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Wheat is the second largest food crop with a very good breeding system and pedigree record in China. Investigating the genomic footprints of wheat cultivars will unveil potential avenues for future breeding efforts 1,2 . Here we report chromosome-level genome assemblies of 17 wheat cultivars that chronicle the breeding history of China. Comparative genomic analysis uncovered a wealth of structural rearrangements, identifying 249,976 structural variations with 49.03% (122,567) longer than 5 kb. Cultivars developed in 1980s displayed significant accumulations of structural variations, a pattern linked to the extensive incorporation of European and American varieties into breeding programmes of that era. We further proved that structural variations in the centromere-proximal regions are associated with a reduction of crossover events. We showed that common wheat evolved from spring to winter types via mutations and duplications of the VRN-A1 gene as an adaptation strategy to a changing environment. We confirmed shifts in wheat cultivars linked to dietary preferences, migration and cultural integration in Northwest China. We identified large presence or absence variations of pSc200 tandem repeats on the 1RS terminal, suggesting its own rapid evolution in the wheat genome. The high-quality genome assemblies of 17 representatives developed and their good complementarity to the 10+ pan-genomes offer a robust platform for future genomics-assisted breeding in wheat., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Unilateral adrenal artery embolization (AAE) has emerged as an alternative treatment for patients with primary aldosteronism due to aldosterone-producing adenomas or idiopathic hyperaldosteronism with bilateral adrenal hyperplasia. This study aimed to investigate the effectiveness and safety of bilateral AAE in idiopathic hyperaldosteronism. We enrolled a total of 58 patients with idiopathic hyperaldosteronism who underwent successful bilateral AAE, and 55 of them completed 6-month follow-up. Bilateral AAE significantly lowered blood pressure of patients with IHA at 1, 3, and 6 months (all P < 0.01). Six months after the procedure, office, home, and 24-hour ambulatory blood pressure decreased by 20.3/13.5, 18.4/12.6, and 13.7/9.9 mmHg, respectively. Among them, 92.7%, 90.9%, and 89.1% had significant or moderate improvement in blood pressure control at 1, 3, and 6 months after the procedure. Bilateral AAE substantially decreased plasma aldosterone levels, reversed plasma renin suppression, decreased aldosterone-to-renin ratio, and corrected hypokalemia. Importantly, the procedure did not significantly change serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, and the cortisol and ACTH circadian rhythms remained intact three months after the procedure. Additionally, 16 patients underwent ACTH stimulation tests three months post-procedure and all of them had normal results except for one with a decreased response due to exogenous steroid therapy. Flank pain was the most common side effect which happened in 96.4% of the patients and resolved within 48 h. There were no long-term side effects in the 6 months. The present study provides evidence that bilateral AAE is an effective and safe alternative treatment for patients with IHA. Changes in office and 24h ambulatory blood pressure at 1, 3, and 6 months after bilateral adrenal artery embolization in patients with idiopathic hyperaldosteronism., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

This work aims to address key issues in the ballistic performance of ceramic-based composite armor, particularly at the joints of spliced ​​bulletproof panels. The edge structure of C/C-SiC ceramic plates and ultra-high molecular weight polyethylene is redesigned to superimpose the joint areas. These structurally optimized composite pads are examined by numerical simulation of impact dynamics to understand their anti-penetration performance whose accuracy is then validated by live fire tests. The results reveal that (1) the ceramic plates with improved edge design enhance the anti-penetration efficiency, (2) the established dynamic constitutive model of penetration resistance effectively predicts the ballistic performance of the armor pad, and (3) inability to penetrate high-speed real bullets through the armor suggests that the ballistic performance fully meets the protection requirements of the MIL-A-46103EIII Class 2 A standard. In this regard, structural regulation of the shape of the ceramic-based composite plates allows for the design of lightweight armor with improved bulletproof capability., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In this real-world study, 153 adult T-cell lymphoblastic lymphoma (T-LBL) patients from sixteen centers in Shanghai were enrolled. Out of them, 103 (67.3%) achieved complete remission (CR). The 2-year overall survival (OS) and progression-free survival (PFS) were 56.3% and 47.6%, respectively. In multivariate analysis, CR after induction treatment significantly improved the OS (p = 0.002) and PFS (p = 0.001). Among CR patients, allogeneic peripheral blood stem cell transplantation (allo-PBSCT) significantly lowered the cumulative incidence of relapse (CIR) compared to autologous PBSCT (p = 0.043) and non-SCT (p = 0.001). Among patients undergoing allo-PBSCT in CR, early (within four induction courses) and late CR (after four induction courses) didn't impact the prognosis with similar 2-year OS (p = 0.590), PFS (p = 0.858), CIR (p = 0.50), and non-relapse mortality (NRM) (p = 0.110). Early and deferred allo-PBSCT for early CR patients also yielded similar 2-year OS (p = 0.640), PFS (p = 0.970), CIR (p = 0.994), and NRM (p = 0.974). As a time-dependent covariate, allo-PBSCT presented a positive effect on PFS (p = 0.018) and had a trend toward better OS (p = 0.064). These data suggested that allo-PBSCT should be considered for T-LBL patients upon achieving CR to enhance survival and reduce relapse risk., Competing Interests: Competing interests: The authors declare no competing interests. Patient consent statement: The studies involving humans were approved by Ethics Committee of Shanghai General Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with national legislation and institutional requirements., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma (HCC) is often detected at advanced stages among patients with hepatitis B virus (HBV), underscoring the urgency for more precise surveillance tests. Here, we compare the clinical performance of the novel - GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], protein-induced by vitamin K absence-II [PIVKA-II]) and GALAD (gender [biological sex], age, AFP, Lens-culinaris AFP [AFP-L3]), PIVKA-II) algorithms to assess the utility of AFP-L3 for distinguishing HCC from benign chronic liver disease (CLD) in Chinese patients with predominantly chronic HBV infection. Eligible adults were enrolled, and biomarkers were measured using Elecsys (Cobas) or µTASWAKO assays. In total, 411 participants provided serum samples (HCC, n = 176 [early-stage, n = 110]; CLD, n = 136; specificity n = 101). HBV was the underlying disease etiology for most participants (HCC, 95%; benign CLD, 72%). For GAAD (Cobas), GALAD (Cobas), and GALAD (µTASWAKO), AUCs were 93.1% (95% CI: 90.0-96.2), 93.2% (90.0-96.3), and 92.7% (88.4-96.9) for early-stage, and 95.6% (93.6-97.6), 95.6% (93.6-97.7), and 95.8% (93.2-98.3) for all-stage HCC, versus CLD, respectively. Interestingly, both GAAD and GALAD algorithms demonstrated comparable diagnostic performance regardless of disease etiology (HBV vs. non-HBV), presence of cirrhosis, geographic region, and within pan-tumor specificity panels (p < 0.001), indicating AFP-L3 may have a negligible role in HCC surveillance., Competing Interests: Declarations. Competing interests: HLYC reports consultancy fees from Arbutus Biopharma, Gilead Sciences, Glaxo-Smith-Kline, Roche, Vir Biotechnology, Aligos Therapeutics, Vaccitech, and Virion Therapeutics; and speaker’s bureau participation for Echosens, Gilead Sciences, Roche, and Viatris. YH has no conflicts of interest to declare. KMad, KK, and AS are employees of Roche Diagnostics International AG. KMal is an employee of Microcoat Biotechnologie, contracted by Roche Diagnostics. JH reports speaker’s bureau participation for Glaxo-Smith-Kline, Gilead Sciences, and Roche Diagnostics; has received grant/research support from Gilead Sciences and BMS; and has served on an advisory committee or review panel for Aligos, Assembly, Glaxo-Smith-Kline, Gilead Sciences, Johnson Pharmaceutica, and Roche., (© 2024. The Author(s).)

The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval All experiments with mice were performed with the approval of Xinxiang medical university and according to the regulations of people’s republic of China on the administration of experimental animals (XYLL-20220487). Human samples were obtained with informed consent of patients, and all experimental procedures were performed following guidelines from regulations of the people’s republic of China on the management of human genetic resources (XYLL-20220488)., (© 2024. The Author(s).)

Aircraft parts are often designed as thin-walled structures to reduce the weight of the aircraft. However, thin-walled structures are prone to deformation during the milling process, leading to a decrease in machining accuracy. To address this problem, a method combining milling and electrochemical machining, known as electrolytic milling, is proposed to minimize deformation and enhance the accuracy of thin-walled parts. The factors that affect the machining accuracy of electrolytic milling were analysed, and a model for predicting the thickness of the material removed was established. Electrolytic milling experiments were designed, and the model was solved. Based on the built model, the influences of feed rate, spindle speed, radial cutting depth, voltage and electrolyte concentration on material removal thickness were investigated. Compared with the milling method, the electrolytic milling method can improve the machining accuracy of thin-walled parts. Electrolytic milling experiments were conducted on box-shaped parts to verify the reliability of the proposed method., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Pollen coat proteins (PCPs) are cysteine-rich small-molecule proteins, which exhibit high levels of polymorphism and are expressed in gametocytes. Previous investigations have revealed that PCP genes are involved in pollen wall synthesis, pollen-stigma recognition, and pollen development and germination. However, gene expression and function of PCP family in pollen development is not well understood in Wucai (Brassica campestris L.). In this study, genome-wide identification and expression analysis of the BcPCP gene family members were conducted, including their physical and chemical properties, chromosome localization, phylogenetic relationships, gene structure, and tertiary structure. A total of 20 BcPCP genes were identified and classified into three subfamilies showing high homology to Arabidopsis thaliana. Expression pattern analysis indicated that the BcPCP gene family exhibits higher expression levels in reproductive organs, suggesting their potential involvement in the reproductive development. Notably, BraA02g002400.3 C, potentially associated with male sterility, was identified through multiple transcriptomic and proteomic datasets. Subsequently, sequence analysis revealed its homology with the Arabidopsis GRP20 gene, and thus it was named BcGRP20. Functional analysis of this gene showed that overexpression of BcGRP20 gene in the Arabidopsis grp20 mutant could restore anther fertility. Overall, our findings indicate that BcGRP20 plays a critical role in pollen development and may be the causative gene for male sterility in Wucai. This study provides candidate genes for further functional identification of BcPCP genes in Wucai, which are crucial for anther development., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

5-Methylcytosine (m 5 C) is closely associated with cancer. However, the role of m 5 C in breast cancer(BC)remains unclear. This study combined single-cell RNA sequencing (scRNA-Seq) and transcriptomics datasets to screen m 5 C regulators associated with BC progression and analyze their clinical values. Firstly, This study elucidates the mechanisms of the m 5 C landscape and the specific roles of m 5 C regulators in BC patients. we found that the dysregulation of m 5 C regulators with m 5 Cscore play the essential role of the carcinogenesis and progression in epithelial cells and myeloid cells of BC at single cell level. External validation was conducted using an independent scRNA-Seq datasets. Then, three distinct m 5 C modification patterns were identified by transcriptomics datasets. Based on the m 5 C differentially expressed regulators, the m 5 Cscore was constructed, and used to divide patients with BC into high and low m 5 Cscore groups. Patients with a high m 5 Cscore had more abundant immune cell infiltration, stronger antitumor immunity, and better prognoses. Finally, Quantitative real-time (PCR) and immunohistochemistry were used for the in vitro experimental validation, which had extensive prognostic value. In this study, we aimed to assess the expression of m 5 C regulators involved in BC and investigate their correlation with the tumor microenvironment, clinicopathological characteristics, and prognosis of BC. The m 5 C regulators could be used to effectively assess the cell specific regulation prognosis of patients with BC and develop more effective immunotherapy strategies., Competing Interests: Declarations Ethics approval and consent to participate The studies involving human participants were reviewed and approved by Ethics Committee of the First Hospital of Shanxi Medical University, the ethics number is K-K0109. The patients provided their written informed consent to participate in this study. Consent for publication The patients involved have obtained ethical approval and written informed consent for the publication of any potentially identifiable images or data included in this article. Competing interests The authors declare no competing interests. Statement All methods were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s).)

The study aimed to compare the effectiveness between Hiporfin-photodynamic therapy (PDT) and loop electrosurgical excision procedure (LEEP) in treating cervical high-grade squamous intraepithelial lesion (HSIL). We conducted a retrospective analysis of 104 women diagnosed with cervical HSIL at our hospital from April 2019 to July 2023. With 1:1 matched case-control, 52 cases received Hiporfin-PDT and 52 cases underwent LEEP. All PDT-treated cases received Hiporfin (2 mg/kg) I.V. and a diode laser at a wavelength of 630-nm. T-test, Chi-square test, Fisher's exact test, and Yates's correction for continuity were conducted for statistical. A P value < 0.05 was considered significant. The complete response (CR) post-PDT at 3rd-6th months,10th-12th months and 24th months was in 98.1% (51/52),100.0% (45/45) and 100.0% (22/22) patients respectively, compared to 98.1% (51/52), 100.0% (46/46) and 100.0% (24/24) patients respectively after LEEP. HPV clearance rates after PDT at 3rd-6th months,10th-12th months and 24th months was 76.9% (40/52), 88.9% (40/45) and 95.5% (21/22) respectively, compared to 69.2% (36/52), 93.5% (43/46) and 95.8% (23/24) respectively after LEEP, with no significant difference between the two groups (P = 0.508, P = 0.687 and P = 1.000, respectively). Postoperative complications in the PDT group were tolerable. The cure rates and HPV eradication of Hiporfin-PDT were comparable with that of LEEP in the management of cervical HSIL. Hiporfin-PDT may serve an alternative method for organ-saving in cervical HSIL., (© 2024. The Author(s).)

Wind power DC collection system, as a crucial component of wind farms, plays a vital role in ensuring the safe and stable operation of the entire wind farm. This paper proposes a reliability assessment method for wind power DC collection systems based on MLFTA-SMC. Firstly, it analyzes the topology and key equipment of wind power DC collection systems. Secondly, based on the topology of different wind power DC collection systems, it constructs multi-level fault tree models to calculate the comprehensive importance of different events, thus providing data support for subsequent reliability assessment. Then, it utilizes the MLFTA-SMC method to assess and analyze the reliability of different wind power DC collection system topologies. Finally, taking a 100 MW wind farm in Northwest China as an example, the proposed reliability assessment method is verified through simulation. The results indicate that this method exhibits good effectiveness and superiority., (© 2024. The Author(s).)

The spread of SARS-CoV-2 to animals has the potential to evolve independently. In this study, we distinguished several sentinel animal species and genera for monitoring the re-emergence of COVID-19 or the new outbreak of COVID-19-like disease. We analyzed SARS-CoV-2 genomic data from human and nonhuman mammals in the taxonomic hierarchies of species, genus, family and order of their host. We find that SARS-CoV-2 carried by domestic dog (Canis lupus familiaris), domestic cat (Felis catus), mink (Neovison vison), and white-tailed deer (Odocoileus virginianus) cluster closely to human-origin viruses and show no differences in the majority of amino acids, but have the most positively selected sites and should be monitored to prevent the re-emergence of COVID-19 caused by novel variants of SARS-CoV-2. Viruses from the genera Panthera (especially lion (Panthera leo)), Manis and Rhinolophus differ significantly from human-origin viruses, and long-term surveillance should be undertaken to prevent the future COVID-19-like outbreaks. Investigation of the variation dynamics of sites 142, 501, 655, 681 and 950 within the S protein may be necessary to predict the novel animal SARS-CoV-2 variants., (© 2024. The Author(s).)

In this study, the chloride ion (Cl - ) binding rate of sulfoaluminate cement (SAC) mortars containing different mineral admixtures was investigated. This is essential to improve the durability of concrete structures in high Cl - environments, especially where they are susceptible to Cl - attack such as coastlines and marine structures. The effects of Cl - concentration, curing age, and the type and amount of mineral admixture on the Cl - binding rate of SAC mortars were analyzed. It was found that the content of water-soluble Cl - in SAC mortars decreased with the increase of curing age, while the Cl - binding ratio increased accordingly, indicating that its resistance to internal Cl - permeation increased. The addition of fly ash (FA) and ground granulated blast furnace slag (GGBS) can significantly improve the Cl - binding rate of SAC mortars, and the Cl - binding rate increases to 46.6% with 20% of FA and 38.7% with 40% of GGBS. The effects of mineral admixtures on the microstructure and phase composition of SAC mortars were further investigated by X-ray diffraction (XRD) analysis. The results showed that the addition of FA and GGBS promoted the formation of C-S-H (calcium silicate hydrate) gels and improved the resistance of SAC mortars to Cl - penetration. On the other hand, the excessive addition of silica fume (SF) decreased the Cl - binding rate, whereas a moderate amount of limestone powder (LP) improved the Cl - binding rate. The study of the Cl - binding rate of SAC mortars can help to evaluate their resistance to Cl - erosion in real projects, thus guiding the optimization of concrete formulations and the improvement of durability., (© 2024. The Author(s).)

Pulmonary embolism is a rare but serious complication in Mycoplasma pneumoniae pneumonia patients, leading to serious sequelae and even death. We aim to retrospectively analyze the clinical features of Mycoplasma pneumoniae pneumonia with pulmonary consolidation in children and to explore the independent risk factors for progression to pulmonary embolism. Clinical data of 207 children with Mycoplasma pneumoniae pneumonia complicated with pulmonary consolidation were collected, and the patients were divided into the pulmonary embolism group (69 patients) and the control group (138 patients). Multivariate logistic regression was used to analyze the risk factors and the predictive efficacy was evaluated by receiver operating characteristic curve. Multivariate logistic regression analysis showed that fever days, D-dimer, immunoglobulin A, chest pain, extra-respiratory symptoms, plastic bronchitis and cutaneous mucosal system complications were the independent risk factors. Fever days ≥ 7.5, D-dimer ≥ 0.895 mg/L, immunoglobulin A ≥ 1.015 g/L, chest pain, extra-respiratory symptoms, plastic bronchitis and cutaneous mucous system complications significantly increased the risk of pulmonary embolism in children with Mycoplasma pneumoniae pneumonia complicated with pulmonary consolidation., (© 2024. The Author(s).)

The Ruddlesden-Popper (R-P) bilayer nickelate, La 3 Ni 2 O 7 , was recently found to show signatures of high-temperature superconductivity (HTSC) at pressures above 14 GPa (ref.  1 ). Subsequent investigations achieved zero resistance in single-crystalline and polycrystalline samples under hydrostatic pressure conditions 2-4 . Yet, obvious diamagnetic signals, the other hallmark of superconductors, are still lacking owing to the filamentary nature with low superconducting volume fraction 2,4,5 . The presence of a new 1313 polymorph and competing R-P phases obscured proper identification of the phase for HTSC 6-9 . Thus, achieving bulk HTSC and identifying the phase at play are the most prominent tasks. Here we address these issues in the praseodymium (Pr)-doped La 2 PrNi 2 O 7 polycrystalline samples. We find that substitutions of Pr for La effectively inhibit the intergrowth of different R-P phases, resulting in a nearly pure bilayer structure. For La 2 PrNi 2 O 7 , pressure-induced orthorhombic to tetragonal structural transition takes place at P c  ≈ 11 GPa, above which HTSC emerges gradually on further compression. The superconducting transition temperatures at 18-20 GPa reach T c onset = 82.5 K and T c zero = 60 K , which are the highest values, to our knowledge, among known nickelate superconductors. Importantly, bulk HTSC was testified by detecting clear diamagnetic signals below about 75 K with appreciable superconducting shielding volume fractions at a pressure of above 15 GPa. Our results not only resolve the existing controversies but also provide directions for exploring bulk HTSC in the bilayer nickelates., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In systemic lupus erythematosus, loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage 1 . How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here we set out to dissect layers and hierarchies of autoimmune kidney inflammation to identify tissue-specific cellular hubs that amplify autoinflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blockade and genetic deficiency, we show that tissue-resident NKp46 + innate lymphoid cells (ILCs) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signalling in a distinct subset of group 1 ILCs (ILC1s) instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46 + ILCs promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody clone mNCR1.15; ref.  2 ) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data provide support for the idea that NKp46 + ILC1s promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1s therefore constitutes a previously unrecognized, crucial tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to assess the potential of home monitoring using a monitoring application for the early prediction of acute exacerbations (AEs) in patients with fibrosing interstitial lung diseases (F-ILDs) by tracking symptoms, peripheral blood oxygen saturation (SpO 2 ), and heart rate (HR). Data on symptoms, SpO 2 , and HR before and after a 1-min sit-to-stand test (1STST) were collected using an online home monitoring application. Symptoms were recorded at least 3 times a week, including cough intensity and frequency (Cough Assessment Test scale (COAT) score), breathlessness grade (modified Medical Research Council (mMRC) score), and SpO 2 and HR before and after 1STST. Eighty-five patients with stable F-ILDs were enrolled. We observed a significant increase in COAT and mMRC scores, alongside a significant decrease in SpO 2 before and after 1STST, 2 weeks before the first recorded AE. Furthermore, a combination of variables-an increase in COAT (≥ 4) and mMRC(≥ 1) scores, a decrease in SpO 2 at rest (≥ 5%), and a decrease in SpO 2 after 1STST (≥ 4%)- proved the most effective in predicting AE onset in patients with F-ILDs at 2 weeks before the first recorded AE. Home telemonitoring of symptoms, SpO 2 holds potential value for early AE detection in patients with F-ILDs., (© 2024. The Author(s).)

The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

A sensitive and efficient imaging technique is required to assess the subtle abnormalities occurring in the normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in patients with relapsing-remitting multiple sclerosis (RRMS). In this study, a fast 3D macromolecular proton fraction (MPF) quantification based on spin-lock (fast MPF-SL) sequence was proposed for brain MPF mapping. Thirty-four participants, including 17 healthy controls and 17 RRMS patients were prospectively recruited. We conducted group comparison and correlation between conventional MPF-SL, fast MPF-SL, and DWI, and compared differences in quantified parameters within MS lesions and the regional NAWM, NAGM, and normal-appearing deep grey matter (NADGN). MPF of MS lesions was significantly reduced (7.17% ± 1.15%, P < 0.01) compared to all corresponding normal-appearing regions. MS patients also showed significantly reduced mean MPF values compared with controls in NAGM (4.87% ± 0.38% vs 5.21% ± 0.32%, P = 0.01), NAWM (9.49% ± 0.69% vs 10.32% ± 0.59%, P < 0.01) and NADGM (thalamus 5.59% ± 0.67% vs 6.00% ± 0.41%, P = 0.04; caudate 5.10% ± 0.55% vs 5.53% ± 0.58%, P = 0.03). MPF and ADC showed abnormalities in otherwise normal appearing close to lesion areas (P < 0.01). In conclusion, time-efficient MPF mapping of the whole brain can be acquired efficiently (< 3 min) using fast MPF-SL. It offers a promising alternative way to detect white matter abnormalities in MS., (© 2024. The Author(s).)

Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security 1 . Here we examined the genetic and phenotypic diversity of the A. E. Watkins landrace collection 2 of bread wheat (Triticum aestivum), a major global cereal, by whole-genome re-sequencing of 827 Watkins landraces and 208 modern cultivars and in-depth field evaluation spanning a decade. We found that modern cultivars are derived from two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium-based haplotypes and association genetics analyses link Watkins genomes to the thousands of identified high-resolution quantitative trait loci and significant marker-trait associations. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritized quantitative trait loci in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilizing genetic diversity in crop improvement to achieve sustainable food security., (© 2024. The Author(s).)

Endothelins and their receptors, ET A and ET B , play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET A antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET A in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET A antagonist, respectively. Notably, a specialized anti-ET A antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET A and ET B , and the agonist BQ3020-bound ET B , in complex with G q , unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET A . Furthermore, our results suggest that ECL2 in ET A can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors., (© 2024. The Author(s).)

RNA-binding proteins (RBPs) are a class of proteins that primarily function by interacting with different types of RNAs and play a critical role in regulating the transcription and translation of cancer-related genes. However, their role in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed RNA sequencing data and the corresponding clinical information of patients with HCC to screen for prognostic RBPs. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was identified as an independent prognostic factor for liver cancer. It is upregulated in HCC and is associated with a poor prognosis. Elevated IGF2BP3 expression was validated via immunohistochemical analysis using a tissue microarray of patients with HCC. IGF2BP3 knockdown inhibited the proliferation of Hep3B and HepG2 cells, whereas IGF2BP3 overexpression promoted the expansion of HuH-7 and MHCC97H cells. Mechanistically, IGF2BP3 modulates cell proliferation by regulating E2F1 expression. DNA hypomethylation of the IGF2BP3 gene may increase the expression of IGF2BP3, thereby enhancing cell proliferation in HCC. Therefore, IGF2BP3 may act as a novel prognostic biomarker and a potential therapeutic target for HCC., (© 2024. The Author(s).)

Aim of this study was to explore the optimal training interval and times of microperimetric biofeedback training (MBFT) in maculopathies. Twenty-nine patients with maculopathies were divided into two groups: daily training (Group A) or alternate daily training (Group B). Both groups underwent 15 MBFT sessions. We compared the BCVA, reading speed, and fixation stability at baseline, after 5, 10, 15 sessions. After 15 sessions of MBFT, all visual parameters in both groups improved. There was a significant increase in BCVA after 5 sessions in both groups (P=0.016, and P<0.001 respectively), but Group A showed further improvement after 10 sessions (P<0.001). Regarding reading speed, Group A showed significant improvement from baseline after 15 sessions(P=0.020), Group B improved significantly after 5 sessions (P=0.047) and continued to improve after 10 sessions (P=0.030). Additionally, P1 and LgBCEA of Group A significantly improved after 10 sessions (P=0.001, and P=0.001 respectively), while Group B significantly improved after 5 sessions (P=0.002, and P<0.001 respectively). There was no significant difference in visual outcomes between the two groups (P>0.05) except LgBCEA (P=0.046) after 15 sessions. We concluded that the both MBFT frequencies are effective at improving vision and quality of life in patients with maculopathies. The alternate daily training group showed less time-dependent of improvement in all parameters and a greater benefit in fixation stability. Ten sessions are the optimal number of treatment sessions for alternate daily training., (© 2024. The Author(s).)

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γ c ) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC., (© 2024. The Author(s).)

This cross-sectional study investigated the association between glaucoma and B vitamin dietary intake. A total of 5025 enrolled individuals participated in self-reported glaucoma questionnaire and 3264 participated in International Society Geographical and Epidemiological Ophthalmology (ISGEO) criteria. In self-reported glaucoma, the risk of having self-reported glaucoma was lower in the third quartile of vitamin B1 intake (odds ratio [odds ratio [OR] 0.63, 95% confidence interval [CI] 0.40-0.97), and P trend (P trend = 0.004) for vitamin B12 was significant; in males, the third quartile of vitamin B1 intake (OR 0.44, 95% CI 0.24-0.83) and the fourth quartile of vitamin B2 intake (OR 0.39, 95% CI 0.17-0.89) were associated with a lower risk. In glaucoma based on ISGEO criteria, the increase of niacin intake (OR 0.94, 95% CI 0.89-0.99) was negatively associated with the odds of self-reported glaucoma. After sex-stratified analysis, the third quartile of vitamin B6 intake (OR 0.21, 95% CI 0.08-0.60) in males were associated with reduced odds of glaucoma. The restricted cubic spline analysis revealed a nonlinear association of vitamin B2 (p for nonlinearity = 0.04) and B9 (p for nonlinearity = 0.024) intake with glaucoma diagnosed by ISGEO criteria in females., (© 2024. The Author(s).)

There is a deficiency in population-based studies investigating the impact of HPV infection on vaginal microenvironment, which influences the risk of persistent HPV infection. This prospective study aimed to unravel the dynamics of vaginal microbiota (VM) and vaginal metabolome in reaction to the changed state of HPV infection. Our results propose that the vaginal metabolome may be a superior indicator to VM when assessing the impact of altered HPV state on the vaginal microenvironment., (© 2024. The Author(s).)

This study employs a multifaceted approach, encompassing field investigations, borehole surveys, surface deformation displacement monitoring, deep-seated deformation monitoring, and numerical simulation analysis, to conduct an exhaustive examination of the deformation processes and characteristics exhibited by the Mala Landslide. The findings elucidate a close correlation between the deformation of the Mala Landslide and the elevation of the reservoir water level. During the escalation of the reservoir water level, the landslide body progressively developed surface cracks, spanning from the frontal edge to the rear edge. The centre of the sliding body is situated in the central-lower downstream region, and presently, the landslide is undergoing a phase of comprehensive creep deformation. Due to the reservoir water level fluctuation rate being greater than the permeability coefficient, the deformation of the landslide displays a delayed response. As the reservoir water level reaches 1401 m during high-water operation, the two important ingredients, the buoyancy weight reduction effect and the influence of submerged reservoir water, significantly reduce the sliding resistance of the sliding mass, thereby exacerbating the deformation of the landslide. Following a comprehensive analysis of the findings, it can be firmly concluded that this landslide conforms to the characteristic traits of a typical buoyant force reduction type-retrogressive type landslide., (© 2024. The Author(s).)

Circular RNAs (circRNAs) play a crucial role in regulating various tumors. However, their biological functions and mechanisms in gastric cancer (GC) have not been well understood. Here, we discovered a stable cytoplasmic circRNA named circUSP1 (hsa&#95;circ&#95;000613) in GC. CircUSP1 upregulation in GC tissues was correlated with tumor size and differentiation. We observed that circUSP1 promoted GC growth and metastasis. Mechanistically, circUSP1 mainly interacted with the RRM1 domain of an RNA-binding protein (RBP) called HuR, stabilizing its protein level by inhibiting β-TrCP-mediated ubiquitination degradation. The oncogenic properties of HuR mediated promotive effects of circUSP1 in GC progression. Moreover, we identified USP1 and Vimentin as downstream targets of HuR in post-transcriptional regulation, mediating the effects of circUSP1. The parent gene USP1 also enhanced the viability and mobility of GC cells. Additionally, tissue-derived circUSP1 could serve as an independent prognostic factor for GC, while plasma-derived circUSP1 showed promise as a diagnostic biomarker, outperforming conventional markers including serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA19-9). Our study highlights that circUSP1 promotes GC progression by binding to and stabilizing oncogenic HuR, thereby facilitating the upregulation of USP1 and Vimentin at the post-transcriptional level. These findings suggest that circUSP1 could be a potential therapeutic target and a diagnostic and prognostic biomarker for GC., (© 2024. The Author(s).)

Our prior study has suggested that percutaneous superselective adrenal arterial embolization (SAAE) with ethanol reduces blood pressure in patients with primary aldosteronism. This study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with idiopathic hyperaldosteronism. In this prospective, randomized, controlled trial, we randomly assigned patients with idiopathic hyperaldosteronism in a 1:1 ratio to undergo SAAE (n = 29) or receive MRA (n = 30) treatment. The primary endpoint was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The secondary endpoints included changes in office blood pressure, home blood pressure, correction of aldosterone-to-renin ratio, and adverse events at 6 months. The mean change in 24-h ambulatory systolic blood pressure from baseline to 6-month follow-up was significantly different between the two groups (-8.4 mmHg; 95% confidence interval, -15.2 to -2.1 mmHg; P < 0.01). Office, home, and ambulatory blood pressure reduction at 6 months was more pronounced in the SAAE group than the MRA group (all P < 0.05). Aldosterone-to-renin ratio was lower in the SAAE group than the MRA group at 1 and 3 months (both P < 0.01), while it had no difference between the two groups at 6 months. None of the patients experienced serious adverse events in the perioperative and 6-month follow-up periods. SAAE, as a hormonal debulking procedure, is superior to MRA in blood pressure control and correction of biochemical abnormalities in patients with idiopathic hyperaldosteronism., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape., (© 2024. The Author(s).)

This primary objective of our study was to investigate the relationship between serum calcium levels and the occurrence of sudden cardiac arrest (SCA) in stroke patients. We analyzed the clinical data of 10,423 acute stroke patients admitted to the intensive care unit. The association between serum calcium and SCA following an acute stroke was assessed through multivariate logistic regression. We explored the non-linear connection between serum calcium levels and SCA in stroke patients using a generalized additive model and smooth curve fitting. Our study uncovered that serum calcium serves as an independent risk factor for sudden cardiac arrest in stroke patients. Notably, we observed that the relationship between serum calcium levels upon admission and the occurrence of SCA in stroke patients within the hospital was non-linear. Furthermore, we identified inflection points in serum calcium levels at 8.2 and 10.4 mg/dL. These findings emphasize a non-linear relationship between serum calcium levels and the risk of SCA in stroke patients. Maintaining serum calcium within the range of 8.2-10.4 mg/dL could lead to a significant reduction in the incidence of cardiac arrest among stroke patients., (© 2024. The Author(s).)

Validating the direct photocatalytic activity of colloidal plasmonic nanoparticles is challenging due to their limited stability and needed support materials that can often contribute to the chemical reactions. Stable gold nanoparticles (AuNPs) with tunable sizes are prepared across porous polymer particles without any chemical bonds where the resulting composite particles exhibit intense surface plasmon resonances (SPRs) in the visible region. These composite particles are then tested as photocatalysts under a broadband solar-simulated light source to examine the contribution degree of photothermal heating and SPR coming from the incorporated AuNPs in the C-C bond forming homocoupling reaction. Generally, the thermal and photothermal heating are the main driving force to increase the reactivity of relatively smaller AuNPs (~ 44 nm in diameter) with a narrower SPR band. However, the SPR-induced catalytic activity is much greater for the composite particles containing larger AuNPs (~ 87 nm in diameter) with a broader SPR. As the polymer particle matrix does not influence the catalytic activity (e.g., inducing charge delocalization and/or separation), the unique SPR role of the colloidal AuNPs in the catalytic reaction is assessable under light irradiation. This study experimentally demonstrates the possibility of evaluating the direct contribution of SPRs to photocatalytic chemical reactions., (© 2024. The Author(s).)

Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist, which passed phase III clinical trials and was newly approved in China for use as an adjunct to diet and exercise in glycemic control in adult patients with Type 2 Diabetes (T2D). To explore the circulating protein signatures associated with the administration of chiglitazar in T2D patients, we conducted a comparative longitudinal study using plasma proteome profiling. Of the 157 T2D patients included in the study, we administered chiglitazar to a specific group, while the controls were given either placebo or sitagliptin. The plasma proteomes were profiled at baseline and 12 and 24 weeks post-treatment using data-independent acquisition mass spectrometry (DIA-MS). Our study indicated that 13 proteins were associated with chiglitazar treatment in T2D patients, including 10 up-regulated proteins (SHBG, TF, APOA2, APOD, GSN, MBL2, CFD, PGLYRP2, A2M, and APOA1) and 3 down-regulated proteins (PRG4, FETUB, and C2) after treatment, which were implicated in the regulation of insulin sensitivity, lipid metabolism, and inflammation response. Our study provides insight into the response of chiglitazar treatment from a proteome perspective and demonstrates the multi-faceted effects of chiglitazar in T2D patients, which will help the clinical application of chiglitazar and further study of its action mechanism., (© 2024. The Author(s).)

The robustness and generalization of medical image segmentation models are being challenged by the differences between different disease types, different image types, and different cases.Deep learning based semantic segmentation methods have been providing state-of-the-art performance in the last few years. One deep learning technique, U-Net, has become the most popular architecture in the medical imaging segmentation. Despite outstanding overall performance in segmenting medical images, it still has the problems of limited feature expression ability and inaccurate segmentation. To this end, we propose a DTA-UNet based on Dynamic Convolution Decomposition (DCD) and Triple Attention (TA). Firstly, the model with Attention U-Net as the baseline network uses DCD to replace all the conventional convolution in the encoding-decoding process to enhance its feature extraction capability. Secondly, we combine TA with Attention Gate (AG) to be used for skip connection in order to highlight lesion regions by removing redundant information in both spatial and channel dimensions. The proposed model are tested on the two public datasets and actual clinical dataset such as the public COVID-SemiSeg dataset, the ISIC 2018 dataset, and the cooperative hospital stroke segmentation dataset. Ablation experiments on the clinical stroke segmentation dataset show the effectiveness of DCD and TA with only a 0.7628 M increase in the number of parameters compared to the baseline model. The proposed DTA-UNet is further evaluated on the three datasets of different types of images to verify its universality. Extensive experimental results show superior performance on different segmentation metrics compared to eight state-of-art methods.The GitHub URL of our code is https://github.com/shuaihou1234/DTA-UNet ., (© 2024. The Author(s).)

Adrenal gland hormones play a critical role in the development and maintenance of hypertension. Adrenal ablation has been used to treat primary aldosteronism but not essential hypertension. The present study aimed to investigate the effectiveness and safety of unilateral adrenal gland ablation in treating spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of anhydrous ethanol or a sham procedure. Blood pressure was monitored by both tail-cuff plethysmography and telemetry until 6 months after the procedure. Adrenal ablation significantly lowered systolic and diastolic blood pressure of the SHR (P < 0.05 or P < 0.01) but not WKY from 4 to 24 weeks after the procedure. Adrenal ablation substantially damaged adrenal cortex and medulla with fibrosis in SHR and WKY rats. The ablation procedure remarkably reduced the levels of renin, angiotensin II, aldosterone, cortisol, noradrenaline, and epinephrine in SHR (all P < 0.05) but not in WKY. Hypokalemia in SHR was significantly improved by adrenal ablation (P < 0.05), while the serum sodium levels were not affected by adrenal ablation in either SHR or WKY rats. Additionally, adrenal ablation improved cardiac, renal, and vascular remodeling and function measured 3 months after the procedure in SHR. In conclusion, the present study shows that ethanol ablation of adrenal gland can effectively lower blood pressure and prevent target organ damage in SHR. These findings suggest that unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension., Methods: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of ethanol or a sham procedure. Blood pressure was monitored for 24 weeks., Results: Adrenal ablation significantly lowered systolic and diastolic blood pressure of SHR but not WKY from 4 to 24 weeks after the procedure., Conclusion: Unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

More than 80 million people worldwide permanently live at high altitudes, and living in such a hypoxic environment can impair cognitive functions. However, it is largely unknown how long-term exposure to high altitude affects neural oscillations underlying these cognitive functions. The present study employed a Go/NoGo task to investigate the effects of long-term exposure to high altitude on neural oscillations during cognitive control. We compared event-related spectral perturbations between the low-altitude and high-altitude groups, and the results revealed increased theta event-related synchronization (ERS) and decreased alpha and beta event-related desynchronizations (ERDs) during the NoGo condition compared to the Go condition. Importantly, the high-altitude group showed reduced alpha and beta ERDs compared to the low-altitude group, while the theta ERS was not affected by altitude. We suggest that long-term exposure to high altitude has an impact on top-down inhibitory control and movement preparation and execution in the Go/NoGo task., (© 2023. The Author(s).)

Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal vascular malformations (AVMs), constituting approximately 70% of all spinal AVMs. The impact of various clinical and radiologic features on the outcomes in patients with SDAVFs is still controversial. The purpose of the study is to investigate the clinical outcomes and prognostic factors in patients with surgically treated SDAVFs in a single center. A retrospective review was performed for all patients with SDAVFs from January 2013 to September 2021 who underwent surgery at our institution. Medical records and pre- and postoperative imaging data were analyzed. Neurological function status was evaluated by modified Aminoff-Logue Scale (mALS). Student's t-test, Wilcoxon rank sum test, χ 2 test and logistic regression were used to find significant prognostic factors. P values < 0.05 were considered significant. One hundred and eighteen patients were ultimately included in the study. By comparing preoperative and postoperative mALS, 69 (58.5%) patients experienced improvement, and 49 (41.5%) patients showed no improvement (worse or unchanged). Wilcoxon rank sum test showed that there was a difference between the improvement group and the no improvement group in preoperative mALS Micturition score and preoperative mALS Defecation score. The logistic regression revealed that preoperative mALS Gait score was associated with clinical improvement after surgery in patients with SDAVFs. Surgical treatment of SDAVFs is a safe and effective procedure and can lead to symptom improvement or stabilization in most patients. Preoperative neurological function status was the only factor associated with clinical prognosis., (© 2023. Springer Nature Limited.)

Mitochondrial dysfunction plays a critical role in the pathogenesis of pathological cardiac hypertrophy. Transmembrane protein 117 modulate mitochondrial membrane potential that may be involved in the regulation of oxidative stress and mitochondrial function. However, its role in the development of angiotensin II (Ang-II)-induced cardiac hypertrophy is unclear. Cardiac-specific TMEM117-knockout and control mice were subjected to cardiac hypertrophy induced by Ang-II infusion. Small-interfering RNAs against TMEM117 or adenovirus-based plasmids encoding TMEM117 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) before Ang-II stimulation. We found that TMEM117 was upregulated in hypertrophic hearts and cardiomyocytes and TMEM117 deficiency attenuated Ang-II-induced cardiac hypertrophy in vivo. Consistently, the in vitro data demonstrated that Ang-II-induced cardiomyocyte hypertrophy significantly alleviated by TMEM117 knockdown. Conversely, overexpression of TMEM117 exacerbated cardiac hypertrophy and dysfunction. An Ang II-induced increase in cardiac (cardiomyocyte) oxidative stress was alleviated by cardiac-specific knockout (knockdown) of TMEM117 and was worsened by TMEM117 supplementation (overexpression). In addition, TMEM117 knockout decreased endoplasmic reticulum stress induced by Ang-II, which was reversed by TMEM117 supplementation. Furthermore, TMEM117 deficiency mitigated mitochondrial injury in hypertrophic hearts and cardiomyocyte, which was abolished by TMEM117 supplementation (overexpression). Taken together, these findings suggest that upregulation of TMEM117 contributes to the development of cardiac hypertrophy and the downregulation of TMEM117 may be a new therapeutic strategy for the prevention and treatment of cardiac hypertrophy., (© 2023. The Author(s).)

The role of lysophosphatidic acid (LPA) signaling in psychiatric disorders and drug abuse is significant. LPA receptors are widely expressed in the central nervous system, including the lateral habenula (LHb). Recent studies suggest that LHb is involved in a negative emotional state during alcohol withdrawal, which can lead to relapse. The current study examines the role of LHb LPA signaling in the negative affective state associated with alcohol withdrawal. Adult male Long-Evans rats were trained to consume either alcohol or water for eight weeks. At 48 h of withdrawal, alcohol-drinking rats showed anxiety- and depression-like symptoms, along with a significant increase in LPA signaling and related neuronal activation molecules, including autotaxin (ATX, Enpp2), LPA receptor 1/3 (LPA1/3), βCaMKII, and c-Fos. However, there was a decrease in lipid phosphate phosphatase-related protein type 4 (LPPR4) in the LHb. Intra-LHb infusion of the LPA1/3 receptor antagonist ki-16425 or PKC-γ inhibitor Go-6983 reduced the abnormal behaviors and elevated relapse-like ethanol drinking. It also normalized high LPA1/3 receptors and enhanced AMPA GluA1 phosphorylation in Ser831 and GluA1/GluA2 ratio. Conversely, selective activation of LPA1/3 receptors by intra-LHb infusion of 18:1 LPA induced negative affective states and upregulated βCaMKII-AMPA receptor phosphorylation in Naive rats, which were reversed by pretreatment with intra-LHb Go-6983. Our findings suggest that disturbances in LPA signaling contribute to adverse affective disorders during alcohol withdrawal, likely through PKC-γ/βCaMKII-linked glutamate signaling. Targeting LPA may therefore be beneficial for individuals suffering from alcohol use disorders., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Nintedanib reduces the decline in forced vital capacity and extends the time to the first acute exacerbation of interstitial lung disease (AE-ILD). However, the effect of additional nintedanib administration after AE-ILD onset is unknown. This study aimed to investigate the efficacy and safety of nintedanib administration after AE-ILD development. We retrospectively collected the data of 33 patients who developed AE-ILD between April 2014 and January 2022. Eleven patients who received nintedanib after AE-ILD development and the remaining who did not were classified into the N and No-N groups, respectively. The survival time in the N group tended to be longer than that in the No-N group. The generalized Wilcoxson test revealed that the cumulative mortality at 90 days from AE-ILD onset was significantly lower in the N group. The time to subsequent AE-ILD development was significantly longer in the N group than that in the No-N group. The incidence of adverse gastrointestinal effects and liver dysfunction in the N group was 9-18%. Treatment without nintedanib after AE-ILD development and the ratio of arterial oxygen partial pressure to fractional inspired oxygen were significant independent prognostic factors in the multivariate analysis. Thus, nintedanib administration may be a treatment option for AE-ILD., (© 2023. The Author(s).)

Diabetic cardiomyopathy (DCM), a common complication of diabetes, is defined as ventricular dysfunction in the absence of underlying heart disease. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in the development of DCM. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify key modules in DCM-related pathways. DCM-related miRNA-mRNA network and DCM-related ceRNA network were constructed by miRNA-seq to identify hub genes in these modules. We identified five hub genes that are associated with the onset of DCM, including Troponin C1 (Tnnc1), Phospholamban (Pln), Fatty acid binding proteins 3 (Fabp3), Popeye domain containing 2 (Popdc2), and Tripartite Motif-containing Protein 63 (Trim63). miRNAs that target the hub genes were mainly involved in TGF-β and Wnt signaling pathways. GO BP enrichment analysis found these miRNAs were involved in the signaling of TGF-β and glucose homeostasis. Q-PCR results found the gene expressions of Pln, Fabp3, Trim63, Tnnc1, and Popdc2 were significantly increased in DCM. Our study identified five hub genes (Tnnc1, Pln, Fabp3, Popdc2, Trim63) whose associated ceRNA networks are responsible for the onset of DCM., (© 2023. The Author(s).)

The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Here, observational study demonstrated no severe adverse effects were observed in KTRs and healthy participants (HPs) after first or second dose of SARS-CoV-2 inactivated vaccine. Different from HPs with excellent immunity against SARS-CoV-2, IgG antibodies against S1 subunit of spike protein, receptor-binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after the second dose of inactivated vaccine. Specific T cell immunity response was detectable in 40% KTRs after the second dose of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentrations. Multivariate logistic regression analysis found that blood unconjugated bilirubin and tacrolimus concentration were significantly negatively associated with SARS-CoV-2 specific T cell immunity response in KTRs. Altogether, these data suggest compared to humoral immunity, SARS-CoV-2 specific T cell immunity response are more likely to be induced in KTRs after administration of inactivated vaccine. Reduction of unconjugated bilirubin and tacrolimus concentration might benefit specific cellular immunity response in KTRs following vaccination., (© 2023. The Author(s).)

Metasurfaces are of great interest as they exhibit unique electromagnetic properties. Currently, metasurface design focuses on generating new meta-atoms and their combinations. Here a topological database, reticular chemistry structure resource (RCSR), is introduced to bring a new dimension and more possibilities for metasurface design. RCSR has over 200 two-dimensional crystal nets, among which 72 are identified as suitable for metasurface design. Using a simple metallic cross as the metaatom, 72 metasurfaces are constructed from the atom positions and lattice vectors of the crystal nets templates. The transmission curves of all the metasurfaces are calculated using the finite-difference time-domain method. The calculated transmission curves have good diversity, showing that the crystal nets approach is a new engineering dimension for metasurface design. Three clusters are found for the calculated curves using the K-means algorithm and principal component analysis. The structure-property relationship between metasurface topology and transmission curve is investigated, but no simple descriptor has been found, indicating that further work is still needed. The crystal net design approach developed in this work can be extended to three-dimensional design and other types of metamaterials like mechanical materials., (© 2023. The Author(s).)

Recent studies indicate that stimulation of the rostromedial tegmental nucleus (RMTg) can drive a negative affective state and that nociceptin/orphanin FQ (N/OFQ) may play a role in affective disorders and drug addiction. The N/OFQ precursor prepronociceptin encoding genes Pnoc are situated in RMTg neurons. To determine whether N/OFQ signaling contributes to the changes in both behavior phenotypes and RMTg activity of alcohol withdrawn (Post-EtOH) rats, we trained adult male Long-Evans rats, randomly assigned into the ethanol and Naïve groups to consume either 20% ethanol or water-only under an intermittent-access procedure. Using the fluorescence in situ hybridization technique combined with retrograde tracing, we show that the ventral tegmental area projecting RMTg neurons express Pnoc and nociceptin opioid peptide (NOP) receptors encoding gene Oprl1. Also, using the laser capture microdissection technique combined with RT-qPCR, we detected a substantial decrease in Pnoc but an increase in Oprl1 mRNA levels in the RMTg of Post-EtOH rats. Moreover, RMTg cFos expression is increased in Post-EtOH rats, which display anxiety- and depression-like behaviors. Intra-RMTg infusion of the endogenous NOP agonist nociceptin attenuates the aversive behaviors in Post-EtOH rats without causing any notable change in Naïve rats. Conversely, intra-RMTg infusion of the NOP selective antagonist [Nphe 1 ]nociceptin(1-13)NH 2 elicits anxiety- and depression-like behaviors in Naïve but not Post-EtOH rats. Furthermore, intra-RMTg infusion of nociceptin significantly reduces alcohol consumption. Thus, our results show that the deficiency of RMTg NOP signaling during alcohol withdrawal mediates anxiety- and depression-like behaviors. The intervention of NOP may help those individuals suffering from alcohol use disorders., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Prostate cancer (PCa) is the second most prevalent malignancy in males across the world. A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa. Herein, we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients, including gene mutations, mRNA/protein/surface protein distributions, and pharmaceutical responses. The multi-omics analyses identify Anterior Gradient 2 (AGR2) as a pre-operative prognostic biomarker in PCa. Through the drug library screening, we describe crizotinib as a selective compound for malignant PCa primary cells. We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations. Surprisingly, the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model. Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses, allowing for more precise diagnosis and therapies., (© 2023. The Author(s).)

With the continuous development of information technology and the running speed of computers, the development of informatization has led to the generation of increasingly more medical data. Solving unmet needs such as employing the constantly developing artificial intelligence technology to medical data and providing support for the medical industry is a hot research topic. Cytomegalovirus (CMV) is a kind of virus that exists widely in nature with strict species specificity, and the infection rate among Chinese adults is more than 95%. Therefore, the detection of CMV is of great importance since the vast majority of infected patients are in a state of invisible infection after the infection, except for a few patients with clinical symptoms. In this study, we present a new method to detect CMV infection status by analyzing high-throughput sequencing results of T cell receptor beta chains (TCRβ). Based on the high-throughput sequencing data of 640 subjects from cohort 1, Fisher's exact test was performed to evaluate the relationship between TCRβ sequences and CMV status. Furthermore, the number of subjects with these correlated sequences to different degrees in cohort 1 and cohort 2 were measured to build binary classifier models to identify whether the subject was CMV positive or negative. We select four binary classification algorithms: logistic regression (LR), support vector machine (SVM), random forest (RF), and linear discriminant analysis (LDA) for side-by-side comparison. According to the performance of different algorithms corresponding to different thresholds, four optimal binary classification algorithm models are obtained. The logistic regression algorithm performs best when Fisher's exact test threshold is 10 -5 , and the sensitivity and specificity are 87.5% and 96.88%, respectively. The RF algorithm performs better at the threshold of 10 -5 , with a sensitivity of 87.5% and a specificity of 90.63%. The SVM algorithm also achieves high accuracy at the threshold value of 10 -5 , with a sensitivity of 85.42% and specificity of 96.88%. The LDA algorithm achieves high accuracy with 95.83% sensitivity and 90.63% specificity when the threshold value is 10 -4 . This is probably because the two-dimensional distribution of CMV data samples is linearly separable, and linear division models such as LDA are more effective, while the division effect of nonlinear separable algorithms such as random forest is relatively inaccurate. This new finding may be a potential diagnostic method for CMV and may even be applicable to other viruses, such as the infectious history detection of the new coronavirus., (© 2023. The Author(s).)

Post-acute pancreatitis diabetes mellitus (PPDM-A) is the main component of pancreatic exocrine diabetes mellitus. Timely diagnosis of PPDM-A improves patient outcomes and the mitigation of burdens and costs. We aimed to determine risk factors prospectively and predictors of PPDM-A in China, focusing on giving personalized treatment recommendations. Here, we identify and evaluate the best set of predictors of PPDM-A prospectively using retrospective data from 820 patients with acute pancreatitis at four centers by machine learning approaches. We used the L1 regularized logistic regression model to diagnose early PPDM-A via nine clinical variables identified as the best predictors. The model performed well, obtaining the best AUC = 0.819 and F1 = 0.357 in the test set. We interpreted and personalized the model through nomograms and Shapley values. Our model can accurately predict the occurrence of PPDM-A based on just nine clinical pieces of information and allows for early intervention in potential PPDM-A patients through personalized analysis. Future retrospective and prospective studies with multicentre, large sample populations are needed to assess the actual clinical value of the model., (© 2023. The Author(s).)