in specific genes encoding regulators of B. velezensis, including ywcC, comA, comP, degS, degQ and spo0F. The coevolutionary partner, P. stutzeri increased its exopolysaccharide production that could be explained by a frame shift mutation in cpsA gene encoding capsular polysaccharide (CPS) biosynthesis protein. Compared with the mono-evolution, co-evolved B. velezensis populations showed greater mutation accumulation in intergenic regions, which led to greater genetic parallelism. Furthermore, the dissimilarity between mono-evolved and co-evolved populations increased over time. Our study reveals intricate genetic diversification and fitness differentiation within a biofilm consortium, shaped by both abiotic conditions and biotic interactions.

microbiology↗

bioRxiv2024

Increased pathogenicity and transmission of SARS-CoV-2 Omicron XBB.1.9 sublineage, including HK.3 and EG.5.1

With the SARS-CoV-2 Omicron XBB.1.9 sublineage circulating worldwide, two XBB.1.9 variants, EG.5.1 and HK.3 spread rapidly and became dominant from middle 2023. However, the spike features, pathogenicity, and transmissibility of HK.3 are largely unknown. Here, we performed multiscale investigations to reveal the virological features of XBB.1.9 subvariants, especially the newly emerging HK.3. HK.3 revealed high replication efficiency in vitro. The HK.3 spike exhibited enhanced processing, although its infectivity, fusogenicity, and hACE2 binding affinity were comparable to those of the EG.5 and XBB.1 spikes. All XBB.1.9.1, EG.5.1 and HK.3 strains demonstrated efficient transmission in hamsters, although XBB.1.9.1 exhibited stronger fitness in the upper airways. HK.3 and EG.5.1 exhibited greater pathogenicity than XBB.1.9.1 and BA.2 in H11-K18-hACE2 hamsters. Our studies provide insight into the newly emerging pathogens HK.3 and EG.5.1. ImportanceIn animal models, the ongoing attenuated pathogenicity and poor transmission of Omicron subvariants seems to reach a consensus. However, our results revealed that Omicron XBB.1.9 subvariants, including one of the key variants of interest, EG.5 with its another key subvariant HK.3, universally exhibited both increased pathogenicity and highly transmission. This study reemphasized the importance of surveillance in characteristics of epidemic Omicron subvariants.

microbiology↗

bioRxiv2024

Bridging the Gap: biofilm-mediated establishment of Bacillus velezensis on Trichoderma guizhouense mycelia

Bacterial-fungal interactions (BFIs) are important in ecosystem dynamics, especially within the soil rhizosphere. The bacterium Bacillus velezensis SQR9 and the fungus Trichoderma guizhouense NJAU 4742 have garnered considerable attention due to their roles in promoting plant growth and protecting their host against pathogens. In this study, we utilized these two model microorganisms to investigate BFI. We firstly demonstrate that while co-inoculation of B. velezensis and T. guizhouense could promote tomato growth, these two microorganisms display mutual antagonism on agar solidified medium. To resolve this contradiction, we developed an inoculation method, that allows B. velezensis colonization of T. guizhouense hyphae and performed a transcriptome analysis. During colonization of the fungal hyphae, B. velezensis SQR9 upregulates expression of biofilm related genes (e.g. eps, tasA, and bslA) that is distinct from free-living cells. This result suggested an intricate association between extracellular matrix expression and hyphae colonization. In accordance, deletion epsD, tasA, or both epsD and tasA genes of B. velezensis diminished colonization of the T. guizhouense hyphae. The insights from our study demonstrate that soil BFIs are more complex than we understood, potentially involving both competition and cooperation. These intricate biofilm-mediated BFI dynamics might contribute to the remarkable diversity observed within soil microbiota, providing a fresh perspective for further exploration of BFIs in the plant rhizosphere.

microbiology↗

bioRxiv2024

Combination of bortezomib and venetoclax targets the pro-survival function of LMP-1 and EBNA-3C of Epstein-Barr virus in post-transplant lymphoproliferative disorder

Epstein-Barr virus (EBV) manipulates the ubiquitin-proteasome system and regulators of Bcl-2 family to enable the persistence of the virus and survival of the host cells through the expression of viral proteins in distinct latency patterns. We postulate that the combination of bortezomib (proteasome inhibitor) and venetoclax (Bcl-2 inhibitor) [bort/venetoclax] will cause synergistic killing of post-transplant lymphoproliferative disorder (PTLD) through targeting the pro-survival function of latent viral proteins such as latent membrane protein-1 (LMP-1) and EBV nuclear antigen-3C (EBNA-3C). Bort/venetoclax could synergistically kill spontaneous lymphoblastoid cell lines (sLCLs) derived from patients with PTLD and EBV-associated hemophagocytic lymphohistiocytosis by inducing DNA damage response, apoptosis and G1-S cell cycle arrest in a ROS-dependent manner. Bortezomib potently induced the expression of Noxa, a pro-apoptotic initiator and when combined with venetoclax, inhibited Mcl-1 and Bcl-2 simultaneously. Bortezomib prevented LMP-1 induced proteasomal degradation of I{kappa}B leading to the suppression of the NF-{kappa}B signaling pathway. Bortezomib also rescued Bcl-6 from EBNA-3C mediated proteasomal degradation thus maintaining the repression of cyclin D1 and Bcl-2 causing G1-S arrest and apoptosis. Concurrently, venetoclax inhibited Bcl-2 upregulated by either LMP-1 or EBNA-3C. Bort/venetoclax decreased the expression of phosphorylated p65 and Bcl-2 at serine 70 thereby suppressing the NF-{kappa}B signaling pathway and promoting apoptosis, respectively. These data corroborated the marked suppression of the growth of xenograft of sLCL in SCID mice (p<0.001). Taken together, the combination of bortezomib and venetoclax targets the pro-survival function of LMP-1 and EBNA-3C of Epstein-Barr virus in post-transplant lymphoproliferative disorder. Author SummaryEpstein-Barr virus (EBV) is an oncogenic virus associated with different cancers and can directly drive the development of a lymphoma type condition in organ transplant patients known as post-transplant lymphoproliferative disorder (PTLD) as a result of weakened immune surveillance of EBV. The malignant spectrum of PTLD will require multi-agent chemotherapy regimen which is not well tolerated by the immunocompromised patients. Here, we combined bortezomib (proteasome inhibitor) with venetoclax (Bcl-2 inhibitor) as a novel strategy to target the pro-survival function of key EBV onco-proteins, namely LMP-1 and EBNA-3C. We demonstrated that this chemotherapy-free regimen could be highly effective in killing patient-derived spontaneous lymphoblastoid cell lines which represent cell models of PTLD. The novel drug regimen can avoid the toxic effects of chemotherapy and may have high efficacy and specificity for the treatment of PTLD.

molecular biology↗

bioRxiv2024

Daily glycome and transcriptome profiling reveals polysaccharide structures and glycosyltransferases critical for cotton fiber growth

Cotton fiber length and strength are key determinants of its quality. Dynamic changes in the pectin, xyloglucan, xylan, and cellulose polysaccharide epitopes content during fiber growth contribute to complex remodeling of fiber cell wall (CW) and quality. Detailed knowledge about polysaccharide compositional and structural alteration in the fiber during fiber elongation and strengthening is vastly limited. Here, large-scale glycome profiling coupled with fiber phenotype and transcriptome profiling was conducted on fiber collected daily covering the most critical fiber developmental window. High temporal resolution profiling allowed us to identify specific polysaccharide epitopes associated with distinct fiber phenotypes that might contribute to fiber quality. This study revealed the critical role of highly branched RG-I pectin epitopes such as, {beta}-1,4-linked-galactans, {beta}-1,6-linked-galactans, and arabinogalactans, in addition to earlier reported homogalacturonans and xyloglucans in the formation of cotton-fiber-middle-lamella and contributing to fiber plasticity and elongation. We also propose the essential role of heteroxylans (Xyl-MeGlcA and Xyl-3Ar), as a guiding factor for secondary CW cellulose-microfibril arrangement, thus contributing to fiber strength. Correlation analysis of glycome and transcriptome data identified several key putative glycosyltransferases involved in synthesizing the critical polysaccharide epitopes. Novel details discovered here provide a foundation to identify molecular factors that dictate important fiber traits.

plant biology↗

bioRxiv2024

Modulation of endogenous opioid signaling by inhibitors of puromycin sensitive aminopeptidase

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

pharmacology and toxicology↗

bioRxiv2024

CCQM-P199b: Interlaboratory comparability study of SARS-CoV-2 RNA copy number quantification

Nucleic acid amplification tests including reverse transcription quantitative PCR (RT-qPCR) are used to detect RNA from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Standardized measurements of RNA can facilitate comparable performance of laboratory tests in the absence of existing reference measurement systems early on in a pandemic. Interlaboratory study CCQM P199b "SARS-CoV-2 RNA copy number quantification" was designed to test the fitness-for-purpose of developed candidate reference measurement procedures (RMPs) for SARS-CoV-2 genomic targets in purified RNA materials, and was conducted under the auspices of the Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology (CCQM) to evaluate the measurement comparability of national metrology institutes (NMIs) and designated institutes (DIs), thereby supporting international standardization. Twenty-one laboratories participated in CCQM P199b and were requested to report the RNA copy number concentration, expressed in number of copies per microliter, of the SARS-CoV-2 nucleocapsid (N) gene partial region (NC_045512.2: 28274-29239) and envelope (E) gene (NC_045512.2: 26245-26472) (optional measurements) in samples consisting of in vitro transcribed RNA or purified RNA from lentiviral constructs. Materials were provided in two categories: lower concentration ({approx} (101-104) /L in aqueous solution containing human RNA background) and high concentration ({approx} 109 /L in aqueous solution without any other RNA background). For the measurement of N gene concentration in the lower concentration study materials, the majority of laboratories (n = 17) used one-step reverse transcription-digital PCR (RT-dPCR), with three laboratories applying two-step RT-dPCR and one laboratory RT-qPCR. Sixteen laboratories submitted results for E gene concentration. Reproducibility (% CV or equivalent) for RT-dPCR ranged from 19 % to 31 %. Measurements of the high concentration study material by orthogonal methods (isotope dilution-mass spectrometry and single molecule flow cytometry) and a gravimetrically linked lower concentration material were in a good agreement, suggesting a lack of overall bias in RT-dPCR measurements. However methodological factors such as primer and probe (assay) sequences, RT-dPCR reagents and dPCR partition volume were found to be potential sources of interlaboratory variation which need to be controlled when applying this technique. This study demonstrates that the accuracy of RT-dPCR is fit-for-purpose as a RMP for viral RNA target quantification in purified RNA materials and highlights where metrological approaches such as the use of in vitro transcribed controls, orthogonal methods and measurement uncertainty evaluation can support standardization of molecular methods.

molecular biology↗

bioRxiv2024

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

The activation of hepatic stellate cells (HSCs) is the central link in the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSCs activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals and N6-methyladenosine (m6A) modification is closely related to autophagy. In this study, we find that m6A demethylase fat mass and obesity-associated protein (FTO) is upregulated during HSCs activation and bile duct ligation (BDL)-induced hepatic fibrosis, which is the m6A methylase with the most significant difference in expression. Importantly, we identify that FTO overexpression aggravates HSCs activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is the target of FTO due to FTO mainly mediates the m6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and activation of HSCs. Noteworthy, m6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level via recognizing the m6A binding site and ultimately inhibits autophagy and activation of HSCs. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSCs autophagy and reveal ULK1 as a novel potential therapeutic target for hepatic fibrosis treatment. Graphical Abstractm6A demethylases FTO promoted autophagy via recognizing the ULK1 m6A binding site, thus triggering HSCs activation, and eventually leading to liver fibrosis. In this process, YTHDC2 participated in the translation of ULK1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/584975v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@4fdd01org.highwire.dtl.DTLVardef@136791forg.highwire.dtl.DTLVardef@149f448org.highwire.dtl.DTLVardef@44ca9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Development of alcoholic liver disease model for drug evaluation from human induced pluripotent stem cell derived liver organoids

Alcoholic liver disease (ALD) poses a significant health challenge, demanding comprehensive research efforts to enhance our comprehension and treatment strategies. However, the development of effective treatments is hindered by the limitations of existing liver disease models. Liver organoids, characterized by their cellular complexity and three-dimensional (3D) tissue structure closely resembling the human liver, hold promise as ideal models for liver disease research. In this study, we employ a meticulously designed protocol involving the differentiation of human induced pluripotent stem cells (hiPSCs) into liver organoids. This process incorporates a precise combination of cytokines and small molecule compounds within a 3D culture system to guide the differentiation process. Subsequently, these differentiated liver organoids are subjected to ethanol treatment to induce ALD, thus establishing a disease model. Rigorous assessment through a series of experiments reveals that this model partially replicates key pathological features observed in clinical ALD, including cellular mitochondrial damage, elevated cellular reactive oxygen species (ROS) levels, fatty liver, and hepatocyte necrosis. In addition, this model offers potential utility in screening drugs for ALD treatment. Taken together, the liver organoids model of ALD, derived from hiPSCs differentiation, emerges as an invaluable platform for advancing our understanding and management of ALD in clinical settings.

cell biology↗

bioRxiv2024

Exo70 promotes herpesvirus secretory vesicle tethering and virion release in an exocyst complex-dependent manner

The exocyst complex, a multisubunit protein complex, mediates secretory vesicles fusion with the plasma membrane (PM) to deliver materials to the cell surface or to release cargoes to the extracellular space, but whether it is related to viral secretory vesicles tethering and virion release is unknown. Here, we identified that the exocyst complex subunit Exo70 promotes the trafficking of herpesvirus secretory vesicles and the release of mature virions in an exocyst complex-dependent manner. Mechanistically, mutation of Exo70 Lys632 and Lys635 diminishes viral secretory vesicles anchoring to PM. Moreover, the small GTPase Rab11a is necessary for the transport of viral secretory vesicles, and the Snapin-Exo70-SNAP23 axis is involved in fusion of viral secretory vesicles to the PM and release of virions. Most significantly, we discovered that Endosidin2 (ES2), an inhibitor of exocytosis via the exocyst complex, provides protection against herpesvirus infection in cells and mice. Overall, these findings unveil a previously uncharacterized role and mechanism of the exocyst complex in viral replication, highlighting its potential as an effective strategy against herpesvirus infection. Author summaryHerpesviruses, such as herpes simplex virus 1 (HSV-1) and bovine herpes virus type 1 (BoHV-1), are highly prevalent pathogens that establish lifelong infections and cause various diseases in humans and animals. While the mechanisms underlying the transport of herpesvirus secretory vesicles from the Golgi to the PM and the subsequent viral release are still poorly understood. In our study, we have discovered that Exo70 promotes the trafficking of HSV-1 and BoHV-1 secretory vesicles and facilitates the release of mature virions in an exocyst complex-dependent manner. Mechanistically, both knockdown of Exo70 and a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-binding-deficient mutant of Exo70 caused virions to be trapped in the cytoplasm and unable to tether to PM, indicating that the binding of Exo70 to PI(4,5)P2 is critical for the docking virus secretory vesicles with PM. Additionally, the Snapin-Exo70-SNAP23 axis plays a pivotal role in the fusion between viral secretory vesicles and the PM, ultimately facilitating the release of virions. We found that Rab11a is necessary for viral secretory vesicle trafficking mediated by Exo70. Most importantly, we discovered that ES2, a transport inhibitor that combines with Exo70 to terminate the final stage of exocytosis via the exocyst complex, can protect cells and mice from -herpesvirus infection.

microbiology↗

bioRxiv2024

5-Aza-Cytidine Enhances Terminal Polyadenylation Site Usage for Full-Length Transcripts in Cells

As an inhibitor of DNA methyltransferases (DNMTs) and an anti-cancer drug, 5-aza-cytidine (5-azaC)s many effects on gene expression remains unclear. Here, we show that 5-azaC treatment of cultured GH3 pituitary tumour cells increases relative usage of genomic terminal exons (GTEs) across the transcriptome. This effect is largely achieved by shifting mRNA polyadenylation from proximal poly(A) sites to GTEs, which harbour a more optimal consensus motif of poly(A) signals. Consistent with this shift, 5-azaC upregulates the mRNA anti-termination factors Scaf4 and Scaf8 while downregulating the early termination enhancer E2f2. In MOLM-13 leukaemia cells, 5-azaC similarly promotes the production of full-length transcripts and regulates alternative polyadenylation factors, some of which in the same direction as observed in GH3 cells. Moreover, PCF11, a factor known to promote proximal poly(A) site usage, is upregulated in both cell lines, suggesting a homeostatic response by these cells to counteract transcript lengthening during 5-azaC treatment. Together, these findings uncover a previously unrecognized effect of 5-azaC on gene expression: directional promotion of terminal polyadenylation site usage, driving a transcriptome-wide switch from shortened to full-length mRNAs in tumour or cancer cells and consequently altering the alternative usage of multiple 3' exons.

cell biology↗

bioRxiv2024

Epigenetic Control of Adaptive or Homeostatic Splicing of Alternative Exons and Prolactin Gene Expression During Interval-Training Activities of Pituitary Cells

Interval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of the Prolactin and other hormone genes. The nature of these splicing responses depends on the exons DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of the Prolactin gene is also reliant on MeCP2, whose disruption during ITD leads to exacerbated overexpression and multi-exon aberrant splicing of the hormone gene transcripts, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, depending on how many times cells are stimulated, exons may exhibit different splicing responses to cell activities. During the ITD, epigenetic control is crucial for both adaptive or homeostatic splicing and the steady expression of the Prolactin hormone gene. Disruption in this regulation may have significant implications for the development of progressive diseases.

cell biology↗

bioRxiv2024

Interpretable Drug Response Prediction through Molecule Structure-aware and Knowledge-Guided Visible Neural Network

Precise prediction of anti-cancer drug responses has become a crucial obstruction in anti-cancer drug design and clinical applications. In recent years, various deep learning methods have been applied to drug response prediction and become more accurate. However, they are still criticized as being non-transparent. To offer reliable drug response prediction in real-world applications, there is still a pressing demand to develop a model with high predictive performance as well as interpretability. In this study, we propose DrugVNN, an end-to-end interpretable drug response prediction framework, which extracts gene features of cell lines through a knowledge-guided visible neural network (VNN), and learns drug representation through a node-edge communicative message passing network (CMPNN). Additionally, between these two networks, a novel drug-aware gene attention gate is designed to direct the drug representation to VNN to simulate the effects of drugs. By evaluating on the GDSC dataset, DrugVNN achieved state-of-the-art performance. Moreover, DrugVNN can identify active genes and relevant signaling pathways for specific drug-cell line pairs with supporting evidence in the literature, implying the interpretability of our model.

bioinformatics↗

bioRxiv2024

Human Amniotic Epithelial Cells Promote Chx10-/Pax6+ Muller Glia Subpopulation Reprogramming into Photoreceptor-like Cells

Reprogramming Muller glia to regenerate neurons is a promising strategy for treating retinal degeneration, but whether Muller glia contain subpopulations with different regenerative fates remains unclear. Here, using single-cell RNA-seq analysis and Muller glia lineage-tracing mice with retinal degeneration, we reveal that Muller glia were heterogeneous and identify a specific Muller glial subpopulation (Chx10-/Pax6+) in healthy retinas that is activated and migrate to the outer nuclear layer (ONL) during photoreceptor degeneration. Transplantation of human amniotic epithelial cells (hAECs) facilitates the activation and extensive migration of the Chx10-/Pax6+ Muller glial subpopulation to the ONL, where they are reprogrammed into photoreceptor-like cells. Mechanistically, hAECs degrade the inhibitory extracellular matrix through regulating matrix metalloproteinases, which probably induces remodeling of the microenvironment of Muller glia and contributes to cell reprogramming. Consequently, hAEC transplantation improves visual function in rd10 mice. Our findings uncover a distinctive Muller glial subpopulation with the potential for reprogramming into photoreceptors.

cell biology↗

bioRxiv2024

Polaris Neurosense: A General-Purpose Non-invasive Neurotechnology Research Platform

This article describes our initial work toward a general-purpose platform for non-invasive neurotechnology research. This platform consists of a multi-modal wireless recording device, an associated software API, and full integration into BCI2000 software. The device is placed on the forehead and features two electroencephalographic (EEG) sensors, an inertial movement sensor (IMU), a photoplethysmogram (PPG) sensor, a microphone, and vibration-based feedback. Herein, we demonstrate different technical characteristics of our platform and its use in the context of sleep monitoring/modulation, simultaneous and synchronized recordings from different hardware, and evoked potentials. With further development and widespread dissemination, our platform could become an important tool for research into new non-invasive neurotechnology protocols in humans.

bioengineering↗

bioRxiv2023

Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, {psi}-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, {psi}-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.

pharmacology and toxicology↗