Biology subjects

Qin, L.

Publications and source records attributed to Qin, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Transcription factor ScWRKY4 in sugarcane negatively regulates the resistance to pathogen infection through the JA signaling pathway

WRKY transcription factor, the transcriptional regulators unique to plants, plays an important role in plant defense response to pathogen infection. However, the disease resistance mechanism of WRKY gene in sugarcane remains unclear. Previously, we identified a ScWRKY4 gene, a member of class IIc of the WRKY gene family, from the sugarcane cultivar ROC22. This gene could be induced by the stresses of salicylic acid (SA) and methyl jasmonate (MeJA). Interestingly, the expression of the ScWRKY4 gene was down-regulated in smut-resistant sugarcane cultivars but up-regulated in smut-susceptible sugarcane cultivars under Sporisorium scitamineum stress. Besides, stable overexpression of the ScWRKY4 gene in Nicotiana benthamiana enhanced susceptibility to Fusarium solani var. coeruleum and caused the down-regulated expression of immune marker-related genes. Furthermore, transcriptome analysis indicated that, the expression of most JAZ genes was suppressed in plant signal transduction pathway. In addition, ScWRKY4 could interact with ScJAZ13 and repress the expression of ScJAZ13. We thus hypothesized that the ScWRKY4 gene was involved in the regulatory network of plant disease resistance, most probably through the JA signaling pathway. The present study depicted the molecular mechanism of the ScWRKY4 gene involved in sugarcane disease resistance and laid the foundation for the subsequent investigation. HighlightTransgenic plants overexpressing the ScWRKY4 gene negatively regulated resistance to pathogen by inhibiting the expression of the JAZ genes.

plant biology↗

bioRxiv2023

Intestinal microbiota modulates the anti-tumor effect of oncolytic virus vaccine in colorectal cancer

BackgroundImmunotherapy such as oncolytic virus has become a powerful cancer treatment but only a part of cancer patients can benefit from it, especially to advanced-stage cancer patients are required new therapeutic strategies to facilitate extended survival. Intestinal microbiota may contribute to colorectal cancer (CRC) carcinogenesis and response to immunotherapy. However, whether and how the modulating effect of intestinal microbiota on oncolytic virus vaccine (OVV) in CRC remains to be investigated. MethodsWe generated a MC38-gp33 CRC mouse model and treated with OVV-gp33 in early- and advanced-stages. Probiotics, fecal microbiota transplantation (FMT) and antibiotics (ABX) were treated to regulate the microbial composition of CRC mice of advanced stage. The tumor growth rate and survival time of mice were recorded. 16S rDNA sequencing analyzed the microbial composition and flow cytometry detected the T cells subsets activity. ResultsOVV-gp33 treatment led to inhibited tumor growth and prolonged survival in the early stage of CRC but did not have a significant effect on the advanced stage of CRC. Moreover, 16S rDNA sequence analysis and flow cytometry showed significant differences in intestinal microbiota composition, microbial metabolites and T-cell subsets in early- and advanced-stage CRC. Probiotic and FMT treatment significantly enhanced the antitumor effect of OVV in advanced stage of CRC with an increased abundance of activated CD8+ T cells and a decreased ratio of Treg cells, while depletion of the microbiota by ABX eliminated the antitumor activity of OVV with decreased CD8+ T-cell activation and upregulated Treg cells. ConclusionsThese results indicate that intestinal microbiota and microbial metabolites play an important role in the OVV antitumor effect in CRC, furthermore, altering the intestinal microbiota composition can modulate the antitumor and immunomodulatory effect of OVV in CRC.

physiology↗

bioRxiv2023

Single Cell RNA Sequencing Reveals Emergent Notochord-Derived Cell Subpopulations in the Postnatal Nucleus Pulposus

Intervertebral disc degeneration is a leading cause of chronic low back pain. Cell-based strategies that seek to treat disc degeneration by regenerating the central nucleus pulposus hold significant promise, but key challenges remain. One of these is the inability of therapeutic cells to effectively mimic the performance of native nucleus pulposus cells, which are unique amongst skeletal cell types in that they arise from the embryonic notochord. In this study we use single cell RNA sequencing to demonstrate emergent heterogeneity amongst notochord-derived nucleus pulposus cells in the postnatal mouse disc. Specifically, we established the existence of early and late stage nucleus pulposus cells, corresponding to notochordal progenitor and mature cells, respectively. Late stage cells exhibited significantly higher expression levels of extracellular matrix genes including aggrecan, and collagens II and VI, along with elevated TGF-{beta} and PI3K-Akt signaling. Additionally, we identified Cd9 as a novel surface marker of late stage nucleus pulposus cells, and demonstrated that these cells were localized to the nucleus pulposus periphery, increased in numbers with increasing postnatal age, and co-localized with emerging glycosaminoglycan-rich matrix. Finally, we used a goat model to show the Cd9+ nucleus pulposus cell numbers decrease with moderate severity disc degeneration, suggesting that these cells are associated with maintenance of the healthy nucleus pulposus extracellular matrix. Improved understanding of the developmental mechanisms underlying regulation of ECM deposition in the postnatal NP may inform improved regenerative strategies for disc degeneration and associated low back pain.

cell biology↗

bioRxiv2023

Anabolic phenotype in cartilage-specific Mitogen-inducible gene-6 knockout mice is independent of Transforming growth factor-α

Background/ObjectiveOsteoarthritis (OA) is a whole joint disorder with no disease modifying treatment currently available. The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in cartilage/bone development and its ligand transforming growth factor- (TGl{middle dot}) is upregulated in OA. In contrast, Mitogen-inducible gene 6 (Mig6) is a negative regulator of EGFR, and our studies demonstrate that cartilage-specific Mig-6 deletion results in anabolic effects on cartilage and formation of chondro-osseus nodules (CON). We aimed to attenuate EGFR signaling by inhibiting TGF production in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs. MethodsWe generated double knockout mice by crossing cartilage-specific Mig-6fl/flCol2a1-Cre+/- and whole-body Tgfa+/- mice to generate experimental and control wild-type mice. Knee and elbow sections were stained with toluidine blue to examine articular cartilage thickness and cell density, and tartrate-resistant acid phosphatase for osteoclast activity. Additionally, immunohistochemistry was completed to analyze phospho-EGFR and SOX9. ResultsMig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGF ligand presence. Similarly, articular cartilage cell density is increased in Mig-6fl/flCol2a1-Cre+/-Tgfa-/- and Mig-6fl/flCol2al-Cre+/- mice, but not Tgfa-/- mice, and displays increased SOX9 and phospho-EGFR staining. ConclusionThe articular cartilage displays increased thickness, increased cell density, and CON formation independent of the presence of TGF, suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGF/EGFR binding. The anabolic phenotype may be due to an alternative EGFR ligand activation, or perhaps due to other non-EGFR specific mechanism. More research is required to elucidate the exact pathway responsible for the anabolic effects.

physiology↗

bioRxiv2023

YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulated bone development

Endochondral ossification requires coordinated mobilization of osteoblast precursors with blood vessels. During adult bone homeostasis, vessel adjacent osteoblast precursors respond to and are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Previously, we found that deletion of the mechanoresponsive transcriptional regulators, YAP and TAZ, from Osterix-expressing osteoblast precursors and their progeny caused perinatal lethality. Here, we show that embryonic YAP/TAZ signaling couples vessel-associated osteoblast precursor mobilization to angiogenesis in developing long bones. Osterix-conditional YAP/TAZ deletion impaired endochondral ossification in the primary ossification center but not intramembranous osteogenesis in the bone collar. Single-cell RNA sequencing revealed YAP/TAZ regulation of the angiogenic chemokine, Cxcl12, which was expressed uniquely in vessel-associated osteoblast precursors. YAP/TAZ signaling spatially coupled osteoblast precursors to blood vessels and regulated vascular morphogenesis and vessel barrier function. Further, YAP/TAZ signaling regulated vascular loop morphogenesis at the chondro-osseous junction to control hypertrophic growth plate remodeling. In human cells, mesenchymal stromal cell co-culture promoted 3D vascular network formation, which was impaired by stromal cell YAP/TAZ depletion, but rescued by recombinant CXCL12 treatment. Lastly, YAP and TAZ mediated mechanotransduction for load-induced osteogenesis in embryonic bone.

developmental biology↗

bioRxiv2023

MCB-613 exploits a collateral sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

cancer biology↗

bioRxiv2022

Evaluation of a scalable approach to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells

Genome-wide association studies (GWASs) have revolutionized our understanding of the genetics of complex diseases, such as osteoporosis; however, the challenge has been converting associations to causal genes. Studies have demonstrated the utility of transcriptomics data in linking disease-associated variants to genes; though for osteoporosis, few population transcriptomics datasets have been generated on bone or bone cells, and an even smaller number have profiled individual cell-types. To begin to evaluate approaches to address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions, a popular model of osteoblast differentiation and activity, from five Diversity Outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model for the generation of cell-type specific transcriptomic profiles of mesenchymal lineage cells derived from large populations of mice to inform genetic studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were nearly identical from a transcriptomic perspective to cells isolated directly from bone. We also demonstrated the ability to multiplex single cells and subsequently assign cells to their "mouse-of-origin" using demultiplexing approaches based on genotypes inferred from coding SNPs. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell-types. SCENIC was used to reconstruct gene regulatory networks (GRNs) and we showed that identified cell-types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of BMD heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically informative model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells in large mouse, and potentially human, populations.

bioinformatics↗

bioRxiv2022

Targeted degradation of PRC1 components, BMI1 and RING1B, via a novel protein complex degrader strategy

Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). BMI1 and RING1B are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited, and small-molecule inhibitors of PRC1 displayed limited effectiveness in killing cancer cells. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, was discovered via a novel protein complex degradation strategy that utilizes the target proteins interacting partner protein (EED) to degrade BMI1 and RING1B. MS147, which comprises an EED small-molecule binder linked to a ligand of the E3 ligase VHL, degrades BMI1 and RING1B in an EED-, VHL-, ubiquitination- and time-dependent manner. MS147 is selective and preferentially degrades BMI1 and RING1B over PRC2 core components: EED, EZH2 and SUZ12. Consequently, MS147 effectively reduces H2AK119ub, but not H3K27me3, which is catalyzed by PRC2. Furthermore, MS147, but not the parent EED binder or known PRC2 degraders, effectively inhibits the proliferation of cancer cell lines that are insensitive to EZH2 knockout or PRC2 degraders. Overall, this study provides a novel degrader targeting BMI1 and RING1B, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which could potentially expand the degradable human proteome.

biochemistry↗

bioRxiv2022

Three-dimensional molecular architecture of mouse organogenesis

Mammalian embryos have sophisticated cell organizations that are orchestrated by molecular regulation at cellular and tissue level. It has recently been appreciated that the cells that make up the animal body themselves harbor significant heterogeneity in the context of both cellular and particularly spatial dimension. However, current spatial transcriptomics profiling of embryonic tissues either lack three-dimensional representation or are restricted to limited depth and organs. Here, we reported a holistic spatial transcriptome atlas of all major organs at embryonic day 13.5 of mouse embryo and delineated a 3D rendering of the molecular regulation of embryonic patterning. By integrating with corresponding single-cell transcriptome data, the spatial organogenesis atlas provides rich molecular annotation of the dynamic organ nature, spatial cellular interaction, embryonic axes and divergence of cell fates underlying mammalian development, which would pave the way for precise organ-engineering and stem-cell based regenerative medicine.

developmental biology↗

bioRxiv2022

Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice

The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes a severe osteopenia in both young and aged mice by impairing osteoblast function without affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. At the molecular level, vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin production in osteocytes. Deleting Sost expression reverses the osteopenic phenotypes caused by vinculin loss in mice. We demonstrate that estrogen is a major regulator of vinculin expression in osteocytes and that more importantly vinculin loss mediates estrogen deficiency induction of bone loss in mice. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.

developmental biology↗

bioRxiv2022

Activin A promotes bone fracture repair and acts through a novel myofibroblastic cell population in callus

Insufficient bone fracture repair represents a significant clinical burden, and identification of novel therapeutics enhancing repair would have substantial clinical and societal impact. Activin A is a TGF-{beta} protein superfamily member known to stimulate ectopic bone formation, but its roles in fracture repair and its therapeutic potentials remain unclear. Using two mouse tibia fracture repair models, here we mapped activin A expression at the tissue and single cell levels, tested its requirement for normal repair and evaluated its ability to enhance repair when provided exogenously. Activin A was minimally expressed in periosteum of intact bones but was markedly upregulated in developing callus soon after fracture. Single cell RNA-sequencing revealed that the activin A-encoding gene Inhba marked a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character which emerged over repair time and lay at the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of a neutralizing activin A antibody impaired fracture repair and its endochondral and intramembranous phases, whereas local delivery of recombinant activin A enhanced repair. Activin A delivery also induced SMAD2 phosphorylation in vivo and increased the fraction of SMA+ myofibroblasts within fracture callus. Gain- and loss-of-function experiments in vitro showed that activin A directly stimulated myofibroblast differentiation, chondrogenesis and osteogenesis in periosteal progenitor cells. Together, these data identify a unique population of Inhba-expressing proliferative progenitor cells that give rise to chondrocytes and osteoblasts during fracture healing and establish activin A as a potential new therapeutic tool to enhance it. One Sentence SummaryDeficits in bone fracture repair remain a clinical challenge and the present study provides evidence for the therapeutic potentials of activin A

pathology↗

bioRxiv2022

Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone

Colony stimulating factor 1 (Csf1) is an essential growth factor for osteoclast progenitors and thus an important regulator for bone resorption. It remains elusive which mesenchymal cells synthesize Csf1 stimulating osteoclastogenesis. We recently identified a novel mesenchymal cell population, marrow adipogenic lineage precursors (MALPs), in bone. Single cell RNA- sequencing indicated specific expression of Csf1 in MALPs, which is further increased during aging. To investigate its role, we constructed Csf1 CKO mice using Adipoq-Cre. These mice showed increased femoral trabecular bone over time, but their cortical bone appeared normal. In comparison, depletion of Csf1 in the entire mesenchymal lineage using Prx1-Cre led to a more striking high bone mass phenotype, suggesting that additional mesenchymal subpopulations secrete Csf1. TRAP staining revealed diminished osteoclasts in the femoral secondary spongiosa region of Csf1 CKOAdipoq mice, but not at the chondral-osseous junction nor at the endosteal surface of cortical bone. Moreover, Csf1 CKOAdipoq mice were resistant to LPS-induced calvarial osteolysis. Bone marrow cellularity, hematopoietic progenitors, and macrophages were also reduced in these mice. Taken together, our studies demonstrate that MALPs are a critical player in controlling bone remodeling and hematopoiesis.

cell biology↗

bioRxiv2022

An auto-inhibited state of protein kinase G and implications for selective activation

Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cGMP signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and axon guidance. Campaigns targeting nitric oxide synthases and cyclic nucleotide phosphodiesterases in this signaling axis suggest that understanding how cGMP differentially triggers mammalian PKG isoforms could lead to new therapeutics that inhibit or activate PKGs. Alternate splicing of PRKG1 transcripts confers distinct leucine zippers, linkers, and auto-inhibitory pseudo-substrate sequences to PKG I and I{beta} that result in isoform-specific activation properties, but the mechanism of enzyme auto-inhibition and its alleviation by cGMP is still not well understood. Here we present a crystal structure of PKG I{beta} in which the auto-inhibitory sequence and the cyclic nucleotide binding domains are bound to the catalytic domain, providing a snapshot of the auto-inhibited state. Specific contacts between the PKG I{beta} auto-inhibitory sequence and the enzyme active site help explain isoform-specific activation constants and the effects of phosphorylation in the linker. We also present a crystal structure of a PKG I cyclic nucleotide binding domain with an activating mutation linked to Thoracic Aortic Aneurysms and Dissections. Similarity of this structure to wild type cGMP-bound domains and differences with the auto-inhibited enzyme provide a mechanistic basis for constitutive activation. We show that PKG I{beta} auto-inhibition is mediated by contacts within each monomer of the native full-length dimeric protein, and using the available structural and biochemical data we develop a model for the regulation and activation of PKGs.

biochemistry↗

bioRxiv2022

IFT20 governs mesenchymal stem cell fate through positively regulating TGF-β-Smad2/3-Glut1 signaling mediated glucose metabolism

Aberrant lineage allocation of mesenchymal stem cells (MSCs) could cause bone marrow osteoblast-adipocyte imbalance, and glucose as an important nutrient is required for the maintenance of the MSCs fate and function. Intraflagellar transport 20 (IFT20) is one of the IFT complex B protein which regulates osteoblast differentiation, and bone formation, but how IFT20 regulates MSCs fate remains undefined. Here, we demonstrated that IFT20 controls MSC lineage allocation through regulating glucose metabolism during skeletal development. IFT20 deficiency in the early stage of MSCs caused significantly shortened limbs, decreased bone mass and significant increase in marrow fat. However, deletion of IFT20 in the later stage of MSCs and osteocytes just slightly decreased bone mass and bone growth and increased marrow fat. Additionally, we found that loss of IFT20 in MSCs promotes adipocyte formation, which enhances RANKL expression and bone resorption. Conversely, ablation of IFT20 in adipocytes reversed these phenotypes. Mechanistically, loss of IFT20 in MSCs significantly decreased glucose tolerance and suppressed glucose uptake and lactate and ATP production. Moreover, loss of IFT20 significantly inhibited TGF-{beta}-Smad2/3 signaling and decreased the binding activity of Smad2/3 to Glut1 promoter to downregulate Glut1 expression. These findings indicate that IFT20 plays essential roles for preventing MSC lineage allocation into adipocytes through controlling TGF-{beta}-Smad2/3-Glut1 mediated glucose metabolism.

developmental biology↗

bioRxiv2021

A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine. One sentence summaryA sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

microbiology↗

bioRxiv2021

Molecular basis for the R-type anion channel QUAC1 activity in guard cells

The rapid (R)-type anion channel plays a central role in controlling stomatal closure in plant guard cells, thus regulating the exchange of water and photosynthetic gas (CO2) in response to environmental stimuli. The activity of the R- type anion channel is regulated by malate. However, the molecular basis of the R-type anion channel activity remains elusive. Here, we describe the first cryo-EM structure of the R-type anion channel QUAC1 at 3.5 [A] resolution in the presence of malate. The structure reveals that the QUAC1 is a symmetrical dimer, forming a single electropositive T-shaped pore for passing anions across the membrane. The transmembrane and cytoplasmic domains are assembled into a twisted bi-layer architecture, with the associated dimeric interfaces nearly perpendicular. Our structural and functional analyses reveal that QUAC1 functions as an inward rectifying anion channel and suggests a mechanism for malate-mediated channel activation. Altogether, our study uncovers the molecular basis for a novel class of anion channels and provides insights into the gating and modulation of the R-type anion channel.

plant biology↗

bioRxiv2021

A Promising Chemical Series of Positive Allosteric Modulators of the μ-Opioid Receptor that Enhance the Antinociceptive Efficacy of Opioids but not their Adverse Effects

Positive allosteric modulators (PAMs) of the {micro}-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.

neuroscience↗

bioRxiv2021

Characterization of novel regulatory modules controlling leaf angle in maize

Leaf angle is an important agronomic trait determining maize planting density and light penetration into the canopy, and contributes significantly to the yield gain in modern maize hybrids. However, little is known about its molecular mechanism beyond the Liguless1 (LG1) and Liguless2 (LG2) genes. In this study, we found that transcription factor ZmBEH1 is targeted by ZmLG2 and regulates the leaf angle formation by influencing the sclerenchyma cells layers on the adaxial side. ZmBEH1 can interact with transcription factor ZmBZR1, whose expression is directly activated by ZmLG1. Both ZmBEH1 and ZmBZR1 bind to the promoter of ZmSCL28, the third transcription factors that influences the leaf angle. Our study demonstrates novel regulatory modules controlling leaf angle, and provides new gene editing targets for creating optimal maize architecture suitable for dense-planting.

plant biology↗