Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.

The transcriptional hub SHORT INTERNODES1 integrates hormone signals to orchestrate rice growth and development.

Plants have evolved sophisticated mechanisms to coordinate their growth and stress responses via integrating various phytohormone signaling pathways. However, the precise molecular mechanisms orchestrating integration of the phytohormone signaling pathways remain largely obscure. In this study, we found that the rice (Oryza sativa) short internodes1 (shi1) mutant exhibits typical auxin-deficient root development and gravitropic response, brassinosteroid (BR)-deficient plant architecture and grain size as well as enhanced abscisic acid (ABA)-mediated drought tolerance. Additionally, we found that the shi1 mutant is also hyposensitive to auxin and BR treatment but hypersensitive to ABA. Further, we showed that OsSHI1 promotes the biosynthesis of auxin and BR by activating the expression of OsYUCCAs and D11, meanwhile dampens ABA signaling by inducing the expression of OsNAC2, which encodes a repressor of ABA signaling. Furthermore, we demonstrated that 3 classes of transcription factors, AUXIN RESPONSE FACTOR 19 (OsARF19), LEAF AND TILLER ANGLE INCREASED CONTROLLER (LIC), and OsZIP26 and OsZIP86, directly bind to the promoter of OsSHI1 and regulate its expression in response to auxin, BR, and ABA, respectively. Collectively, our results unravel an OsSHI1-centered transcriptional regulatory hub that orchestrates the integration and self-feedback regulation of multiple phytohormone signaling pathways to coordinate plant growth and stress adaptation.

In Situ Spontaneous Construction of Zinc Phosphate Coating Layer Toward Highly Reversible Zinc Metal Anodes.

Aqueous zinc ion batteries have received widespread attention due to their merits of high safety, high theoretical specific capacity, low cost, and environmental benignity. Nevertheless, the irreversible issues of Zn anode deriving from side reactions and dendrite growth have hindered its commercialization in large-scale energy storage systems. Herein, a zinc phosphate tetrahydrate (Zn3(PO4)2·4H2O, ZnPO) coating layer is in situ formed on the bare Zn by spontaneous redox reactions at room temperature to tackle the above issues. Particularly, the dense and brick-like ZnPO layer can effectively separate the anode surface from the aqueous electrolyte, thus suppressing the serious side reactions. Moreover, the ZnPO layer with high ionic conductivity, high Zn2+ transference number, and low nucleation barrier permits rapid Zn2+ transport and enables uniform Zn deposition, ensuring dendrite-free Zn deposition. As a result, the ZnPO@Zn symmetric battery achieves a high Coulombic efficiency of 99.8% and displays ultrahigh cycle stability over 6000 h (> 8 months), far surpassing its counterparts. Furthermore, the ZnPO@Zn||MnO2 full battery exhibits excellent electrochemical performances. Therefore, this work provides a new reference for simple and large-scale preparation of highly reversible Zn metal anodes, and has great potential for practical applications.

Cold to Hot: Tumor Immunotherapy by Promoting Vascular Normalization Based on PDGFB Nanocomposites.

Immunotherapy is a promising cancer therapeutic strategy. However, the "cold" tumor immune microenvironment (TIME), characterized by insufficient immune cell infiltration and immunosuppressive status, limits the efficacy of immunotherapy. Tumor vascular abnormalities due to defective pericyte coverage are gradually recognized as a profound determinant in "cold" TIME establishment by hindering immune cell trafficking. Recently, several vascular normalization strategies by improving pericyte coverage have been reported, whereas have unsatisfactory efficacy and high rates of resistance. Herein, a combinatorial strategy to induce tumor vasculature-targeted pericyte recruitment and zinc ion-mediated immune activation with a platelet-derived growth factor B (PDGFB)-loaded, cyclo (Arg-Gly-Asp-D-Phe-Lys)-modified zeolitic imidazolate framework 8 (PDGFB@ZIF8-RGD) nanoplatform is proposed. PDGFB@ZIF8-RGD effectively induced tumor vascular normalization, which facilitated trafficking and infiltration of immune effector cells, including natural killer (NK) cells, M1-like macrophages and CD8+ T cells, into tumor microenvironment. Simultaneously, vascular normalization promoted the accumulation of zinc ions inside tumors to trigger effector cell immune activation and effector molecule production. The synergy between these two effects endowed PDGFB@ZIF8-RGD with superior capabilities in reprogramming the "cold" TIME to a "hot" TIME, thereby initiating robust antitumor immunity and suppressing tumor growth. This combinatorial strategy for improving immune effector cell infiltration and activation is a promising paradigm for solid tumor immunotherapy.

A gene-based score for the risk stratification of stage IA lung adenocarcinoma.

OBJECTIVE: We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine. METHODS: Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance. RESULTS: Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD. CONCLUSIONS: The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.

Human lens epithelial-secreted exosomes attenuate ocular angiogenesis via inhibiting microglial activation.

The lens is an avascular tissue, where epithelial cells (LECs) are the primary living cells. The role of LECs-derived exosomes (LEC-exos) is largely unknown. In our study, we determined the anti-angiogenic role of LEC-exos, manifested as regressed retinal neovascularization (NV) using the oxygen-induced retinopathy (OIR), and reduced choroidal NV size and pathological vascular leakage using the laser-induced choroidal neovascularization (laser-induced CNV). Furthermore, the activation and accumulation of microglia were also restricted by LEC-exos. Based on Luminex multiplex assays, the expressions of chemokines such as SCYB16/CXCL16, MCP-1/CCL2, I-TAC/CXCL11, and MIP 3beta/CCL19 were decreased after treatment with LEC-exos. Transwell assays showed that LEC-exos restricted the migration of the mouse microglia cell line (BV2 cells). After incubation with LEC-exos-treated BV2 cells, human umbilical vein endothelial cells (hUVECs) were collected for further evaluation using tube formation, Transwell assays, and 5-ethynyl-2'-deoxyuridine (EDU) assays. Using in vitro experiments, the pro-angiogenic effect of microglia was restricted by LEC-exos. Hence, it was investigated that LEC-exos attenuated ocular NV, which might attribute to the inhibition of microglial activation and accumulation.

Reaction strategies for the meta-selective functionalization of pyridine through dearomatization.

The pyridine moiety is a crucial structural component in various pharmaceuticals. While the direct ortho- and para-functionalization of pyridines is relatively straightforward, the meta-selective C-H functionalization remains a significant challenge. This review highlights dearomatization strategies as a key area of interest in expanding the application of meta-C-H functionalization of pyridines. Dearomatization enables the meta-functionalization through various catalytic methods that directly generate dearomatization products, and some products can be rearomatized back to pyridine derivatives. Furthermore, this article also covers the dearomatization of multiple positions of pyridine in the synthesis of polycyclic compounds. It offers a comprehensive overview of the latest advancements in dearomatization at different positions of pyridine, aiming to provide a valuable resource for researchers in this field. It also highlights the advantages and limitations of existing technologies, aiming to inform a broader audience about this important field and foster its future development.

Copper-catalyzed C2-selective alkynylation of chromones via 1,4-conjugate addition.

Copper-catalyzed selective alkynylation with N-propargyl carboxamides as nucleophiles has been successfully developed for the synthesis of C2-functionalized chromanones. Under optimized reaction conditions, 21 examples were obtained in one-pot procedure through 1,4-conjugate addition. This protocol features readily available feedstocks, easy operations, and moderate to good yields, which provides viable access to pharmacologically active C2-functionalized chromanones.

Bioactive VS4-based sonosensitizer for robust chemodynamic, sonodynamic and osteogenic therapy of infected bone defects.

BACKGROUND: Most bone defects caused by bone disease or trauma are accompanied by infection, and there is a high risk of infection spread and defect expansion. Traditional clinical treatment plans often fail due to issues like antibiotic resistance and non-union of bones. Therefore, the treatment of infected bone defects requires a strategy that simultaneously achieves high antibacterial efficiency and promotes bone regeneration. RESULTS: In this study, an ultrasound responsive vanadium tetrasulfide-loaded MXene (VSM) Schottky junction is constructed for rapid methicillin-resistant staphylococcus aureus (MRSA) clearance and bone regeneration. Due to the peroxidase (POD)-like activity of VS4 and the abundant Schottky junctions, VSM has high electron-hole separation efficiency and a decreased band gap, exhibiting a strong chemodynamic and sonodynamic antibacterial efficiency of 94.03%. Under the stimulation of medical dose ultrasound, the steady release of vanadium element promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The in vivo application of VSM in infected tibial plateau bone defects of rats also has a great therapeutic effect, eliminating MRSA infection, then inhibiting inflammation and improving bone regeneration. CONCLUSION: The present work successfully develops an ultrasound responsive VS4-based versatile sonosensitizer for robust effective antibacterial and osteogenic therapy of infected bone defects.

M2 microglia-derived exosomes promote vascular remodeling in diabetic retinopathy.

Diabetic retinopathy (DR) is a vision-threatening diabetic complication that is characterized by microvasculature impairment and immune dysfunction. The present study demonstrated that M2 microglia intensively participated in retinal microangiopathy in human diabetic proliferative membranes, mice retinas, retinas of mice with oxygen-induced retinopathy (OIR) mice, and retinas of streptozotocin-induced DR mice. Further in vivo and in vitro experiments showed that exosomes derived from M2 polarized microglia (M2-exo) could reduce pericyte apoptosis and promote endothelial cell proliferation, thereby promoting vascular remodeling and reducing vascular leakage from the diabetic retina. These effects were further enhanced by M2-exo that facilitated M2 polarization of retinal microglia. Collectively, the study demonstrated the capability of M2-exo to induce retinal microvascular remodeling, which may provide a new therapeutic strategy for the treatment of DR.

Biological ultrathin amniotic membrane flap to close refractory macular holes associated with high myopia.

PURPOSE: To propose an ultrathin biological amniotic membrane (btAM) thinner than 10 µm as the graft to treat highly myopic macular holes (MH). METHODS: This pilot study included 14 patients affected by refractory macular holes associated with high myopia. btAM was used as a bandage covering the holes. The best-corrected visual acuity (BCVA), fundus photography, and optical coherence tomography (OCT) before and after surgery were compared. RESULTS: The mean MH size was 865.93 ± 371.72 µm and all the MHs achieved anatomical closure. The btAM located centrally and fully on MHs from fundus photography yet no obvious visual masking was complained. The average BCVA 1 month, 3, and 6 months after surgery were 0.95 ± 0.24, 0.92 ± 0.23, 0.92 ± 0.23 logMAR, respectively, improved significantly compared to pre-operative BCVA (1.24 ± 0.42 logMAR, all P < 0.05). Ten out of 14 (71.4%) exhibited 2C closure patterns (formally closed and no bare RPE) on OCT. CONCLUSION: The btAM thinner showed a favorable anatomical success with less risk of parafoveal atrophy or iatrogenic injuries and shortened the dissolving time.

M1 macrophage-related gene model for NSCLC immunotherapy response prediction.

Patients diagnosed with non-small cell lung cancer (NSCLC) have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for antitumor immunity. This study aims to develop an immunotherapy response evaluation model for NSCLC patients based on transcription. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy are downloaded from the POPLAR and OAK projects. Immune cell infiltration in NSCLC patients is examined, and thereafter, different coexpressed genes are identified. Next, the impact of M1 macrophage-related genes on the prognosis of NSCLC patients is investigated. Six M1 macrophage coexpressed genes, namely, NKX2-1, CD8A , SFTA3, IL2RB, IDO1, and CXCL9, exhibit a strong association with the prognosis of NSCLC and serve as effective predictors for immunotherapy response. A response model is constructed using a Cox regression model and Lasso Cox regression analysis. The M1 genes are validated in our TD-FOREKNOW NSCLC clinical trial by RT-qPCR. The response model shows excellent immunotherapy response prediction and prognosis evaluation value in advanced-stage NSCLC. This model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

Isobavachalcone, a natural sirtuin 2 inhibitor, exhibits anti-triple-negative breast cancer efficacy in vitro and in vivo.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype and lacks effective targeted therapies at present. Isobavachalcone (IBC), the main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor and characterized the potential mechanisms underlying the inhibition of TNBC. Molecular dynamics analysis, enzyme activity assay, and cellular thermal shift assay were performed to evaluate the combination of IBC and SIRT2. The therapeutic effects, mechanism, and safety of IBC were analyzed in vitro and in vivo using cellular and xenograft models. IBC effectively inhibited SIRT2 enzyme activity with an IC50 value of 0.84 ± 0.22 µM by forming hydrogen bonds with VAL233 and ALA135 within its catalytic domain. In the cellular environment, IBC bound to and stabilized SIRT2, consequently inhibiting cellular proliferation and migration, and inducing apoptosis and cell cycle arrest by disrupting the SIRT2/α-tubulin interaction and inhibiting the downstream Snail/MMP and STAT3/c-Myc pathways. In the in vivo model, 30 mg/kg IBC markedly inhibited tumor growth by targeting the SIRT2/α-tubulin interaction. Furthermore, IBC exerted its effects by inducing apoptosis in tumor tissues and was well-tolerated. IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/ß-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.

Hard SyDR: A Benchmarking Environment for Global Navigation Satellite System Algorithms.

A Global Navigation Satellite System (GNSS) is widely used today for both positioning and timing purposes. Many distinct receiver chips are available as Application-Specific Integrated Circuit (ASIC)s off-the-shelf, each tailored to the requirements of various applications. These chips deliver good performance and low energy consumption but offer customers little-to-no transparency about their internal features. This prevents modification, research in GNSS processing chain enhancement (e.g., application of Approximate Computing (AxC) techniques), and design space exploration to find the optimal receiver for a use case. In this paper, we review the GNSS processing chain using SyDR, our open-source GNSS Software-Defined Radio (SDR) designed for algorithm benchmarking, and highlight the limitations of a software-only environment. In return, we propose an evolution to our system, called Hard SyDR to become closer to the hardware layer and access new Key Performance Indicator (KPI)s, such as power/energy consumption and resource utilization. We use High-Level Synthesis (HLS) and the PYNQ platform to ease our development process and provide an overview of their advantages/limitations in our project. Finally, we evaluate the foreseen developments, including how this work can serve as the foundation for an exploration of AxC techniques in future low-power GNSS receivers.

Characteristics of painful temporomandibular disorders and their influence on jaw functional limitation and oral health-related quality of life.

BACKGROUND: There is limited knowledge about the impact of painful temporomandibular disorders (TMDs) and pain characteristics on jaw functional limitation and oral health-related quality of life (OHRQoL) in TMD patients. OBJECTIVES: The influence of painful TMDs and pain characteristics on jaw functional limitation and OHRQoL was investigated. Inter-relationships between limitation in jaw function and various OHRQoL domains, along with facial pain attributes predicting impaired jaw function and diminished OHRQoL were also examined. METHODS: TMD patients were recruited from a university-based hospital. A comprehensive questionnaire comprising demographic variables, the DC/TMD Symptom Questionnaire, Graded Chronic Pain Scale, Jaw Functional Limitation Scale-8 (JFLS-8) and Oral Health Impact Profile-TMD (OHIP-TMD) was administered. Participants underwent a protocolized physical examination, and TMD diagnoses were determined utilising the DC/TMD algorithms. Participants were subsequently stratified into intra-articular/pain-related/combined TMD groups, as well as no TMD pain, acute/chronic pain and low/high-intensity pain groups. Data were assessed using non-parametric and hierarchical linear regression analyses (α = .05). RESULTS: The final sample consisted of 280 participants (mean age 31.2 (SD 11.8) years; 79.3% women). Significant differences in pain characteristics, JFLS-8, and global OHIP scores were observed across the various TMD subtypes, pain chronicity and pain intensity categories. Pain intensity and pain-related interference exhibited moderate correlations with JFLS-8 and global OHIP scores (rs = 0.53-0.60). Moderate associations were also noted between JFLS-8 and global OHIP, as well as most OHIP domains (rs = 0.42-0.64). Both jaw functional limitation and OHRQoL were predicted by sex, pain intensity and pain-related interference. CONCLUSIONS: Sex, pain intensity and pain-related interference are key determinants for both impaired jaw function and diminished OHRQoL, with pain-related interference exerting a more pronounced effect.

Exercise therapy in postoperative patients with temporomandibular joint internal derangement: A systematic review.

OBJECTIVE: Postoperative patients with temporomandibular joint internal derangement (ID) often have problems such as limited mouth opening and pain. Exercise therapy can be advantageous for improving the recovery of patients following surgery. However, there is continuing discussion on the precise aspects of the exercise program, including the optimal timing, length, intensity, and use of assistive equipment. Hence, this study aimed to incorporate pre-existing exercise treatment regimens and investigate their impact. METHODS: Publications that detailed the clinical treatment of patients with temporomandibular joint ID who received postoperative exercise therapy interventions were included. Nine databases were searched until October 1st, 2023. The JBI critical appraisal tools were used to assess the methodological quality of the included studies. RESULTS: Five studies were finally included for subsequent analysis; two were randomised controlled studies, and three were quasi-experimental. Exercises suitable for such patients encompass vertical, transverse, and horizontal stretching, among which vertical stretch can be divided into active and passive movements. The start time ranged from the first to the fifth week after surgery, with a duration of 1-6 months. Although the data in the studies could not be integrated and further analysed, preliminary results showed that maximum mouth opening and pain in patients improved significantly. The therapeutic effect of combining three exercise methods was best and was related to patient compliance. CONCLUSION: Exercise therapy positively affects postoperative rehabilitation in patients with temporomandibular joint ID. It is proposed that targeted, comprehensive studies be conducted to provide a basis for designing more sophisticated exercise therapy regimens and further confirm its curative effect.

Effectiveness of different intrusion modes of maxillary anterior teeth with mini-implants in clear aligner treatment: a three-dimensional finite element analysis.

BACKGROUND: The intrusion of maxillary anterior teeth is often required and there are various intrusion modes with mini-implants in clear aligner treatment. The objective of this study was to evaluate the effectiveness of maxillary anterior teeth intrusion with different intrusion modes, aiming to provide references for precise and safe intrusion movements in clinical practice. METHODS: Cone-beam computed tomography and intraoral optical scanning data of a patient were collected. Finite element models of the maxilla, maxillary dentition, periodontal ligaments (PDLs), clear aligner (CA), attachments, and mini-implants were established. Different intrusion modes of the maxillary anterior teeth were simulated by changing the mini-implant site (between central incisors, between central and lateral incisor, between lateral incisor and canine), loading site (between central incisors, on central incisor, between central and lateral incisor, between lateral incisor and canine), and loading mode (labial loading and labiolingual loading). Ten conditions were generated and intrusive forces of 100 g were applied totally. Then displacement tendency of the maxillary anterior teeth and CA, and stress of the PDLs were analyzed. RESULTS: For the central incisor under condition L14 and for the canine under conditions L11, L13, L23, and L33, the intrusion amount was negative. Under other conditions, the intrusion amount was positive. The labiolingual angulation of maxillary anterior teeth exhibited positive changes under all conditions, with greater changes under linguoincisal loading. The mesiodistal angulation of canine exhibited positive changes under labial loading, while negative changes under linguoincisal loading except for condition L14. CONCLUSIONS: The intrusion amount, labiolingual and mesiodistal angulations of the maxillary anterior teeth were affected by the mini-implant site, loading site, and loading mode. Labial and linguoincisal loading may have opposite effects on the intrusion amount of maxillary anterior teeth and the mesiodistal angulation of canine. The labiolingual angulation of the maxillary incisors would increase under all intrusion modes, with greater increases under linguoincisal loading.

Can Socially Assistive Robots Be Accepted by Older People Living Alone in the Community?: Empirical Findings from a Social Work Project in China.

A pilot study was undertaken between March 2019 and September 2021, loaning socially assistive robots (SARs) for a 7-day trial to older people living alone in China. Quantitative assessments of participants' acceptance of technology and loneliness were conducted before and after the intervention, supplemented with qualitative interviews. Unexpectedly, participants' intention to use SARs decreased significantly, largely due to emotional anxiety. Meanwhile, participants' level of loneliness remained unchanged. Follow-up interviews revealed anxious emotion, hesitant attitudes, unreal social presence, usability difficulties as contributing factors. The study provides social workers with valuable insights into introducing SARs into community care of older people.

[Prospective,multi-center,and large-scale hospital centralized monitoring of clinical safety of Reduning Injection in 100249 children cases].

This study utilized a prospective, large-sample, multi-center, and registered key specialty approach of hospitals to monitor the application of Reduning Injection. A total of 100 249 adolescent patients aged 14 years and below who received Reduning Injection were monitored, resulting in 83 cases of adverse events, with 76 of them being classified as adverse drug reaction(ADR). The calculated incidence rate of ADR for Reduning Injection was 0.076%, indicating a very rare ADR. The main symptoms of ADR were pruritus, diarrhea, abdominal pain, vomiting, high fever, dyspnea, convulsion, and chills. All ADR cases were reported for the first time, including three new ADR cases and 73 known ADR cases. The categories of ADR was general ADR. All ADR was mild in severity. There were more males than females in ADR patients. One patient had a history of ADR, and the drug causing ADR was buprofen. The largest number of ADR cases occurred when the dosage of Reduning injection was 5-10 mL. The dropping speed was 30 drops or less per min, and the solvent type was 5% glucose injection. The most common manifestation of ADR patients was pruritus, followed by diarrhea, abdominal pain, vomiting, high fever, dyspnea, convulsions, and chills. 72 patients(94.74% of ADR patients) discontinued the drug, and three patients(3.95% of ADR patients) were given oxygen inhalation. 47 cases(61.84% of ADR patients) were treated with medication, of which dexamethasone was the most used(24 cases, 46.15% of ADR patients). 76 ADR patients were cured or improved. ADRs are more likely to occur when diagnosed with acute bronchitis by western medicine and cough by traditional Chinese medicine(TCM), TCM syndrome type is wind heat syndrome, and the combination medicine is ambroxol hydrochloride and bromhexine hydrochloride injection, ascorbic acid/vitamin C injection. This result provides an evidence-based safety basis for active pharmacovigilance of Reduning Injection in adolescents aged 14 years and below.

A deleterious Sar1c variant in rice inhibits export of seed storage proteins from the endoplasmic reticulum.

KEY MESSAGE: We identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm. Higher plants accumlate large amounts of seed storage proteins (SSPs). However, mechanisms underlying SSP trafficking are largely unknown, especially the ER-Golgi anterograde process. Here, we showed that a rice glutelin precursor accumulation13 (gpa13) mutant exhibited floury endosperm and overaccumulated glutelin precursors, which phenocopied the reported RNAi-Sar1abc line. Molecular cloning revealed that the gpa13 allele encodes a mutated Sar1c (mSar1c) with a deletion of two conserved amino acids Pro134 and Try135. Knockdown or knockout of Sar1c alone caused no obvious phenotype, while overexpression of mSar1c resulted in seedling lethality similar to the gpa13 mutant. Transient expression experiment in tobacco combined with subcellular fractionation experiment in gpa13 demonstrated that the expression of mSar1c affects the subcellular distribution of all Sar1 isoforms and Sec23c. In addition, mSar1c failed to interact with COPII component Sec23. Conversely, mSar1c competed with Sar1a/b/d to interact with guanine nucleotide exchange factor Sec12. Together, we identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm.