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Ubr1 and Ubr2 are E3 ligases that target substrates by the N-end rule, and it is the UBR box that is needed for substrate recognition. The structures of the UBR boxes of human UBR1 and UBR2 show that they adopt a previously undescribed fold stabilized by zinc. One of the zinc-binding ligands is mutated in Johnson-Blizzard syndrome and leads to UBR box unfolding. The N-end rule links the half-life of a protein to the identity of its N-terminal residue. Destabilizing N-terminal residues are recognized by E3 ubiquitin ligases, termed N-recognins. A conserved structural domain called the UBR box is responsible for their specificity. Here we report the crystal structures of the UBR boxes of the human N-recognins UBR1 and UBR2, alone and in complex with an N-end rule peptide, Arg-Ile-Phe-Ser. These structures show that the UBR box adopts a previously undescribed fold stabilized through the binding of three zinc ions to form a binding pocket for type 1 N-degrons. NMR experiments reveal a preference for N-terminal arginine. Peptide binding is abrogated by N-terminal acetylation of the peptide or loss of the positive charge of the N-terminal residue. These results rationalize and refine the empirical rules for the classification of type 1 N-degrons. We also confirm that a missense mutation in UBR1 that is responsible for Johanson-Blizzard syndrome leads to UBR box unfolding and loss of function.

Epidural anesthetic techniques for postoperative analgesia are rarely considered in spinal surgery, and high thoracic epidural analgesia (TEA) is considered medically risky. We present a successful case of surgical retrograde placement of a thoracic (T6-T7) epidural catheter under direct surgical visualization via T2 laminectomy in a patient who underwent combined thoracotomy and spinal surgery. TEA was confirmed by epidurogram, provided adequate postoperative pain relief, and the patient was discharged home three days post-surgery.

Research on organic electronics (or plastic electronics) is driven by the need to create systems that are lightweight, unbreakable, and mechanically flexible.With the remarkable improvement in the performance of organic semiconductor materials during the past few decades, organic electronics appeal to innovative, practical, and broad-impact.

It is of much interest to understand the efficacy of abiraterone acetate (AA) in routine clinical practice. We assessed the clinical outcome of AA in patients with metastatic castration‐resistant prostate cancer (mCRPC) and determined clinical factors associated with AA treatment duration in real‐world setting. This real‐world cohort consisted of 93 patients with mCRPC treated with AA in Thailand (58.1%) and Malaysia (41.9%). Primary endpoints were overall survival (OS) and biochemical progression‐free survival (bPFS). Secondary endpoints were predictors associated with AA treatment duration evaluated with Cox proportional hazards regression. Around 74% were chemotherapy‐naïve. The median AA treatment duration was 10 months (IQR 5.6‐17.1). Malaysians had a relatively lower median OS and bPFS (OS 17.8 months; 95% CI 6.4‐29.1, bPFS 10.4 months; 95% CI 8.8‐12.0) compared to Thais (OS 27.0 months; 95% CI 11.3‐42.7, bPFS 14.0 months; 95% CI 5.8‐22.2), although it did not achieve statistical significance (P > .05). Patients with longer AA treatment duration (>10 months) had lower risk of death and longer bPFS, compared to those with shorter AA treatment duration (≤10 months) (hazard ratio [HR] 0.10, 95% CI 0.05‐0.22 and HR 0.13, 95% CI 0.06‐0.25, respectively). Multivariable analysis showed that PSA at AA initiation, presence of PSA response and chemotherapy‐naive were independently associated with AA duration (P < .05). Abiraterone acetate is well‐tolerated in the Southeast Asian cohort with comparable survival benefits to other Asian populations in real‐world setting. Lower PSA levels at AA initiation, presence of PSA response, and chemotherapy‐naive were significant in determining AA treatment duration. Association of abiraterone acetate duration with (a) overall survival and (b) biochemical progress free survival in metastatic castration‐resistant prostate cancer.

Plant–soil feedback (PSF) was initially developed in the field of agricultural practices. In recent years, PSF has been extended to various ecosystems. Root exudates, essential for the exchange of materials, energy, and information at the plant–soil interface, significantly influence PSF. However, how PSF is driven by root secretions and the role of these secretions in different PSF pathways still needs to be further explored, particularly in forest ecosystems. Soil nutrients, microbial communities, and nematodes are important research topics in the process of PSF driven by root exudates. Investigating these aspects driven by root exudates provides valuable insights into the complex interactions both above ground and below the surface. This research can offer theoretical support and guidance for building stable, healthy, and sustainable forest ecosystems in the future.

We tested the hypothesis that modulation of neurocomputational inputs to value-based decision-making affects the rationality of economic choices. The brain’s right temporoparietal junction (rTPJ) has been functionally associated with both social behavior and with domain-general information processing and attention. To identify the causal function of rTPJ in prosocial decisions, we administered focal high definition transcranial direct current stimulation (HD-tDCS) while participants allocated money between themselves and a charity in a modified dictator game. Anodal stimulation led to improved rationality as well as increased charitable giving and egalitarianism, resulting in more consistent and efficient choices and increased sensitivity to the price of giving. These results are consistent with the theory that anodal stimulation of the rTPJ increases the precision of value computations in social decision-making. Our results demonstrate that theories of rTPJ function should account for the multifaceted role of the rTPJ in the representation of social inputs into value-based decisions.

Key messageILR3 and PYE function in a regulatory network that modulates GLS accumulation under iron deficiency.The molecular processes involved in the cross talk between iron (Fe) homeostasis and other metabolic processes in plants are poorly understood. In Arabidopsis thaliana the transcription factor IAA-LEUCINE RESISTANT3 (ILR3) regulates iron deficiency response, aliphatic glucosinolate (GLS) biosynthesis and pathogen response. ILR3 is also known to interact with its homolog, POPEYE (PYE), which also plays a role in Fe response. However, little is known about how ILR3 regulates such diverse processes, particularly, via its interaction with PYE. Since GLS are produced as part of a defense mechanism against wounding pathogens, we examined pILR3::β-GLUCURONIDASE expression and found that Fe deficiency enhances the wound-induced expression of ILR3 in roots and that ILR3 is induced in response to the wounding pathogen, sugarbeet root cyst nematode (Heterodera schachtii). We also examined the expression pattern of genes involved in Fe homeostasis and aliphatic GLS biosynthesis in pye-1, ilr3-2 and pye-1xilr3-2 (pxi) mutants and found that ILR3 and PYE differentially regulate the expression of genes involved these processes under Fe deficiency. We measured GLS levels and sugarbeet root cyst nematode infection rates under varying Fe conditions, and found that long-chain GLS levels are elevated in ilr3-2 and pxi mutants. This increase in long-chain GLS accumulation is correlated with elevated nematode resistance in ilr3-2 and pxi mutants in the absence of Fe. Our findings suggest that ILR3 and PYE function in a regulatory network that controls wounding pathogen response in plant roots by modulating GLS accumulation under iron deficiency.

Novel magnetic molecularly imprinted polymer nanoparticles (MMIPs) were synthesized by surface imprinting technology with a sol–gel process, using di(2-ethylhexyl)phthalate (DEHP) as the template. The MMIPs were characterized using Fourier transform–infrared spectroscopy (FT–IR), transmission electron microscopy (TEM), and vibrating sample magnetometry (VSM). The MMIPs displayed good adsorption selectivity for DEHP, with selectivity coefficients of 5.2 and 4.8 with respect to di- n -octyl phthalate and dibutyl phthalate, respectively. The reusability of MMIPs was demonstrated for at least eight repeated cycles without significant loss in adsorption capacity. A novel method for selective preconcentration and determination of trace DEHP in aqueous solutions was developed by using the magnetic DEHP-imprinted nanoparticles as adsorbent for solid-phase extraction (SPE) coupled with gas chromatography–mass spectrometry (GC–MS). The optimum SPE conditions were as follows: adsorbent amount, 50 mg; sample volume, 100 mL; adsorption time, 20 min; eluent, chloroform; and desorption time, 5 min. Results showed that the limit of detection (LOD) and limit of quantification (LOQ) for DEHP were 0.02 and 0.075 μg L −1 , respectively. The proposed method was applied to the determination of DEHP in different real water samples, with spiked recovery of 93.3–103.2 % and RSD of 1.2–3.2 %. Therefore, the developed analytical method is rapid, sensitive, and accurate, which provides a new option for the detection of trace DEHP in aqueous samples.

Melanoma is the most lethal skin cancer originating from the malignant transformation of epidermal melanocyte. The dysregulation of cellular metabolism is a hallmark of cancer, including in melanoma. Aberrant branched-chain amino acids (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Herein, we reported that the critical BCAA metabolism enzyme branched-chain amino acid transaminase 2 (BCAT2) is an oncogenic factor in melanoma by activating lipogenesis via the epigenetic regulation of fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) expressions. Firstly, we found that BCAT2 expression was prominently increased in melanoma, and highly associated with clinical stage. Then, it was proved that the deficiency of BCAT2 led to impaired tumor cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Further, RNA sequencing technology and a panel of biochemical assays demonstrated that BCAT2 regulated de novo lipogenesis via the regulation of the expressions of both FASN and ACLY. Mechanistically, the inhibition of BCAT2 suppressed the generation of intracellular acetyl-CoA, mitigating P300-dependent histone acetylation at the promoter of FASN and ACLY , and thereby their transcription. Ultimately, zinc finger E-box binding homeobox 1 (ZEB1) was identified as the upstream transcriptional factor responsible for BCAT2 up-regulation in melanoma. Our results demonstrate that BCAT2 promotes melanoma progression by epigenetically regulating FASN and ACLY expressions via P300-dependent histone acetylation. Targeting BCAT2 could be exploited as a promising strategy to restrain tumor progression in melanoma.

Purpose The low objective response of immune checkpoint inhibitors (ICIs) remains a great challenge in advanced melanoma therapy. Interferon-alpha has been proven to be a promising combination regimen with ICI in a phase Ib/II trial. Herein, we evaluated the efficacy and safety of interferon-alpha 1b plus PD-1 monoantibody in a real-world Chinese metastatic melanoma cohort. Methods Profiles of patients diagnosed with unresectable stage IV (AJCC 8th Edition) between December 1st, 2018 and February 28th, 2022 from the Department of Dermatology, Xijing Hospital were reviewed. All of them received the combination treatment of interferon-alpha 1b (600 μg every other day) plus PD-1 monoantibody (Pembrolizumab 2 mg/kg or Toripalimab 240 mg or Sintilimab 200 mg, every 3 weeks) for at least 12 weeks. The efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The safety data were identified according to Common Terminology Criteria for Adverse Events (CTC AE) V.5.0. Results In total, 70 patients were included. 50% were females. 52.9% were with ECOG performance status ≥ 1. The fraction of patients receiving Pembrolizumab, Toripalimab, and Sintilimab was 28.6%, 67.1%, and 4.3%, respectively. Acral and mucosal subtypes accounted for 48.6% and 20%. The median follow-up period is 15.1 months. The objective response rate was 32.8%. The median time of overall survival was 18 months (95% CI 14.2–21.8 months), and the median time of PFS was 5.2 months (95% CI 4.2–6.2 months). The incidence of adverse events (any grade) was 98.6%, but only 8.6% of cases experienced grade 3 or 4 adverse reactions. Conclusion The combination of interferon-alpha 1b and PD-1 monoantibody demonstrated promising anti-tumor effects and acceptable toxicity in Chinese metastatic melanoma patients with cutaneous, acral, and mucosal subtypes.