Stomata are distributed in nearly all major groups of land plants, with the only exception being liverworts. Instead of having stomata on sporophytes, many complex thalloid liverworts possess air ...pores in their gametophytes. At present, whether stomata in land plants are derived from a common origin remains under debate.1,2,3 In Arabidopsis thaliana, a core regulatory module for stomatal development comprises members of the bHLH transcription factor (TF) family, including AtSPCH, AtMUTE, and AtFAMA of subfamily Ia and AtSCRM1/2 of subfamily IIIb. Specifically, AtSPCH, AtMUTE, and AtFAMA each successively form heterodimers with AtSCRM1/2, which in turn regulate the entry, division, and differentiation of stomatal lineages.4,5,6,7 In the moss Physcomitrium patens, two SMF (SPCH, MUTE and FAMA) orthologs have been characterized, one of which is functionally conserved in regulating stomatal development.8,9 We here provide experimental evidence that orthologous bHLH TFs in the liverwort Marchantia polymorpha affect air pore spacing as well as the development of the epidermis and gametangiophores. We found that the bHLH Ia and IIIb heterodimeric module is highly conserved in plants. Genetic complementation experiments showed that liverwort SCRM and SMF genes weakly restored a stomata phenotype in atscrm1, atmute, and atfama mutant backgrounds in A. thaliana. In addition, homologs of stomatal development regulators FLP and MYB88 also exist in liverworts and weakly rescued the stomatal phenotype of atflp/myb88 double mutant. These results provide evidence not only for a common origin of all stomata in extant plants but also for relatively simple stomata in the ancestral plant.
•No evidence exists for bHLH Ia gene duplication in the ancestral land plant•The bHLH Ia/IIIb regulatory module is highly conserved in land plants•MpSMF and MpSCRM1/2 affect the development of the epidermis and gametangiophores•MpSMF weakly complements the functions of AtMUTE and AtFAMA
The bHLH Ia/IIIb regulatory module plays a key role in stomata development. Chang et al. suggest that bryophyte SMF transcription factors possess functions partially similar to AtMUTE and AtFAMA. The stomatal development in the ancestral land plant most likely involved bHLH Ia transcription factors similar to SMF in extant bryophytes.
Inhibition of triple-negative breast cancer metastasis has long been a challenge, mainly due to the difficulty in identifying factors that contribute to this process. In this study, freshly isolated ...triple-negative breast cancer biopsied cells obtained from consenting patients were subjected to flow cytometry and bioinformatic analysis to identify three endothelial cell subclusters: EC (ATP1B3), EC (HSPA1B), and EC (KRT7) in the tumor microenvironment. These endothelial cell subclusters exhibited distinguishing biological features. Based on differentially expressed genes derived from the subclusters, gene set enrichment analysis showed that EC (ATP1B3) and EC (HSPA1B) contribute to the process of metastasis, for example, in fibrosarcoma and anaplastic carcinoma. In this study, we identified the heterogeneity of endothelial cells in the human breast cancer and have provided insights into its role in metastasis.
•MUSE-DTI acquired a better image quality compared to traditional DTI.•MUSE-DTI parameters of the spinal cord at MCL in CSM patients were significantly grade-dependent and all correlated with ...clinical JOA scores.•The ADC2 values can reflect the secondary damage of distal spinal cord.
The most frequent type of spinal cord injury is cervical spondylotic myelopathy (CSM). Conventional structural magnetic resonance imaging (MRI) is the gold diagnosis standard for CSM. Diffusion tensor imaging (DTI) could reflect microstructural changes in the spinal cord by tracing water molecular diffusion in early stages of CSM. However, due to the complex local anatomical structure and small field of view of the spinal cord, the imaging effect of traditional DTI imaging on the spinal cord is limited. MUSE (MUltiplexed Sensitivity-Encoding) -DTI is a novel diffusion-weighted imaging (DWI) sequence that achieves higher signal intensity through multiple excitation acquisition. MUSE sequence may improve the quality of spinal cord DTI imaging.
Prospective study.
This study aimed to investigate the clinical diagnosis value of a novel protocol of MUSE-DTI in patients with cervical spondylotic myelopathy (CSM).
From August 2021 to March 2022, a total of 60 subjects (22–71 years) were enrolled, including 51 CSM patients (22 males, 29 females) and 9 healthy subjects (4 males and 5 females). Each subject underwent a MUSE-DTI examination and a clinical Japanese Orthopedic Association (JOA) scale.
We measured values of FA (Fractional Anisotropy), MD (Mean Diffusivity), AD (Axial Diffusivity), and RD (Radial Diffusivity), and collected the clinical JOA scores of each subject before the MR examination.
A 3.0T MR scanner (Signa Architect, GE Healthcare) performed the MUSE-DTI sequence on each subject. The cervical canal stenosis of subjects was classified from grade 0 to grade Ⅲ according to the method of an MRI grading system. FA, MD, AD, and RD maps were generated by postprocessing MUSE-DTI data on the GE workstation. Regions of interest (ROIs) were manually drawn at the C2 vertebral body level and C2/3-C6/7 intervertebral disc levels by covering the whole spinal cord. The clinical severity of myelopathy of subjects was assessed by the clinical Japanese Orthopedic Association scale (JOA).
MUSE-DTI can acquire a high-resolution diffusion image compared to traditional DTI. The FAMCL values showed a decreasing trend from grade 0 to grade Ⅲ, while the MDMCL, ADMCL, and RDMCL values showed an overall increasing trend. Significant differences in MDMCL, ADMCL, and RDMCL values were found between adjacent groups among grades Ⅰ-Ⅲ (p<.05). The ADC2 values in CSM patients (grade I–Ⅲ) were significantly lower than in healthy individuals (grade 0) (p=.019). The clinical JOA score has a significant correlation with FAMCL (p=.035), MDMCL (p<.001), ADMCL (p<.001), and RDMCL (p<.001) values.
MUSE-DTI displayed a better image quality compared to traditional DTI. MUSE-DTI parameters displayed a grade-dependent trend. All the MUSE-DTI parameters at MCL were correlated with the clinical JOA scores. The ADC2 values can reflect the secondary damage of distal spinal cord. Therefore, MUSE-DTI could be a reliable biomarker for clinical auxiliary diagnosis of spinal cord injury severity in cervical spondylotic myelopathy.
Hepatitis B surface antigen (HBsAg) seropositivity is an important risk factor for hepatocellular carcinoma (HCC), and HBsAg-transgenic mice have been reported to spontaneously develop HCC. The major ...histocompatibility complex class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, we found that HBsAg overexpression in HepG2 cells led to upregulation of 133 and downregulation of 9 microRNAs (miRNAs). Interestingly, several HBsAg-induced miRNAs repressed the expression of MICA and MICB via targeting their 3'-untranslated regions. In addition, the expression of MICA and MICB was significantly reduced upon HBsAg overexpression, which was partially restored by inhibiting the activities of HBsAg-induced miRNAs. Moreover, HBsAg-overexpressing HCC cells exhibited reduced sensitivity to natural killer cell-mediated cytolysis. Taken together, our data suggest that HBsAg supresses the expression of MICA and MICB via induction of cellular miRNAs, thereby preventing NKG2D-mediated elimination of HCC cells.
•Madecassoside (MA) attenuated lipopolysaccharide (LPS)-induced memory impairment in rats.•MA reduced the LPS-stimulated levels of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α in the rat cortex ...and hippocampus.•MA could improve memory function in rats by activating Nrf2-HO-1 signaling to reduce the LPS-stimulated expression of pro-inflammatory cytokines.”
Neuroinflammation is a predisposing factor for several neurodegenerative diseases. The purpose of this study was to evaluate the protective effect of madecassoside (MA) in lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation in rats. MA has many protective effects such as antioxidant and anti-inflammatory properties. We investigated whether MA could improve neurocognitive dysfunction caused by intracerebroventricular injection of LPS. We examined the effects and mechanisms of action of MA on LPS-induced neuroinflammation in the cortex and hippocampus. Our study revealed that MA (120 mg/kg, i.g) treatment for 14 days reduced LPS-induced neurotoxicity by reducing cognitive impairments and suppressing the production of inflammatory cytokines such as interleukin 1 beta (IL-1β), tumor necrosis factor alpha(TNF-α), and interleukin 6(IL-6) via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Furthermore, MA treatment enhanced protein levels of heme oxygenase (HO)-1 by upregulating Nrf2 in LPS-stimulated neurotoxicity. Collectively, these results suggest that MA is effective in preventing neurodegenerative diseases by improving memory functions due to its anti-inflammatory activities and activation of Keap1-Nrf2/HO-1 signaling. As such, MA may be a potential therapy for addressing memory impairment caused by neuroinflammation.
Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of ...cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours.
This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed.
Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 43 male and 40 female in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3–4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven 3%), increased lipase (four 2%), decreased bodyweight (three 1%), decreased appetite (four 2%), decreased neutrophil count (three 1%), and infusion-related reaction (two 1%). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1–17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3–42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0–15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2–40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7–19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7–37·4).
Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours.
Akeso Biopharma.
For the Chinese translation of the abstract see Supplementary Materials section.
Inositol 1, 4, 5-trisphosphate receptor-mediated (IP3R-mediated) calcium (Ca2+) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for ...decades. However, whether and how IP3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle-specific IP3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP3R-mediated Ca2+ release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IP3Rs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IP3Rs also dramatically reduced the phosphorylation of MLC20 and MYPT1 induced by U46619. Furthermore, although the basal blood pressure of smTKO mice remained similar to that of wild-type controls, the increase in systolic blood pressure upon chronic infusion of angiotensin II was significantly attenuated in smTKO mice. Taken together, our results demonstrate an important role for IP3R-mediated Ca2+ release in VSMCs in regulating vascular contractility and hypertension.
Microglial inflammation plays an essential role in the pathogenesis of HIV-associated neurocognitive disorders. A previous study indicated that curcumin relieved microglial inflammatory responses. ...However, the mechanism of this process remained unclear. Autophagy is a lysosome-mediated cell content-dependent degradation pathway, and uncontrolled autophagy leads to enhanced inflammation. The role of autophagy in curcumin-attenuating BV2 cell inflammation caused by gp120 was investigated with or without pretreatment with the autophagy inhibitor 3-MA and blockers of NF-κB, IKK, AKT, and PI3K, and we then detected the production of the inflammatory mediators monocyte chemoattractant protein-1 (MCP-1) and IL17 using ELISA, and autophagy markers ATG5 and LC3 II by Western Blot. The autophagic flux was observed by transuding mRFP-GFP-LC3 adenovirus. The effect of the blockers on gp120-induced BV2 cells was examined by the expression of p-AKT, p-IKK, NF-κB, and p65 in the nuclei and LC3 II and ATG5. gp120 promoted the expression of MCP-1 and IL-17, enhanced autophagic flux, and up-regulated the expression of LC3 II and ATG5, while the autophagy inhibitor 3-MA down-regulated the phenomena above. Curcumin has similar effects with 3-MA, in which curcumin inhibited NF-κB by preventing the translocation of NF-κB p65. Curcumin also inhibited the phosphorylation of p-PI3K, p-AKT, and p-IKK, which leads to down-regulation of NF-κB. Curcumin reduced autophagy via PI3K/AKT/IKK/NF-κB, thereby reducing BV2 cellular inflammation induced by gp120.
A numerical study has been conducted to simulate the liquid/gas interface (meniscus) behaviors and capillary pressures in various capillary channels using the volume of fluid (VOF) method. ...Calculations are performed for four channels whose cross-sectional shapes are circle, regular hexagon, square and equilateral triangle and for four solid/liquid contact angles of 30°, 60°, 120° and 150°. No calculation is needed for the contact angle of 90° because the liquid/gas interface in this case can be thought to be a plane surface. In the calculations, the liquid/gas interface in each channel is assumed to have a flat surface at the initial time, it changes towards its due shape thereafter, which is induced by the combined action of the surface tension and contact angle. After experiencing a period of damped oscillation, it stabilizes at a certain geometry. The interface dynamics and capillary pressures are compared among different channels under three categories including the equal inscribed circle radius, equal area, and equal circumscribed circle radius. The capillary pressure in the circular channel obtained from the simulation agrees well with that given by the Young–Laplace equation, supporting the reliability of the numerical model. The channels with equal inscribed circle radius yield the closest capillary pressures, while those with equal circumscribed circle radius give the most scattered capillary pressures, with those with equal area living in between. A correlation is developed to calculate the equivalent radius of a polygonal channel, which can be used to compute the capillary pressure in such a channel by combination with the Young–Laplace equation.
•This study is an addition to the literature on the association between chronic pain and frailty in older cancer patients.•It is the first study to examine chronic pain and frailty in older cancer ...patients using sleep quality as a mediator.•This study provides new findings on the mechanisms mediating the association between chronic pain and frailty in the older cancer population.
This study aimed to explore the association between chronic pain, sleep quality, and frailty, and whether sleep quality will mediate the relationship between chronic pain and frailty. A cross-sectional study was conducted between June 2020 and July 2021 among 308 patients in Nantong city. The relationship between chronic pain and frailty was tested using linear regression. The bootstrap method was used to examine mediating effect of sleep quality. Chronic pain was significantly correlated with frailty (r=0.271, P<.001). Sleep quality played a partially mediating role between chronic pain and frailty (β=0.160, R2=32%, P<.001). Interventions to scientifically manage chronic pain and improve sleep quality may be effective in reducing the incidence of frailty in elderly cancer patients.
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