其他最新文献

Background: A novel uncapped mRNA platform was developed.

Methods: Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S^δT-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gD^ED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gD^FR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1-400).

Results: Quantifiable target protein expression was achieved in vitro and in vivo with eGFP- and Fluc-mRNA-LNP. S^δT-mRNA-LNP, gD^ED-mRNA-LNP and gD^FR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, S^δT-mRNA-LNP elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gD^ED-mRNA-LNP and gD^FR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1mψTP) in the induction of antibodies via S^δT-mRNA-LNP.

Conclusions: Our uncapped, process-simplified and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.KEY MESSAGESThe mRNA platform described in our paper uses internal ribosome entry site (IRES) (Rapid, Amplified, Capless and Economical, RACE; Register as BH-RACE platform) instead of caps and uridine triphosphate (UTP) instead of N1-methylpseudouridine triphosphate (N1mψTP) to synthesize mRNA.Through the self-developed packaging instrument and lipid nanoparticle (LNP) delivery system, mRNA can be expressed in cells more efficiently, quickly and economically.Particularly exciting is that potent neutralizing antibodies against Delta and Omicron real viruses were induced with the new coronavirus S protein mRNA vaccine from the BH-RACE platform.

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has shown a high incidence rate in rice fields in recent years. Rice resistance breeding is considered as the most effective method for achieving economical and sustainable management of BLB disease. The essential basis for resistance breeding is rooted in the exploration of rice resistance genes and the clarification of the molecular mechanisms that underlie Xoo resistance. In our previous research, we showed that Xanthomonas outer protein XopZ and rice oxysterol-binding related protein ORP1C collaboratively regulate the compatible interaction between Xoo strain PXO99 and Nipponbare rice, but the deeper regulatory mechanisms remain unknown. In this study, we successfully constructed ORP1C overexpression rice using the plant binary expression vector pCAMBIA1301. Through a series of virulence and effector translocation detections in Xoo-rice interactions, we revealed that overexpression of the ORP1C gene largely increases rice resistance to multiple Xoo strains from different countries and regions. Mechanistically, ORP1C plays a Xoo resistant role through negatively regulating transcription activator-like effectors (TALEs) translocation, ORP1C has become a potential candidate gene resource for disease-resistant breeding in rice. Further studies also indicated that XopZ and ORP1C collaboratively regulate the compatible interaction of PXO99-Nipponbare by modulating TALEs translocation.

Background: Occult lymph node metastasis of papillary thyroid carcinoma is common. However, whether undergoing prophylactic lateral lymph node dissections is still controversial. This cross-sectional study with large cohort of patients aims to investigate the clinical value of Delphian and pre-tracheal lymph node in predicting lateral lymph node metastasis of papillary thyroid carcinoma.

Materials and methods: A retrospective analysis was conducted on 865 papillary thyroid carcinoma patients with Delphian and pre-tracheal lymph node data who underwent thyroidectomy plus central and lateral lymph node dissection. Data on clinicopathological characteristics were collected. Subsequently, a predictive model was established based on the results of the univariate and multivariate analyses.

Results: The rates of Delphian and pre-tracheal lymph node metastasis and lateral lymph node metastasis were 54.7% and 39.1%, respectively. Having ≥ 3 or 1-2 Delphian and pre-tracheal lymph node metastasis dramatically increased the risk of lateral lymph node metastasis (OR = 8.5, 95% CI 5.3-13.4 and OR = 3.9, 95% CI 2.7-5.7, respectively). The upper tumour had a 3.7 times higher risk of lateral lymph node metastasis than other locations. Patients ≤ 42 years or tumour size >8 mm had a higher risk of lateral lymph node metastasis.

Conclusions: Delphian and pre-tracheal lymph node metastasis was associated positively with the risk of lateral lymph node metastasis. For patients without clinical lateral lymph node metastasis, the Delphian and pre-tracheal lymph node could be considered to harvest as the first step in a thyroidectomy to facilitate further conduct of the operation.

Background: Maternal colonization with Group B Streptococcus (GBS) disrupts the vaginal microbiota, potentially affecting infant microbiota assembly and growth. While the gut microbiota's importance in infant growth is recognized, the specific effects of maternal GBS on growth remain unclear. This study aimed to explore the effects of maternal vaginal GBS during pregnancy on early infant growth, microbiome, and metabolomics.

Methods: We recruited and classified 453 pregnant women from southern China into GBS or healthy groups based on GBS vaginal colonization. Their infants were categorized as GBS-exposed or GBS-unexposed groups. We comprehensively analyzed infant growth, gut microbiota, and metabolites during early life, along with maternal vaginal microbiota during pregnancy, using 16S rDNA sequencing and targeted metabolomics.

Results: GBS-exposed infants exhibited lower length-for-age z-scores (LAZ) than GBS-unexposed infants, especially at 2 months. Altered gut microbiota and metabolites in GBS-exposed infants correlated with growth, mediating the impact of maternal GBS on infant LAZ. Changes in the vaginal microbiota of the GBS group during the third trimester correlated with infant LAZ. Additionally, differences in neonatal gut microbiota, metabolites, and vaginal microbiota during pregnancy were identified between infants with overall LAZ<-1 within 8 months after birth and their counterparts, enhancing the discriminatory power of fundamental data for predicting the occurrence of LAZ<-1 during the first 8 months of life.

Conclusions: GBS exposure is associated with decreased infant length growth, with altered microbiota and metabolites potentially mediating the effects of maternal GBS on offspring length growth, offering potential targets for predicting and addressing growth impairment.

Objective: Ruptured peripheral cerebral aneurysm (PPCA) associated with moyamoya disease (MMD) is rarely reported, and its optimal treatment remains controversial. This study aims to present the clinical characteristics, treatment strategies, and outcome predictors of this rare clinical entity.

Methods: A retrospective review of patients with hemorrhagic MMD from January 2013 to December 2020 was performed. All medical records were independently compiled and reviewed.

Results: Twenty-three patients were identified, 56.5% of whom were female. The mean age was 45.9 years with a peak age of onset of 51-60 years. Most patients (65.2%) developed intraventricular hemorrhage with or without intracerebral hemorrhage. These aneurysms were frequently located on the anterior (26.1%) and posterior (43.5%) choroidal arteries. Sixteen (69.6%) aneurysms were embolized and the remaining 7 (30.4%) were managed conservatively due to approach inaccessibility. Good outcomes were achieved in 82.6% of all cases, with 81.3% for embolization and 85.7% for observation. Complete occlusion was observed in all 16 aneurysms embolized. Of the conservatively treated aneurysms, 1 (14.3%) re-ruptured, 1 (14.3%) decreased in size, 2 (28.6%) disappeared, and 3 (42.8%) remained stable in size. Aneurysm rebleeding was associated with an unfavorable outcome (P = 0.026).

Conclusions: PPCA should be considered in the differential diagnosis of hemorrhagic MMD. Aneurysm rebleeding appears to be a potential predictor of poor outcome and therefore aggressive intervention should be advocated. Endovascular embolization may be safe and feasible, and conservative observation should be carefully chosen given the high risk of aneurysm re-rupture.

Objective: To investigate the optic disc changes (ODC) in Chinese patients with NLRP3-associated autoinflammatory disease (NLRP3-AID).

Methods: Patients who were diagnosed with NLRP3-AID at the Department of Rheumatology, Peking Union Medical College Hospital between April 2015 and December 2022 were retrospectively reviewed and analyzed.

Results: A total of 20 patients were enrolled in this retrospective study. All 20 patients had a moderate MWS NLRP3-AID phenotype. Thirteen patients (65%) had ocular involvements. The interval between symptoms onset and diagnosis was significantly longer in patients with ocular involvement than in patients without (p = 0.044). The incidence of hearing loss was significantly higher in patients with ocular involvement (p = 0.017), while the incidence of abdominal pain was significantly lower when compared to patients without ocular involvement (p = 0.007). Optic disc swelling (ODS) (50%) was the most common ODC. All of the four T348M mutation carriers within our cohort exhibited ODS with visual-field defects. There was a significant difference between patients with/without ODS regarding the number of patients carrying T348M mutation (p = 0.014). The occurrence of hearing loss and CNS involvement was significantly higher in the group with ODS compared to the group without (p = 0.0014, p = 0.0198). Of the eight patients who underwent lumbar puncture, five presented with intracranial hypertension (IH). ODS was observed in all patients with IH. The serum inflammatory markers were significantly higher in patients with ODS than in those without. Two patients receiving regular subcutaneous IL-1 inhibitor treatment showed improvements in ODC.

Conclusions: ODC is common among Chinese patients with NLRP3-AID, with ODS being the most common manifestation. Hearing loss and CNS involvement often accompany the occurrence of ODS. The serum inflammatory markers are associated with ODS. The T348M mutation is more likely to lead to ODC with visual-field defects.

Background: In recent years, daratumumab (DARA) has gained widespread use in the treatment of systemic light chain (AL) amyloidosis. In this study, we assessed the efficacy and safety of a DARA treatment strategy based on serum free light chain (sFLC) levels and non-fixed cycles.

Methods: The study included 123 patients with Al amyloidosis who received DARA at our center between July 2020 and September 2023. All patients received the standard DARA treatment (16 mg/kg weekly for four weeks) during the first course. Subsequent treatments were adjusted based on sFLC levels and the physician's judgment.

Results: The results demonstrated an impressive overall hematologic response rate (ORR) of 94.3%, with a hematologic very good partial response (VGPR) and complete response (CR) rate of 84.5%. Median time to best hematologic response was 1 months. Cardiac and renal response rates were 39.3% and 60.3%, respectively. Thirty patients experienced grade 1/2 infusion-related reactions after the first infusion. The rate of grade 3/4 adverse events was 21%. The most common adverse events of grade 3 or 4 were pulmonary infection (6.5%), neutropenia and lymphocytopenia (5.7%), elevated transaminases (1.6%), acute kidney injury (1.6%). After a median follow-up of 13 months (range 1-38), The 1-year OS and PFS estimates were 96.5% and 84.4%, respectively.

Conclusion: These findings indicate that the sFLC levels based and non-fixed cycle DARA strategy is an efficacious and safe treatment strategy in both newly diagnosed and relapsed/refractory AL amyloidosis.

Objective: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5⁺DM-ILD) often leads to acute respiratory failure and endangers lives. This study quantitatively analysed chest high-resolution computed tomography (HRCT) images to assess MDA5⁺DM-ILD and establish a risk prediction model for severe ILD within six months.

Methods: We developed a 'Standardized Threshold Ratio Analysis & Distribution' (STRAD) to analyse lung HRCT images. In this retrospective study, 51 patients with MDA5⁺DM-ILD were included and divided into severe-ILD and non-severe-ILD groups based on the occurrence of acute respiratory failure within six months post-diagnosis of MDA5⁺DM. The STRAD parameters, clinical indicators and treatments were compared between the two groups. Least absolute shrinkage and selection operator (LASSO) regression was used to select the optimal STRAD parameters. Multivariate analysis selected clinical factors to be further combined with STRAD to enhance the predictive performance of the final model (STRAD-Ro52 model).

Results: Significant differences were observed between the two groups in STRAD parameters, anti-Ro52 antibody titers, presence of anti-Ro52 antibodies, age, ESR, ALB, Pa/FiO₂, IgM and IL-4 levels. The STRAD parameters were significantly correlated with demographic, inflammatory, organ function and immunological indicators. Lasso logistic regression analysis identified the -699 to -650 HU lung tissue proportion (%V7) as the optimal parameter for predicting severe ILD and S6·%V7, and the distribution of %V7 in the mid lungs was the optimal space parameter. Multifactorial regression of clinical indicators showed that the presence of anti-Ro52 antibodies was an independent risk factor for severe ILD, leading to the establishment of the STRAD-Ro52 model.

Conclusions: The STRAD-Ro52 model assists in identifying MDA5⁺DM patients at risk of developing severe ILD within six months, further optimizing precise disease management and clinical research design.

Wheat is the third most widely consumed cereal in the world, after maize and rice. However, it is regularly attacked by the wheat aphid (Schizaphis graminum), causing considerable damage to wheat crops. The acetylcholinesterase enzyme, which plays a key role in the transmission of the synaptic cholinergic signal, has emerged as a promising target for the development of pest control strategies. Inhibition of this enzyme leads to the paralysis or even death of the aphid. The objective of this study is to identify the bioactive compounds in Securidaca longepedunculata (S. longepedunculata) that are capable of interacting with acetylcholinesterase from Schizaphis graminum and inhibiting its activity. Furthermore, a computer simulation of these compounds in interaction with the key protein was conducted. First, the secondary metabolites of S. longepedunculata were selected on the basis of GC-MS data available from specific reference sources. Subsequently, the compounds were subjected to virtual screening based on their docking scores in order to identify those with inhibitory properties. The compounds with the highest scores were subjected to molecular dynamics simulation over a 50 ns trajectory. Subsequently, MMGBSA free energy calculations were conducted. The results demonstrated that eight compounds exhibited inhibitory properties, four of which (echimidine, populin, salidroside, and farrerol) demonstrated superior stabilizing effects on proteins compared to the remaining compounds. In terms of free energy by MMGBSA and molecular simulation, it was observed that echimidine and populin formed robust and stable hydrogen bonds with the amino acids of the acetylcholinesterase enzyme. This study identifies and attempts to validate the potential inhibitory activities of echimidine and populin against acetylcholinesterase, with a view to developing potent insecticides and unique treatment strategies.

Background: Congenital hypothyroidism (CH) is a common metabolic disorder in children that can impact growth and neurodevelopment, particularly during infancy and early childhood. DUOXA2, a DUOX maturation factor, plays a crucial role in the maturation and activation of dual oxidase DUOX2 (a member of the NADPH oxidase family). DUOX2 can correctly migrate to the plasma membrane from the endoplasmic reticulum (ER) with the help of DUOXA2, and the two proteins together form a stable complex that promotes hydrogen peroxide (H2O2) generation in the synthesis of thyroid hormones. Genetic alterations in DUOXA2 lead to defects function of DUOX2 protein causing inherited CH.

Objectives: This review discusses the relationship between DUOXA2 and CH, including the pathogenic mechanisms of CH in children caused by DUOXA2 mutations and the possibility or promise of DUOXA2 gene screening as a diagnostic marker for CH in the clinic.

Methods: The review synthesizes current research on the biological role of DUOXA2 and DUOX2 in thyroid hormone synthesis, the molecular impact of DUOXA2 mutations, and the clinical implications of genetic screening for CH.

Results: Mutations in DUOXA2 disrupt this process of H2O2 generation in the synthesis of thyroid hormones , leading to inherited CH. Early identification through DUOXA2 gene screening could improve diagnostic accuracy, which facilitates early intervention and personalized treatment.

Conclusions: DUOXA2 gene screening holds promise for enhancing diagnostic accuracy in CH. However, it cannot be used as a sole diagnostic indicator, and to optimize diagnostic sensitivity, it should be combined with the screening of other relevant genetic mutations and diagnostic tools. Further research is needed to refine screening protocols and explore therapeutic options.