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Abstract The ankyrin (ANK) SOCS box (ASB) family, encompassing ASB1–18, is the largest group of substrate receptors of cullin 5 Ring E3 ubiquitin ligase. Nonetheless, the mechanism of substrate recognition by ASB family proteins has remained largely elusive. Here we present the crystal structure of ASB7-Elongin B-Elongin C ternary complex bound to a conserved helical degron. ASB7 employs its ANK3-6 to form an extended groove, effectively interacting with the internal α-helix-degron through a network of side-chain-mediated electrostatic and hydrophobic interactions. Our structural findings, combined with biochemical and cellular analyses, identify the key residues of the degron motif and ASB7 required for their recognition. This will facilitate the identification of additional physiological substrates of ASB7 by providing a defined degron motif for screening. Furthermore, the structural insights provide a basis for the rational design of compounds that can specifically target ASB7 by disrupting its interaction with its cognate degron.

Microbial degradation of petroleum hydrocarbons plays a vital role in mitigating petroleum contamination and heavy oil extraction. In this study, a Saccharomyces cerevisiae capable of degrading hexadecane has been successfully engineered, achieving a maximum degradation rate of up to 20.42%. However, the degradation ability of this strain decreased under various pressure conditions such as high temperature, high osmotic pressure, and acidity conditions. Therefore, a S. cerevisiae with high tolerance to these conditions has been constructed. And then, we constructed an “anti-stress hydrocarbon-degrading” consortium comprising engineered yeast strain SAH03, which degrades hexadecane, and glutathione synthetic yeast YGSH10, which provides stress resistance. This consortium was able to restore the degradation ability of SAH03 under various pressure conditions, particularly exhibiting a significant increase in degradation rate from 5.04% to 17.04% under high osmotic pressure. This study offers a novel approach for improving microbial degradation of petroleum hydrocarbons.

In robot-assisted surgical systems, surgical instrument segmentation is a critical task that provides important information for surgeons to make informed decisions and ensure surgical safety. However, current mainstream models often lack precise segmentation edges and suffer from an excess of parameters, rendering their deployment challenging. To address these issues, this article proposes a lightweight semantic segmentation model based on edge refinement and efficient self-attention. The proposed model utilizes a lightweight densely connected network for feature extraction, which is able to extract high-quality semantic information with fewer parameters. The decoder combines a feature pyramid module with an efficient criss-cross self-attention module. This fusion integrates multi-scale data, strengthens focus on surgical instrument details, and enhances edge segmentation accuracy. To train and evaluate the proposed model, the authors developed a private dataset of endoscopic surgical instruments. It containing 1,406 images for training, 469 images for validation and 469 images for testing. The proposed model performs well on this dataset with only 466 K parameters, achieving a mean Intersection over Union (mIoU) of 97.11%. In addition, the model was trained on public datasets Kvasir-instrument and Endovis2017. Excellent results of 93.24% and 95.83% were achieved on the indicator mIoU, respectively. The superiority and effectiveness of the method are proved. Experimental results show that the proposed model has lower parameters and higher accuracy than other state-of-the-art models. The proposed model thus lays the foundation for further research in the field of surgical instrument segmentation.

Background and aim: Dachengqi Decoction (DCQD) as a classic traditional Chinese medicine has been reported to be effective in treating asthma, but its mechanism remains unknown. This study aimed to reveal the mechanisms of DCQD on the intestinal complications of asthma mediated by group 2 innate lymphoid cells (ILC2) and intestinal microbiota. Experimental procedure: Ovalbumin (OVA) was used to construct asthmatic murine models. IgE, cytokines (e.g., IL-4, IL-5), fecal water content, colonic length, histopathologic appearance, and gut microbiota were evaluated in asthmatic mice treated with DCQD. Finally, we administered DCQD to antibiotic-treated asthmatic mice to measure the ILC2 in the small intestine and colon. Results and conclusion: DCQD decreased pulmonary IgE, IL-4, and IL-5 levels in asthmatic mice. The fecal water content, the colonic length weight loss, and the epithelial damage of jejunum, ileum, and colon of asthmatic mice were ameliorated by DCQD. Meanwhile, DCQD greatly improved intestinal dysbiosis by enriching Allobaculum, Romboutsia and Turicibacter in the whole intestine, and Lactobacillus gasseri only in the colon. However, DCQD caused less abundant Faecalibaculum and Lactobacillus vaginalis in the small intestine of asthmatic mice. A higher ILC2 proportion in different gut segments of asthmatic mice was reversed by DCQD. Finally, significant correlations appeared between DCQD-mediated specific bacteria and cytokines (e.g., IL-4, IL-5) or ILC2. These findings indicate that DCQD alleviated the concurrent intestinal inflammation in OVA-induced asthma by decreasing the excessive accumulation of intestinal ILC2 in a microbiota-dependent manner across different gut locations.

The field of P-band (0.3–1 GHz) absorption has witnessed rapid development in metamaterial absorbers due to their exceptional designability and the absence of restrictions imposed by the one-fourth wavelength rule. In this study, we combined carbonyl iron powder (CIP) composites with a periodic structure composed of metal capacitive patterns and employed a genetic algorithm (GA) to optimize the electromagnetic parameters of the CIP substrate. By selecting the appropriate shape and material for the units of pattern based on transmission line theory, as well as regulating relevant structural parameters, we successfully designed an ultra-thin broadband metamaterial absorber for the P-band. Experimental results demonstrate that within the range of 0.3–0.85 GHz, the reflection loss of our absorber remains below −5 dB, with a maximum value of −9.54 dB occurring at 0.45 GHz. Remarkably, this absorber possesses a thickness equivalent to only 1/293 of its working wavelength. Then, we conducted analyses on electric field distribution, magnetic field distribution, and energy loss density. Our findings suggest that high-performance absorption in metamaterials can be attributed to λ/4 resonant or coupling effects between structural units or diffraction phenomena. This absorber offers several advantages, including broad low-frequency absorption capability, ultra-thin profile, and convenient fabrication process, thus providing valuable theoretical insights for designing metamaterial structures.

Low-cost targeted approach to construct haplotype-resolved assemblies is needed to facilitate population genetic studies. Here, the authors demonstrate assembling high-quality MHC haplotypes with CRISPR-based enrichment and long-read sequencings.

Delayed treatment of testicular torsion (TT) can lead to permanent loss of reproductive capacity. Photoacoustic imaging (PAI) and ultrasound imaging (USI) was tested for detecting TT at early stage in mice based on PAI-obtained oxygen saturation (sO2), and USI-collected color pixel density (CPD), peak systolic velocity (PSV) and resistance index (RI). For complete TT, both CPD (9.08 % ± 3.084 to almost zero) and sO2 data (70.09 % ± 1.656–59.84 % ± 1.427) showed an significant change 2 h post-torsion. For incomplete TT, sO2 data exhibited a strong time relationship (Mean values: 6 h, 64.83 % ± 1.898; 12 h, 60.67 % ± 3.555; 24 h, 57.85 % ± 3.575; P

Currently, the establishment of synthetic microbial consortia with rational strategies has gained extensive attention, becoming one of the important frontiers of synthetic biology. Systems biology can offer insights into the design and construction of synthetic microbial consortia. Taking the high-efficiency production of 2-keto-l-gulonic acid (2-KLG) as an example, we constructed a synthetic microbial consortium “Saccharomyces cerevisiae-Ketogulonigenium vulgare” based on systems biology analysis. In the consortium, K. vulgare was the 2-KLG producing strain, and S. cerevisiae acted as the helper strain. Comparative transcriptomic analysis was performed on an engineered S. cerevisiae (VTC2) and a wild-type S. cerevisiae BY4741. The results showed that the up-regulated genes in VTC2, compared with BY4741, were mainly involved in glycolysis, TCA cycle, purine metabolism, and biosynthesis of amino acids, B vitamins, and antioxidant proteases, all of which play important roles in promoting the growth of K. vulgare. Furthermore, Vitamin C produced by VTC2 could further relieve the oxidative stress in the environment to increase the production of 2-KLG. Therefore, VTC2 would be of great advantage in working with K. vulgare. Thus, the synthetic microbial consortium ''VTC2-K. vulgare'' was constructed based on transcriptomics analyses, and the accumulation of 2-KLG was increased by 1.49-fold compared with that of mono-cultured K. vulgare, reaching 13.2 ± 0.52 g/L. In addition, the increased production of 2-KLG was accompanied by the up-regulated activities of superoxide dismutase and catalase in the medium and the up-regulated oxidative stress-related genes (sod, cat and gpd) in K. vulgare. The results indicated that the oxidative stress in the synthetic microbial consortium was efficiently reduced. Thus, systems analysis confirmed a favorable symbiotic relationship between microorganisms, providing guidance for further engineering synthetic consortia.

A major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activated osteoclasts is still effective for treating osteolytic inflammatory diseases. CDZ173 is a selective PI3K inhibitor widely used in autoimmune-related diseases and inflammatory diseases and is currently under clinical development. However, the role and mechanism of CDZ173 in osteoclast-related bone metabolism remain unclear. The possibility for treating aseptic prosthesis loosening brought on by inflammatory osteolysis illness can be assessed using an LPS-induced mouse cranial calcium osteolysis model. In this study, we report for the first time that CDZ173 has a protective effect on LPS-induced osteolysis. The data show that this protective effect is due to CDZ173 inhibiting the activation of osteoclasts in vivo. Meanwhile, our result demonstrated that CDZ173 had a significant inhibitory effect on RANKL-induced osteoclasts. Furthermore, using the hydroxyapatite resorption pit assay and podosol actin belt staining, respectively, the inhibitory impact of CDZ173 on bone resorption and osteoclast fusion of pre-OC was determined. In addition, staining with alkaline phosphatase (ALP) and alizarin red (AR) revealed that CDZ173 had no effect on osteoblast development in vitro. Lastly, CDZ173 inhibited the differentiation and function of osteoclasts by weakening the signal axis of PI3K-AKT/MAPK-NFATc1 in osteoclasts. In conclusion, our results highlight the potential pharmacological role of CDZ173 in preventing osteoclast-mediated inflammatory osteolysis and its potential clinical application.

Background Forest and plantation intercropping are efficient agroforestry systems that optimize land use and promote agroforestry around the world. However, diverse agroforestry systems on the same upper-plantation differently affect the physical and chemical properties of the soil. Methods The treatments for this study included a single cultivation (CK) pecan control and three agroforestry systems (pecan + Paeonia suffruticosa + Hemerocallis citrina, pecan + Paeonia suffruticosa, and pecan + Paeonia lactiflora). Soil samples were categorized according to the sampling depth (0–20 cm, 20–40 cm, 40–60 cm). Results The results demonstrated that the bulk density (BD) of soil under the pecan agroforestry system (PPH and PPL) was reduced by 16.13% and 7.10%, respectively, and the soil moisture content (MC) and total soil porosity (TPO) increased. Improvements in the physical properties of the soil under the PPS agroforestry system were not obvious when compared with the pecan monoculture. The soil total phosphorus (TP), total nitrogen (TN), available potassium (AK), and total carbon (TC) increased significantly, while the soil urease (S-UE), alkaline phosphatase (S-AKP), and 1,4-β-N-acetylglucosamines (S-NAG) enzyme activity also increased significantly, following agroforestry. Overall, the pecan agroforestry system significantly improved the physical properties of the pecan plantation soil, enriched the soil nutrients, and increased the activity of soil enzymes related to TC, TN, and TP cycles.

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A growing number of human diseases have been found to be associated with aberrant DNA methylation, including cancer. Mutations targeting genes encoding DNA methyltransferase (DNMT), TET family of DNA demethylases, and isocitrate dehydrogenase (IDH1, IDH2) that produce TET inhibitory metabolite, 2-hyoxyglutarate (2-HG), are found in more than half of acute myeloid leukemia (AML). To gain new insights into the regulation of DNA de/methylation and consequence of its alteration in cancer development, we searched for genes which are mutated in a manner that is linked with gene mutations involved in DNA de/methylation in multiple cancer types. We found that recurrent CBFB-MYH11 fusions, which result in the expression of fusion protein comprising core-binding factor β (CBFB) and myosin heavy chain 11 (MYH11) and are found in 6∼8% of AML patients, occur mutually exclusively with DNMT3A mutations. Tumors bearing CBFB-MYH11 fusion show DNA hypomethylation patterns similar to those with loss-of-function mutation of DNMT3A. Expression of CBFB-MYH11 fusion or inhibition of DNMT3A similarly impairs the methylation and expression of target genes of Runt related transcription factor 1 (RUNX1), a functional partner of CBFB. We demonstrate that RUNX1 directly interacts with DNMT3A and that CBFB-MYH11 fusion protein sequesters RUNX1 in the cytoplasm, thereby preventing RUNX1 from interacting with and recruiting DNMT3A to its target genes. Our results identify a novel regulation of DNA methylation and provide a molecular basis how CBFB-MYH11 fusion contributes to leukemogenesis.

Cancers are known to be associated with accelerated aging, but to date, there has been a paucity of systematic and in‐depth studies of the correlation between aging and cancer. DNA methylation (DNAm) profiles can be used as aging markers and utilized to construct aging predictors. In this study, we downloaded 333 paired samples of DNAm, expression and mutation profiles encompassing 11 types of tissues from The Cancer Genome Atlas public access portal. The DNAm aging scores were calculated using the Support Vector Machine regression model. The DNAm aging scores of cancers revealed significant aging acceleration compared to adjacent normal tissues. Aging acceleration‐associated mutation modules and expression modules were identified in 11 types of cancers. In addition, we constructed bipartite networks of mutations and expression, and the differential expression modules related to aging‐associated mutations were selected in 11 types of cancers using the expression quantitative trait locus method. The results of enrichment analyses also identified common functions across cancers and cancer‐specific characteristics of aging acceleration. The aging acceleration interaction network across cancers suggested a core status of thyroid carcinoma and neck squamous cell carcinoma in the aging process. In summary, we have identified correlations between aging and cancers and revealed insights into the biological functions of the modules in aging and cancers.

Abstract Background To investigate the diagnostic value of the interferon-γ release assay (IGRA) for detecting tuberculosis (TB) infection in patients with Behçet’s disease (BD). Methods We retrospective analyzed the data collected from 173 BD patients hospitalized between 2010 and 2015. Ninety-nine healthy volunteers were enrolled as a control group. IGRA was performed using T-SPOT.TB. The diagnosis of active TB (ATB) was based on clinical, radiological, microbiological, histopathological information and the response to anti-TB therapy. Latent TB (LTB) infection was defined as asymptomatic patients with positive T-SPOT.TB. Results TB infection was documented in 59 BD patients (34.1%). The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of T-SPOT.TB for the diagnosis of ATB were 88.9%, 74.8%, 29.1%, 98.3%, 3.53 and 0.15, respectively. The receiver-operating-characteristic curve demonstrated that spot-forming cells (SFCs) of 70/106 PBMC was the optimal cutoff for diagnosing ATB, with an area under the curve of 0.891. Furthermore, the median SFCs in ATB group was significantly higher than those in LTB infection (466/106 PBMC vs. 68/106 PBMC, p = 0.007) or previous TB infection (466/106 PBMC vs. 96/106 PBMC, p = 0.018). A significant discrepancy between T-SPOT.TB and tuberculin skin test was noted (kappa coefficient = 0.391, p = 0.002). Conclusions T-SPOT.TB, an IGRA, may assist in the diagnosis of ATB in BD patients, and the higher SFCs suggest ATB in BD patients.

Vitamin C (VC) is comprehensively applied in foods, cosmetics, pharmaceuticals, and especially clinical medicine. Nowadays, the industrial production of VC mainly relies on the classic two-step fermentation route, and researchers have explored the way for one-step fermentation of VC in recent years. In this study, a VC biosynthesis pathway that directly produced VC from glucose was reconstructed in Saccharomyces cerevisiae, and the protein engineering and metabolic engineering strategies were adopted to improve it. First, five exogenous modules from Arabidopsis were introduced into the chassis cells by synthetic biology approaches to obtain the strain YLAA harboring VC biosynthesis. In addition, L-galactose dehydrogenase (L-GalDH) and L-galactono-1,4-lactone dehydrogenase (L-GLDH) were fused and expressed in S. cerevisiae cells for the first time, which increased the intracellular VC accumulation by 2.78-fold, reaching 9.97 ± 0.09 mg/L. Through copy number engineering, it was further confirmed that the last step catalyzed by L-GLDH is the rate-limiting step. GDP-L-galactose phosphorylase (GPP) encoded by vtc2 is another rate-limiting enzyme confirmed by GAL1p overexpression results. Finally, by balancing gene expression and cell growth, the highest production strain with overexpressing vtc2 by multicopy plasmids was constructed. The VC accumulation reached 24.94 ± 1.16 mg/L, which was currently the highest production from glucose in S. cerevisiae. The production of the recombinant strain reached nearly 44 mg/L with the exogenous addition of L-galactose or glutathione. The results further emphasized the importance of the step catalyzed by GPP. The investigation provided experience for the efficient biosynthesis of VC and the determination of rate-limiting steps.

Abstract Background This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. Method Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. Results Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. Conclusion We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.

In molecular breeding of super rice, it is essential to isolate the best quantitative trait loci (QTLs) and genes of leaf shape and explore yield potential using large germplasm collections and genetic populations. In this study, a recombinant inbred line (RIL) population was used, which was derived from a cross between the following parental lines: hybrid rice Chunyou84, that is, japonica maintainer line Chunjiang16B (CJ16); and indica restorer line Chunhui 84 (C84) with remarkable leaf morphological differences. QTLs mapping of leaf shape traits was analyzed at the heading stage under different environmental conditions in Hainan (HN) and Hangzhou (HZ). A major QTL qLL9 for leaf length was detected and its function was studied using a population derived from a single residual heterozygote (RH), which was identified in the original population. qLL9 was delimitated to a 16.17 kb region flanked by molecular markers C-1640 and C-1642, which contained three open reading frames (ORFs). We found that the candidate gene for qLL9 is allelic to DEP1 using quantitative real-time polymerase chain reaction (qRT-PCR), sequence comparison, and the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR/Cas9) genome editing techniques. To identify the effect of qLL9 on yield, leaf shape and grain traits were measured in near isogenic lines (NILs) NIL-qLL9CJ16 and NIL-qLL9C84, as well as a chromosome segment substitution line (CSSL) CSSL-qLL9KASA with a Kasalath introgressed segment covering qLL9 in the Wuyunjing (WYJ) 7 backgrounds. Our results showed that the flag leaf lengths of NIL-qLL9C84 and CSSL-qLL9KASA were significantly different from those of NIL-qLL9CJ16 and WYJ 7, respectively. Compared with NIL-qLL9CJ16, the spike length, grain size, and thousand-grain weight of NIL-qLL9C84 were significantly higher, resulting in a significant increase in yield of 15.08%. Exploring and pyramiding beneficial genes resembling qLL9C84 for super rice breeding could increase both the source (e.g., leaf length and leaf area) and the sink (e.g., yield traits). This study provides a foundation for future investigation of the molecular mechanisms underlying the source⁻sink balance and high-yield potential of rice, benefiting high-yield molecular design breeding for global food security.