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Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles1. However, both Rht-B1b and Rht-D1b are gain-of-function mutant alleles encoding gibberellin signalling repressors that stably repress plant growth and negatively affect nitrogen-use efficiency and grain filling2–5. Therefore, the green revolution varieties of wheat harbouring Rht-B1b or Rht-D1b usually produce smaller grain and require higher nitrogen fertilizer inputs to maintain their grain yields. Here we describe a strategy to design semi-dwarf wheat varieties without the need for Rht-B1b or Rht-D1b alleles. We discovered that absence of Rht-B1 and ZnF-B (encoding a RING-type E3 ligase) through a natural deletion of a haploblock of about 500 kilobases shaped semi-dwarf plants with more compact plant architecture and substantially improved grain yield (up to 15.2%) in field trials. Further genetic analysis confirmed that the deletion of ZnF-B induced the semi-dwarf trait in the absence of the Rht-B1b and Rht-D1b alleles through attenuating brassinosteroid (BR) perception. ZnF acts as a BR signalling activator to facilitate proteasomal destruction of the BR signalling repressor BRI1 kinase inhibitor 1 (TaBKI1), and loss of ZnF stabilizes TaBKI1 to block BR signalling transduction. Our findings not only identified a pivotal BR signalling modulator but also provided a creative strategy to design high-yield semi-dwarf wheat varieties by manipulating the BR signal pathway to sustain wheat production.

Purpose UVB exposure accelerates skin aging and age-associated pigmentation, but their relationship remains unclear. UVB induces premature senescence and melanin production within melanocytes, along with the upregulation of p53 and cellular tyrosinase (TYR). As a tumor suppressor gene, p53 can keep the genome intact by modulating cell apoptosis and growth arrest during DNA injury. It is also associated with age-associated pigmentation, directly or indirectly regulating pigment-related gene expression. Melatonin effectively regulates tyrosinase activity and resists aging. In this study, we investigated the regulation of p53 on TYR to understand the association between premature senescence and senescence-associated pigmentation and determine the mechanism by which melatonin affects UVB-stimulated melanin production. Methods Primary melanocytes were extracted and identified from the male foreskin. The primary melanocytes were transduced using lentivirus pLKD-CMV-EGFP-2A-Puro-U6-TYR to knock down TYR expression. The melanin content was determined using the NaOH method, 3,4-Dihydroxy-L-phenylalanine (L-DOPA) was oxidized to dopachrome to determine TYR activity, and Western blotting was performed to detect the level of TYR protein. The primary melanocytes were pretreated with Nutlin-3 or PFT-α to upregulate or downregulate p53 levels or melatonin for 12 h and exposed to UVB irradiation at 80 mJ/cm2. The senescence-associated beta-galactosidase (SA-β-gal) kit was used to analyze premature senescence. The levels of p53, p-p53, and TYR protein were detected by performing the automated capillary electrophoresis Western blotting analysis in melanocytes 72 h after UVB irradiation. Wild-type and TYR(–/–) or TYR(+/–) knockout C57BL/6J mice were used to determine the regulatory role of TYR on melanin synthesis in vivo. Additionally, the effect of melatonin on skin erythema and pigmentation induced by UVB irradiation was analyzed in vivo. Results Primary melanocytes turned deep black after L-DOPA staining, indicating higher TYR protein and mRNA expression. Tyrosinase activity and melanin levels induced by UVB irradiation decreased significantly after the primary melanocytes were infected with pLKD-CMV-EGFP-2A-Puro-U6-TYR (P P TYR(–/–) knockout mice were recognized through white hair, whiskers, and paws, and loss of pigments in the eyes. The tyrosinase activity and melanin levels in the whisker follicles of TYR(–/–) knockout mice also decreased significantly (P

Atopic dermatitis (AD) is a heterogeneous disease, with involvement of the T-helper cell (Th) 2, Th22, and potentially Th17 pathways, supporting the use of interleukin (IL)-23 and IL-22 blockade in AD.This phase 2, multicenter, randomized, double-blind, placebo-controlled trial (NCT03706040) evaluated the efficacy and safety of risankizumab, an IL-23 inhibitor, in patients (≥ 12 years old) with moderate-to-severe AD, defined by an Eczema Area and Severity Index (EASI) ≥ 16, affected body surface area ≥ 10%, and a Validated Investigator Global Assessment for AD (vIGA-AD) score ≥ 3. Patients were randomized 2:2:1 to 16-week treatment with risankizumab 150 mg, risankizumab 300 mg, or placebo in period A; patients receiving placebo were re-randomized 1:1 to risankizumab 150 mg or 300 mg and patients receiving risankizumab continued on their randomized dose in 36-week period B. Study drug was administered at baseline and weeks 4, 16, 28, and 40. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction from baseline in EASI (EASI 75) at week 16. Safety was analyzed in all randomized patients who received study medication.Neither the risankizumab 150 mg (n = 69) nor the 300 mg dose group (n = 69) demonstrated a significantly higher proportion of patients achieving EASI 75 at week 16 compared with the placebo group (n = 34; treatment difference [95% CI] 13.0% [-1.7 to 27.7%; P = 0.084] and 10.0% [-4.6 to 24.6%; P = 0.179], respectively). Most adverse events were mild to moderate in severity; five patients receiving risankizumab reported serious adverse events, including two patients who reported cellulitis.Risankizumab was generally well tolerated, with no new safety concerns identified. The study's primary endpoint was not met, with no significant difference in the proportion of patients achieving an EASI 75 response at week 16 with risankizumab 150 mg or 300 mg versus placebo.ClinicalTrials.gov NCT03706040.

It has been assumed that patients with strict immunosuppressive treatment after solid organ transplantation have only marginal risk in developing autoimmune encephalitis. We reported a woman in her late 40 s who presented with generalized convulsions and loss of consciousness. After detailed history review, neuropsychological tests, metagenomic next-generation sequencing of serum and cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) brain, and electroencephalogram, she was diagnosed as anti-CASPR2 encephalitis based on the positive anti-CASPR2 auto-antibody in serum and CSF. The patient underwent liver transplantation and has taken lenvatinib for 2 months, in addition to tacrolimus, mycophenotale mofetil, and entecavir administered for half a year. This case was the first report of anti-CASPR2 encephalitis in post-organ transplantation patients. Together with the reports of other encephalitis cases in organ transplantation, it warns the possibility of developing immune-oriented encephalitis in patients undergoing immunosuppression, especially in combination with other treatments of immunomodulatory activity.

Thyroglobulin antibody(TgAb) was generally used as a prognostic marker of papillary thyroid cancer(PTC) only after total thyroidectomy, but its value in PTC patients with concomitant Hashimoto's thyroiditis(HT) is unclear. We aimed to assess the prognostic significance of the serum TgAb in these patients.This retrospective cohort study included PTC patients and pathologically proven HT from 2007-2016. The Cox proportional hazards model with restricted cubic spline was used to analyze the association between TgAb and structural recurrence, and then survival analysis was performed.Of 839 patients enrolled, 48 recurrences were identified during a median follow-up of 64 months. Macrocarcinoma and lymph node metastasis were significantly associated with higher TgAb (P = 0.006, 0.002), but no significant difference was found for any other characteristics. An increasing preoperative TgAb level up to 2000 IU/ml was associated with shorter recurrence-free survival(RFS) (P 0.001), and the 5-year RFS rates in patients with TgAb ≤400, 400-800 and800 IU/ml were 97.3%, 93.2% and 85.8%, respectively (P 0.05). The difference was found even after adjusting for potential risk factors (P 0.001). Of 337 PTC patients who were treated with lobectomy and had available TgAb data at the first year after surgery, a significant decrease (≥50%) in postoperative TgAb was achieved in 41.8% patients, who had a favorable prognosis compared with others (5-year RFS rate 98.5% vs. 92.0%, P = 0.008).The preoperative serum TgAb seem to effectively stratify PTC patients with concomitant HT who had high risk for recurrence, and the early postoperative trends of TgAb was a good prognostic marker for these patients who treated with lobectomy.

The tumor immunosuppressive microenvironment (IME) significantly affects tumor occurrence, progression, and prognosis, but the underlying molecular mechanisms remain to make known. We investigated the prognostic significance of PDPN and its role in IME in glioma. Weighted gene co-expression network analysis (WGCNA) found PDPN closely related to IDH wildtype status and higher immune score. Correlation analysis suggested PDPN was highly positively relevant to immune checkpoints expression and immune checkpoints block responding status. Correlation analysis together with verification in vitro suggested PDPN highly positively relevant tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs). Least absolute shrinkage and selection operator (LASSO) regression employed to develop the prediction model with TANs and TAMs markers showed that high risk scores predicted worse prognosis. We highlight that PDPN overexpression is an independent prognostic indicator, and promotes macrophage M2 polarization and neutrophil degranulation, ultimately devotes to the formation of an immunosuppressive tumor microenvironment. Our findings contribute to re-recognizing the role of PDPN in IDH wildtype gliomas and implicate promising target therapy combined with immunotherapy for this highly malignant tumor.

Establishing an effective signal amplification strategy is the key to achieving sensitive detection of analytes by electrochemical immunoassay. In this work, a novel sandwich-type electrochemical immunosensor with dual-signal amplification was successfully constructed using PtPd/Cu-TCPP(Fe) as the sensing platform and mesoporous silicon dioxide as the signal amplifier. Firstly, two-dimensional wrinkled Cu-TCPP(Fe) nanomaterials loaded with PtPd nanoparticles have strong affinity for the immobilization of capture antibodies and can generate excellent electrochemical signals. Meanwhile, the mesoporous silicon dioxide with large steric hindrance was used as signal label to further improve the sensitivity of the immunosensor by increasing the difference of the current response signal. Under optimal experimental conditions, the electrochemical immunosensor exhibited a wide linear detection range from 0.1 pg/mL to 1.0 μg/mL, with a detection limit as low as 0.166 fg/mL. The experimental results showed that the constructed immunosensor has a great application prospect in clinical biomarker detection.