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Author(s): D. D. Shoemaker [1]; E. E. Schadt [1]; C. D. Armour; Y. D. He; P. Garrett-Engele; P. D. McDonagh; P. M. Loerch; A. Leonardson; P. Y. Lum; G. Cavet; [...]

Multiple myeloma (MM), the world's second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment. In MM cells, TRIB3, USP10 and SSRP1 form a ternary complex and TRIB3 enhances the deubiquitinating effect of USP10 on SSRP1, leading to malignant progression of MM. In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All the samples of human MM patients used in the study were approved as ethical standards by the Ethics Committee of School of Life Sciences of Central South University and processed in accordance with approved procedure of the committee (approval No. 2022-1-42). Written informed consents were obtained from all patients prior to analysis. All in vivo experiments were approved by the Ethics Committee of School of life sciences of Central South University. Consent for publication: All co-authors have given their consent to the submitted version of the manuscript for publication., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The raccoon dog (Nyctereutes procyonoides), classified in the order Carnivora within the family Canidae, is native to East Asia and widely distributed throughout Japan due to its adaptability to various environments. Despite the close relationship between raccoon dogs and other animals, viruses infecting raccoon dogs have not been thoroughly investigated in Japan. In this study, we performed metatranscriptomic analyses using fecal samples collected from latrines of wild raccoon dogs in two locations on mainland Japan. Nearly complete viral genomes were identified, including viruses belonging to the genus Kobuvirus (CaKoV), an unclassified canine sapelovirus within the subfamily Ensavirinae (CaSaV), the Genius Mamastrovirus (CaAstV), unclassified hepe-astro-like virus (bastrovirus-like) (Bast-like V), and an unclassified dicistrovirus (DiciV) within the family Dicistroviridae. Phylogenetic analyses revealed that raccoon dog CaKoV, CaSaV, and CaAstV are related to canine strains but form independent clusters specific to raccoon dogs, suggesting they have evolved within this host population. Bast-like V, detected for the first time in raccoon dogs, showed high sequence identity with viruses previously identified in Chinese shrews. The shared insectivorous nature of these hosts and in silico host range predictions suggest that Bast-like Vs may originate from arthropod viruses. Although DiciV is likely of dietary origin due to its arthropod hosts, the large number of sequence reads detected and the phylogenetic clustering of raccoon dog DiciVs with mammalian DiciVs indicate the need to assess their potential infectivity in mammals and the risk of spillover. These findings suggest that raccoon dogs harbor endemic viruses within the canine population and may act as potential vectors for viruses with unknown infectivity in mammals but with spillover risk., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The present study was carried out according to the Fundamental Guidelines for Proper Conduct of Animal Experiments and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study is reported in accordance with ARRIVE guidelines ( https://arriveguidelines.org )., (© 2025. The Author(s).)

Early detection of cartilage injuries is crucial due to their limited self-repair capacity and risk of joint dysfunction. Conventional contrast agents like gadolinium-diethylenetriamine-pentaacetic acid (Gd-DTPA) offer low specificity and T1 relaxivity (r1), limiting MRI application. This study introduces NaGdF 4 nanoparticles (NPs) modified with polyethylene glycol (PEG) and cholesterol (CLS) to enhance hydrophilicity and lipophilicity. Targeting is achieved using a matrix metalloproteinase-13 (MMP13) cartilage-binding peptide. NaGdF 4 @PEG-CLS@MMP13 CBP NPs demonstrate an increased r1 value (8.07 mM -1  s -1 ) compared to NaGdF 4 @PEG-CLS NPs (6.65 mM -1  s -1 ) and Gd-DTPA (3.01 mM -1  s -1 ), enabling deeper cartilage penetration and stronger cartilage affinity. Two hours post-injection, these NPs improved the signal-to-noise ratio at injury sites by 2.4-fold over pre-injection values. Biocompatibility was confirmed with no adverse effects in blood or organs, and the NPs were metabolized in kidneys and liver, with excretion via urine. This study supports NaGdF 4 @PEG-CLS@MMP13 CBP NPs as an effective MRI contrast agent, enhancing early detection of cartilage injuries., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: All experimental protocols were approved by the Animal Care and Use Committee of Zhejiang University. All animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals”. ARRIVE guidelines statement: This study adhered to the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines to ensure transparency and scientific rigor in the design, execution, and reporting of animal experiments. Efforts were made to minimize the number of animals used, optimize the experimental design, and implement measures to reduce animal suffering to the greatest extent possible. All animal experiments were approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine and conducted in strict accordance with relevant laws, regulations, and ethical standards., (© 2025. The Author(s).)

Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control., Competing Interests: Competing interests: During the course of this research, D.R.G. consulted for or received support from Amgen, Ventus, ASHA, Boehringer Ingelheim, Mirumus, and Sonata. The authors declare no conflicts of interest. Ethics approval and consent to participate: All Mouse studies were conducted in accordance with protocols approved by the St. Jude Children’s Research Hospital Committee on Care and Use of Animals and in compliance with all relevant ethical guidelines., (© 2025. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Clay-type muddy interlayer is a key control factor leading to the instability of layered slopes, and it is of great significance to carry out the research on the shear characteristics of clay-type muddy interlayer for the safety and stability of layered slope projects. In this paper, the shear characteristics of clay-type muddy interlayer under different conditions of dry density and water moisture content are investigated by improving the test apparatus and data processing method. The results show that: the internal friction angle of clay-type muddy interlayer decreases with the increase of dry density under the condition of low moisture content, while the cohesion increases with the increase of dry density; at medium moisture content, both of them fluctuate with the dry density, but the amplitude is not large; at high moisture content, the response effect with dry density is not obvious. Therefore, higher dry density improves the shear properties of the soil by strengthening the friction and occlusion between particles, while increasing moisture content tends to weaken the shear properties, mainly due to the reduction of the lubrication effect of water, which gradually reduces the cementation between soil particles and the force of water film connection. On the one hand, the research results can enrich the complex mechanical response mechanism of clay-type muddy interlayer in different conditions, and on the other hand, it also provides a certain theoretical basis for the disaster prevention and early warning assessment of this kind of slope engineering., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

BCL-2 family proteins regulate apoptosis by initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors BAX and BAK is controlled by the interplay of anti-apoptotic BCL-2 proteins (e.g., MCL-1) and pro-apoptotic BH3-only proteins (e.g., BIM). Using a genome-wide CRISPR-dCas9 transactivation screen we identified BNIP5 as an inhibitor of BAK-, but not BAX-induced apoptosis. BNIP5 blocked BAK activation in different cell types and in response to various cytotoxic therapies. The BH3 domain of BNIP5 was both necessary and sufficient to block BAK activation. Mechanistically, the BH3 domain of BNIP5 acts as a selective BAK activator, but a poor de-repressor of complexes between BAK and pro-survival BCL-2 family proteins. By promoting the binding of activated BAK to MCL-1 or BCL-xL, BNIP5 inhibits apoptosis when BAX is absent. Based on our observations, BNIP5 can act functionally as an anti-apoptotic BH3-only protein., Competing Interests: Competing interests: The authors declare no competing interests. During the course of the work, D.R.G. consulted for Sonata Therapeutics, Ventus Therapeutics, and ASHA pharmaceuticals. S.R. is an employee of T3 Pharmaceuticals AG., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Osteoarthritis (OA) is characterized by the progressive degeneration of the synovial joint, leading to irreversible damage to articular cartilage and subchondral bone. While animal models have advanced our understanding of OA, numerous unresolved issues still remain. The zebrafish, known for its transparent body, rapid developmental, and impressive regenerative capabilities, offers substantial potential for osteoarthritis research. This study seeks to establish a new OA model utilizing the zebrafish jaw joint, acting as a supplement to traditional animal models. In the future, this model could serve as a valuable platform for delving deeper into the mechanisms of this disease, as well as for advancing drug discovery and therapeutic interventions. Leveraging the skeletal structure of zebrafish, we targeted the largest jaw joint for our research. A custom fixation device was crafted, and a microinjection system was utilized to inject mono-iodoacetate (MIA) or collagenase type II (CTII) into the joint cavity of zebrafish. Subsequent analyses included histological staining, immunohistochemistry, OA research society international (OARSI) scoring, and real-time in vivo imaging were performed at 7, 14, and 28 days post injection. Our results effectively demonstrated the presence of synovial inflammation and cartilage damage within the zebrafish mandible, affirming the feasibility of inducing OA in zebrafish. In conclusion, the local injection of chemical agents into the joint cavity of zebrafish effectively induced the occurrence of OA. Establishing the zebrafish OA model enhances the array of animal models available for OA research. Moreover, zebrafish present distinct advantages, including robust regenerative abilities, genetic editing simplicity, and efficient drug screening. Consequently, this offers a fresh avenue for investigating the pathogenesis, prevention, and potential therapeutic approaches for human OA., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was approved by Institutional Animal Care and Use Committee of the Research Institute of Surgery, Daping Hospital IACUC protocol SYXK- (Army) 2022-0003 and performed in strict with the institutional guidelines for care and use of laboratory animals., (© 2025. The Author(s).)

We propose a double-cavity optomechanical system with nonreciprocal coupling to realize tunable optical nonreciprocity that has the prospect of making an optical device for the manipulation of information processing and communication. Here we investigate the steady-state dynamic processes of the double-cavity system and the transmission of optical waves from opposite cavity directions. The transmission spectrum of the probe field is presented in detail and the physical mechanism of the induced transparency window is analyzed. It is found that the nonreciprocal response of the probe field transmission appears at two different coupling strengths between two cavities, which breaks the spatial symmetry to lead to optical nonreciprocal transmission. In addition, through analytical calculations, we have given the conditions for nonreciprocal effects, and the optimally nonreciprocal effects can be controlled by adjusting both the coupling strengths and the dissipation rates of cavity fields. Due to the simplicity of the device, this study may provide promising opportunities to realize nonreciprocal structures for optical wave transmission., Competing Interests: Declarations. Competing interest: The authors declare that there are no conflicts of interest related to this article., (© 2025. The Author(s).)

Heat shock proteins (HSPs) are a kind of molecular chaperone that helps protein folding, which is closely related to cancer. However, the association between HSPs and clear cell renal clear cell carcinoma (ccRCC) is uncertain. We explored the prognostic value of HSP110, HSP90, HSP70 and HSP60 families in ccRCC and their role in tumor immune microenvironment. The data obtained from the Cancer Genome Atlas (TCGA) were applied to determine the differential expression of HSPs in normal tissues and ccRCC. We comprehensively analyzed the prognostic value of HSPs in ccRCC and constructed a prognostic signature. We further explored the differences of tumor immune microenvironment and targeted therapy based on the signature. Cell proliferation, invasion and metastasis were detected by CCK8 assay, wound healing and transwell. Three clusters were identified with differences in overall survival and tumor stage. 6-gene signature (HSPA8, HSP90B1, HSPA7, HSPA12B, HSPA4L, HSPA1L) was identified to predict ccRCC patients' prognosis. The signature was confirmed in the internal cohort. Survival analysis, receiver operating characteristic (ROC) curve, univariate and multivariate COX regression analysis demonstrated the accuracy and independence of signature. The expression of HSPA7, HSPA8 and HSP90B1 were validated with quantitative real-time PCR. Our signature played a pivotal role in predicting tumor immune microenvironment, immune checkpoint gene expression, drug sensitivity, and tumor mutational burden (TMB) in patients with ccRCC. Our cellular experiments confirmed HSPA7 promotes the proliferation, invasion and metastasis of ccCRC cells. The HSPs signature identified in this study could serve as potential biomarkers for predicting prognosis and treatment response in ccRCC patients. It may provide new ideas for the current research on targeted therapy and immunotherapy strategies for ccRCC patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Elderly patients with multiple concomitant chronic diseases are the particularly vulnerable during the Coronavirus disease 2019 (COVID-19) epidemic, which accounts for a large number of COVID-19-related deaths. The purpose of the study was to investigate the impact of polypharmacy and potentially inappropriate medications (PIMs) on in-hospital mortality in a secondary hospital in China. A cross-sectional, retrospective study was conducted using electronic medical data collected from Shanghai Gonghui Hospital from April 2022 to June 2022. Two types of PIMs were adopted, involving the evaluation of the PIM status of older patients with COVID-19 (age ≥ 60 years) identified by AGS/Beers Criteria (PIM-Beers) and the PIM related to Covid-19 antiviral NMV/r (Nirmatrelvir/ritonavir) (PIM-NMV/r). Multivariate logistic regression was used to identify the risk factors associated with PIM use and in-hospital mortality. A total of 617 older COVID-19 inpatients were included in the study. The prevalence of polypharmacy and excessive polypharmacy were 24.6% and 19.1%, respectively. The prevalence of PIMs, PIM-Beers, and PIM-NMV/r were 25.8%, 22.5%, and 60.8%, respectively. Multivariate regression demonstrated that male (OR: 0.57 [95% CI: 0.33-0.98], p = 0.044), diabetes (OR: 2.05 [95% CI: 1.11-3.80], p = 0.023), the more number of medications (OR: 1.44 [95% CI: 1.20-1.72], p < 0.001) and given NMV/r (OR: 3.67 [95% CI: 1.48-9.10], p = 0.005) were influencing factors associated with PIM use. A multivariate logistic regression demonstrated that severe COVID-19 (OR: 6.56 [95% CI: 1.13-38.03], p = 0.036), polypharmacy (OR: 15.43 [95% CI: 3.20-74.29], p = 0.001), excessive polypharmacy (OR: 51.09 [95% CI: 5.23-499.52], p = 0.001), and long-term hospitalization (OR: 0.08 [95% CI: 0.02-0.32], p < 0.001) were influencing factors associated with in-hospital mortality in older COVID-19 inpatients. The polypharmacy and drug-drug interactions of NMV/r were observed in many older COVID-19 inpatients. Older patients with severe COVID-19, a higher number of medications and long-term hospitalization had a higher in-hospital mortality. This result highlights the importance of conducting clinical pharmacists-led medication reviews to identify PIMs of NMV/r and collaboratively working with the physicians to ensure medication appropriateness., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Superselective adrenal artery embolization (SAAE) offers a novel approach for treating primary aldosteronism (PA). In this study, we aimed to assess the efficacy and safety of SAAE for the treatment of PA based on the lateralization results obtained from adrenal vein sampling (AVS).In this prospective study, we enrolled 40 patients with PA who underwent SAAE. The patients were categorized into two groups, unilateral PA and bilateral PA, based on AVS results. Clinical parameters and biochemical markers were assessed at 3 and 12 months postoperatively. The primary outcomes were changes in blood pressure and defined daily dose (DDD) of antihypertensive medications compared to baseline. Thirty-eight patients achieved technical success, with favorable clinical and biochemical efficacy rates. At three months postoperatively, the clinical efficacy rates were 79.2% and 78.6% for the UPA and BPA groups, respectively. At 12 months, the rates were 83.3% and 71.4%, respectively. Both groups exhibited a significant decrease in average blood pressure at 3 and 12 months compared with baseline (P < 0.001), and there was also a notable reduction in DDD (P < 0.05). At three months, the biochemical efficacy rates were 61.9% and 58.3% in the UPA and BPA groups, respectively. Due to loss to follow-up, biochemical indicators were not assessed at 12 months postoperatively. No severe adverse reactions occurred during or after SAAE. Patients with both UPA and BPA can benefit from SAAE. The superiority of bilateral adrenal artery embolization in the treatment of BPA over unilateral adrenal artery embolization requires further investigation., 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.)

A three-dimensional numerical model of the vacuum sintering furnace was established, combined with the custom program of temperature-voltage feedback regulation. Through simulationand experimental validation, the heating and holding stage as well as the thermal hysteresis phenomenon of the furnace were analyzed, a dimensionless quantity of hysteresis temperature difference was proposed and calculated, the distribution of the electric field and temperature uniformity of the furnace were discussed in detail, while the structural improvement approach was proposed based on simulation. The results show that: during the heating process, the maximum of thermal hysteresis temperature difference between the graphite cylinder and the heating tube is 0.4. The relative error between the simulation and measurement is within 4%, which verifies the accuracy of the model. By optimizing the structure of the heating tube and graphite base plate, the thermal hysteresis effect of the furnace can be effectively reduced, the surface load and the temperature difference between the surface of the heater can be significantly reduced, the temperature field and uniformity of the heating zone can be improved., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The camouflage grouper (Epinephelus polyphekadion) is an economically carnivorous fish widely distributed in the Indo-Pacific. However, no valid reference genome of E. polyphekadion severely hinders further research on biology and genomic breeding programs. Here, we presented a high-quality chromosome-level genome assembly of E. polyphekadion using PacBio sequencing and Hi-C technologies. The chromosome-level genome has a total length of 1.1 Gb with a contig N50 of 40.8 Mb. Approximately 99.4% of the assembly lengths were anchored to 24 pseudochromosomes. In total, 25,165 protein-coding genes were predicted, among which 24,634 genes (97.9%) were functionally annotated. The completeness of the assembly was estimated to be 99.1% using BUSCO. In summary, the first reference genome of E. polyphekadion in this study will not only provide pivotal genetic resources for further biological and evolutionary studies of groupers, but also benefit the development of genomic hybridization breeding in the artificial grouper industry., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The mode mixing problem and inherent mode function selection bias in Fast Ensemble Empirical Mode Decomposition (FEEMD) result in ineffective extraction of fault components during the denoising stage, the loss of coarse-grained information in Multiscale Fuzzy Dispersion Entropy (MFDE) reduces the stability of fault features, and the lack of adaptability of CatBoost hyperparameters leads to reduced diagnostic accuracy. Therefore, a complex variable operating condition fault diagnosis method based on Fast Complementary Ensemble Empirical Mode Decomposition (FCEEMD) - Time-shift Multiscale Fuzzy Dispersion Entropy (TSMFDE) and adaptive Optuna-CatBoost is proposed. We introduce paired white noise with opposite signs in the construction of FCEEMD, effectively suppressing mode aliasing by neutralizing the residual noise generated during decomposition. Then, the Maximum Information Coefficient / Gini Index was introduced to construct a composite screening strategy, retaining the Intrinsic Mode Function (IMF) components that are strongly correlated with the original signal and have a fault impact to reconstruct the denoised signal. Secondly, time-shift multiscale is introduced into the coarse-grained process, and the constructed TSMFDE effectively extracts complete and stable fault features. Finally, with the introduction of the Optuna hyperparameter optimization framework, the adaptive Optuna-CatBoost can accurately diagnose bearing faults. The average fault diagnosis accuracy of the proposed method reached 99.76% and 99.33%, indicating that FCEEMD based on white noise can quickly and accurately decompose non-aliasing vibration modes, and the composite screening strategy can further filter out irrelevant noise modes and improve signal quality; The proposed TSMFDE can extract stable fault features, and its combination with Optuna-CatBoost can further improve the accuracy of fault diagnosis. This model is expected to be applied in more fields of feature extraction and pattern recognition., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Arthritis is one of the most common symptoms of Behcet's Disease (BD) observed in 57% of Japanese patients with BD. The relationship between arthritis and other clinical symptoms of BD and the impact of arthritis on the quality of life (QOL) of patients with BD are still unclear. Therefore, the current study aimed to clarify the differences in clinical symptoms depending on the presence or absence of arthritis and evaluate the impact of arthritis on QOL in these patients. Fifty-three Japanese patients diagnosed with BD and being treated for more than 6 months were included in this study. Patients were divided based on the presence of arthritis symptoms into an arthritis and a non-arthritis group. Clinical symptoms, disease activity, and QOL of both groups were compared using the Patient's global assessment (PGA), Evaluator's global assessment (EGA), and Behcet's disease current activity form (BDCAF) as indices of disease activity. To evaluate disease activity related to lesions other than arthritis, BDCAF excluding arthritis items was also calculated. The Behcet's disease quality of life (BDQOL) scale was used to assess patients' QOL. Oral ulcers and skin lesions were significantly more frequent in the arthritis group than in the non-arthritis group (p = 0.009 and 0.048, respectively). Among skin domains, papulopustular lesions tended to be more frequent in the arthritis group. EGA and BDCAF (both including and excluding arthritis-related items) scores were significantly higher in the arthritis group (p = 0.019, < 0.0001, and 0.0004 respectively). Although PGA and BDQOL tended to be higher in the arthritis group, the difference between the two groups was not statistically significant. The disease course in Japanese BD patients with arthritis was more frequently complicated by oral ulcers and skin lesions than in those without arthritis. In addition, BD patients with arthritis tended to have generally higher disease activity and low QOL than their non-arthritis counterparts. Further research is required to confirm these results., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Faculty of Medicine, Kagawa University (2023-057) and conducted in accordance with the Declaration of Helsinki. The Ethics Committee of the Faculty of Medicine at Kagawa University waived the need for written informed consent due to the retrospective nature of the study., (© 2024. The Author(s).)

Vibratory rollers are generally used in the process of highway subgrade compaction. In the paper, the vibratory roller-subgrade finite element model was established to simulate the field construction by using ABAQUS. We used Hilbert-Huang Transform to analyze the compaction in the field test from the time-frequency domain. By changing the parameters of the vibratory roller and the filler, the comprehensive influence of the parameters such as the elastic modulus of the filler, rolling speed, excitation force, vibration frequency and thickness of the filler on the compaction quality of the subgrade was investigated. We studied the propagation pattern of vibration waves in three-dimensional space. The study shows that the signals of different frequency bands in the Hilbert spectrum represent the compaction degrees of fillers in different zones. The peak acceleration generally decreases with the increase of horizontal and vertical distance, but there is an increase at the boundary of the vibration field. There is an optimal combination of the excitation force, vibration frequency and thickness of the filler. The vibration waves propagate in the form of an ellipsoid in three dimensions, and the amplitude decreases with distance., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Sebaceous carcinoma is difficult to distinguish from chalazion due to their rarity and clinicians' limited experience. This study investigated the potential of AI-generated image training to improve diagnostic skills for these eyelid tumors compared to traditional video lecture-based education. Students from Orthoptics, Optometry, and Vision Research (n = 55) were randomly assigned to either an AI-generated image training group or a traditional video lecture group. Diagnostic performance was assessed using a 50-image quiz before and after the intervention. Both groups showed significant improvement in overall diagnostic accuracy (p < 0.001), with no significant difference between groups (p = 0.124). In the AI group, all 25 chalazion images showed improvement, while only 6 out of 25 sebaceous carcinoma images improved. The video lecture group showed improvement in 19 out of 25 chalazion images and 24 out of 25 sebaceous carcinoma images. The proportion of images with improved accuracy was significantly higher in the AI group for chalazion (P = 0.022) and in the video group for sebaceous carcinoma (P < 0.001). These findings suggest that AI-generated image training can enhance diagnostic skills for rare conditions, but its effectiveness depends on the quality and quantity of patient images used for optimization. Combining AI-generated image training with traditional video lectures may lead to more effective educational programs. Further research is needed to explore AI's potential in medical education and improve diagnostic skills for rare diseases., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid-liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Ca v 1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology., Competing Interests: Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Existing tensioning cable prestress ensures bridge safety. This work presents the micro-hole release technique, which accurately measures the effective prestress of strands in existing prestressed concrete bridges. The strand drilling model was produced in Solidworks and Abaqus. The effect of drilling depth, diameter, deflection angle, and hole edge distance on strand stress release was then examined. The findings indicate that strand drilling tension relief is directly related to hole depth and diameter. As aperture size increases, stress alleviation decreases. The stress release error rate increases as the strand drilling deflection angle increases from 0° to 15°. Portable electric drill bits are 1.5 mm. A 5.0 mm hole was bored into the steel wire. The steel strand drilling wire is 3.0 mm from the hole's edge. The drill bit is designed to maintain a drilling deflection angle of less than 5°, ensuring accuracy and ease of testing. After that, the 1860 grade strand drilling test was used to compare stress release and associated circumstances between P-T and T-P operating conditions. The strain-tension fitting equations for strand release were compared to finite element simulation results under P-T and T-P operating conditions. We found that the formula for fitting the strain-tension force of strand release under T-P condition matches finite element simulation results. It also matches real-world engineering methods., (© 2024. The Author(s).)

This study aimed to find the association between four common clinical biomarkers and subsequent ICICT, developing a risk scoring strategy to assess the ICICT risk. Three terminals for ICICT were : Terminal 1, cancer therapy-related cardiomyopathies; Terminal 2, myocarditis or heart failure; and Terminal 3, myocarditis, heart failure, myocardial infarction, cerebral infarction, atrial fibrillation, or death. The thresholds were : N-terminal-pro-B-type-natriuretic-peptide ≥ 125 pg/mL, cardiac troponin T ≥ 6 ng/L, high-sensitivity C-reactive protein ≥ 3 mg/L, and coronary artery calcium score > 10 U. Each of the four abnormal biomarkers received 1 point. The links between biomarkers, score stage, and ICICT were analyzed. 375 patients with a mean follow-up of 1.91 years were included. All four biomarkers measured before immunotherapy were associated with a higher risk of developing ICICT. These scores were also associated with ICICT risk. The highest risk was the very high stage (score = 4) has 7.29, 8.83, and 7.02 folder higher risk compared to low risk group for Terminal 1-3, respectively. The cumulation of incidences also showed that the higher stages of score had an earlier onset and higher incidence of ICICT. 4 biomarkers and the scoring strategy enables clinicians to assess risk easily., (© 2024. The Author(s).)

Black soldier fly larvae (BSFL) could convert a variety of organic wastes, including spent mushroom substrate (SMS) and wet distiller's grains (WDG). Nevertheless, little is known about the conversion of these wastes by BSFL. Thus, this study investigates the conversion of SMS and WDG in five different proportions by BSFL. This study demonstrates that BSFL can convert SMS, WDG, and their mixtures. It can also encourage the humification of the substrate, increasing the amount of element in the residues. It is evident that there were differences in the carbon and nitrogen element fractionation mode as well as the microbial community present in the residue. The microbial community of the substrate and the physiochemical parameters are intimately related to this. Although the mixture treated with BSFL helps to generate a residue with more humus, it might not be stable., (© 2024. The Author(s).)

Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed β-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with β-cell dysfunction, the most common type of T2D in East Asian countries, including Japan., (© 2024. The Author(s).)

The early diagnosis of esophageal cancer (EC) is extremely challenging due to a lack of effective diagnostic methods. The study presented herein aims to assess whether serum volatile organic compounds (VOCs) could be utilised as emerging diagnostic biomarkers for EC. Gas chromatography-ion mobility spectrometry (GC-IMS) was used to detect VOCs in the serum samples of 55 patients with EC, with samples from 84 healthy controls (HCs) patients analysed as a comparison. All machine learning analyses were based on data from serum VOCs obtained by GC-IMS. A total of 33 substance peak heights were detected in all patient serum samples. The ROC analysis revealed that four machine learning models were effective in facilitating the diagnosis of EC. In addition, the random forests model for 5 VOCs had an AUC of 0.951, with sensitivities and specificities of 94.1 and 96.0%, respectively., (© 2024. The Author(s).)

The emergence of biomagnetism imaging has led to the development of ultrasensitive and compact spin-exchange relaxation-free (SERF) atomic magnetometers that promise high-resolution magnetocardiography (MCG) and magnetoencephalography (MEG). However, conventional optical components are not compatible with nanofabrication processes that enable the integration of atomic magnetometers on chips, especially for elliptically polarized laser-pumped SERF magnetometers with bulky optical systems. In this study, an elliptical-polarization pumping beam (at 795 nm) is achieved through a single-piece metasurface, which results in an SERF magnetometer with a high sensitivity reaching 10.61 fT/Hz 1/2 by utilizing a 87 Rb vapor cell with a 3 mm inner diameter. To achieve the optimum theoretical polarization, our design combines a computer-assisted optimization algorithm with an emerging metasurface design process. The metasurface is fabricated with 550 nm thick silicon-rich silicon nitride on a 2 × 2  cm 2 SiO 2 substrate and features a 22.17° ellipticity angle (a deviation from the target polarization of less than 2%) and more than 80% transmittance. This study provides a feasible approach for on-chip polarization control of future all-integrated atomic magnetometers, which will further pave the way for high-resolution biomagnetism imaging and portable atomic sensing applications., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2024.)

Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval., (© 2024. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis., (© 2024. The Author(s).)

Prediction of glioma is crucial to provide a precise treatment plan to optimize the prognosis of children with glioma. However, studies on the grading of pediatric gliomas using radiomics are limited. Meanwhile, existing methods are mainly based on only radiomics features, ignoring intuitive information about tumor morphology on traditional imaging features. This study aims to utilize multiparametric magnetic resonance imaging (MRI) to identify high-grade and low-grade gliomas in children and establish a classification model based on radiomics features and clinical features. A total of 85 children with gliomas underwent tumor resection, and part of the tumor tissue was examined pathologically. Patients were categorized into high-grade and low-grade groups according to World Health Organization guidelines. Preoperative multiparametric MRI data, including contrast-enhanced T1-weighted imaging, T2-weighted imaging, T2-weighted fluid-attenuated inversion recovery, diffusion-weighted images, and apparent diffusion coefficient sequences, were obtained and labeled by two radiologists. The images were preprocessed, and radiomics features were extracted for each MRI sequence. Feature selection methods were used to select radiomics features, and statistically significant clinical features were identified using t-tests. The selected radiomics features and conventional MRI features were used to train the AutoGluon models. The improved model, based on radiomics features and conventional MRI features, achieved a balanced classification accuracy of 66.59%. The cross-validated areas under the receiver operating characteristic curve for the classifier of AutoGluon frame were 0.8071 on the test dataset. The results indicate that the performance of AutoGluon models can be improved by incorporating conventional MRI features, highlighting the importance of the experience of radiologists in accurately grading pediatric gliomas. This method can help predict the grade of pediatric glioma before pathological examination and assist in determining the appropriate treatment plan, including radiotherapy, chemotherapy, drugs, and gene surgery., (© 2024. The Author(s).)

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach., (© 2024. The Author(s).)

To systematically analyze the damage caused by bedrock and overburden layer slope under seismic action, a set of large-scale shaking table test was designed and completed. Interpolation of the acceleration amplification coefficient, Hilbert-Huang transform and transfer function was adopted. The damage mechanisms of the bedrock and overburden layer slopes under seismic action are systematically summarized in terms of slope displacement, acceleration field, vibration amplitude, energy, vibration frequency, and damage level. The results show a significant acceleration amplification effect within the slope under seismic action and a localized amplification effect at the top and trailing edges of the slope. With an increase in the input seismic intensity, the difference in the vibration amplitude between the overburden layer and bedrock increased, low-frequency energy of the overburden layer was higher than that of the bedrock, and the vibration frequency of the overburden layer was smaller than that of the bedrock. These differences cause the interface to experience cyclic loading continuously, resulting in the damage degree of the overburden layer at the interface being larger than that of the bedrock, reduction of the shear strength, and eventual formation of landslides. The displacement in the middle of the overburden is always greater than that at the top. Therefore, under the action of an earthquake and gravity, the damage mode of the bedrock and overburden layer slope is such that the leading edge of the critical part pulls and slides at the trailing edge, and multiple tensile cracks are formed on the slope surface., (© 2024. The Author(s).)

We investigated the association of retinopathy with the risk of dementia in a general older Japanese population. A total of 1709 population-based residents aged 60 years or older without dementia were followed prospectively for 10 years (2007-2017). They underwent color fundus photography in 2007. Retinopathy was graded according to the Modified Airlie House Classification. Main outcome was the Incidence of dementia. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for the risk of dementia by the presence of retinopathy. During the follow-up period, 374 participants developed all-cause dementia. The cumulative incidence of dementia was significantly higher in those with retinopathy than those without (p < 0.05). Individuals with retinopathy had significantly higher risk of developing dementia than those without after adjustment for potential confounding factors (HR 1.64, 95% CI 1.19-2.25). Regarding the components of retinopathy, the presence of microaneurysms was significantly associated with a higher multivariable-adjusted HR for incident dementia (HR 1.94, 95% CI 1.37-2.74). Our findings suggest that, in addition to systemic risk factors, retinal microvascular signs from fundus photography provide valuable information for estimating the risk of developing dementia., (© 2024. The Author(s).)

Kinetic aspects of enzymatic reactions are described by equations based on the Michaelis-Menten theory for the initial stage. However, the kinetic parameters provide little information on the atomic mechanism of the reaction. In this study, we analyzed structures of glutamate dehydrogenase in the initial and steady stages of the reaction using cryoEM at near-atomic resolution. In the initial stage, four metastable conformations displayed different domain motions and cofactor/ligand association modes. The most striking finding was that the enzyme-cofactor-substrate complex, treated as a single state in the enzyme kinetic theory, comprised at least three different metastable conformations. In the steady stage, seven conformations, including derivatives from the four conformations in the initial stage, made the reaction pathway complicated. Based on the visualized conformations, we discussed stage-dependent pathways to illustrate the dynamics of the enzyme in action., (© 2024. The Author(s).)

Methods that enable specific and sensitive quantification of small extracellular vesicles (sEVs) using flow cytometry are still under development. Aggregation or adsorption of antibodies causes sub-nano sized particles or non-specific binding and largely affects the results of flow cytometric analysis of single sEVs. Comparison of control IgG and target-specific IgG is inappropriate because they have different characters. Here, we evaluate four preparation methods for flow cytometry, including ultracentrifugation, density gradient centrifugation, size exclusion chromatography (SEC), and the TIM4-affinity method by using tetraspanin-deficient sEVs. The ultracentrifugation or density gradient centrifugation preparation method has large false-positive rates for tetraspanin staining. Conversely, preparation methods using SEC or the TIM4-affinity method show specific detection of single sEVs, which elucidate the roles of sEV biogenesis regulators in the generation of sEV subpopulations. The methods are also useful for the detection of rare disease-related markers, such as PD-L1. Flow cytometric analysis using SEC or the TIM4-affinity method could accelerate research into sEV biogenesis and the development of sEV-based diagnostics and therapies., (© 2024. The Author(s).)

In recent years, the association between neuroinflammatory markers and dementia, especially Alzheimer's disease (AD), has attracted much attention. However, the evidence for the relationship between serum-hs-CRP and dementia including AD are inconsistent. Therefore, the relationships of serum high-sensitivity CRP (hs-CRP) with dementia including AD and with regions of interest of brain MRI were investigated. A total of 11,957 community residents aged 65 years or older were recruited in eight sites in Japan (JPSC-AD Study). After applying exclusion criteria, 10,085 participants who underwent blood tests and health-related examinations were analyzed. Then, serum hs-CRP levels were classified according to clinical cutoff values, and odds ratios for the presence of all-cause dementia and its subtypes were calculated for each serum hs-CRP level. In addition, the association between serum hs-CRP and brain volume regions of interest was also examined using analysis of covariance with data from 8614 individuals in the same cohort who underwent brain MRI. After multivariable adjustment, the odds ratios (ORs) for all-cause dementia were 1.04 (95% confidence interval [CI] 0.76-1.43), 1.68 (95%CI 1.08-2.61), and 1.51 (95%CI 1.08-2.11) for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L, and those for AD were 0.72 (95%CI 0.48-1.08), 1.76 (95%CI 1.08-2.89), and 1.61 (95%CI 1.11-2.35), for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L. Multivariable-adjusted ORs for all-cause dementia and for AD prevalence increased significantly with increasing serum hs-CRP levels (p for trend < 0.001 and p = 0.001, respectively). In addition, the multivariable-adjusted temporal cortex volume/estimated total intracranial volume ratio decreased significantly with increasing serum hs-CRP levels (< 1.0 mg/L 4.28%, 1.0-1.9 mg/L 4.27%, 2.0-2.9 mg/L 4.29%, ≥ 3.0 mg/L 4.21%; p for trend = 0.004). This study's results suggest that elevated serum hs-CRP levels are associated with greater risk of presence of dementia, especially AD, and of temporal cortex atrophy in a community-dwelling Japanese older population., (© 2024. The Author(s).)

Urinary incontinence is a common disease among middle-aged and elderly women, which not only affects the physical and mental health of patients, but also brings a great medical burden to society. Obesity is a known risk factor for urinary incontinence and is the most common secondary cause of hyperlipidemia. Most obese patients also suffer from hyperlipidemia in the clinic. However, few studies have explored the role of hyperlipidemia in women with urinary incontinence. Using data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES), we aimed to evaluated the independent associations of high body mass index and hyperlipidemia with urinary incontinence in Americans by conducting a weighted multivariate logistic regression model. Additive interactions were also assessed using the relative excess risk due to interaction (RERI), attributed proportion of interaction (AP) and synergy index (S). This study demonstrated that hyperlipidemia was associated with a higher risk of stress urinary incontinence among women with obesity (OR = 1.52, 95% CI = 1.03-2.25), and there was a significant synergistic effect of hyperlipidemia and obesity on stress urinary incontinence(adjusted RERI: 3.75, 95% CI 0.30-7.20; adjusted AP: 0.67, 95% CI 0.54-0.80; adjusted S: 5.49, 95% CI 4.15-7.27). Moreover, fasting serum triglyceride lipids were the most relevant blood lipid indicator for the risk of stress urinary incontinence, especially among obese women younger than 50 years old, which contributes to the development of more refined lipid control protocols for patients with urinary incontinence in different age groups., (© 2024. The Author(s).)

Large language models (LLMs) have the potential to transform our lives and work through the content they generate, known as AI-Generated Content (AIGC). To harness this transformation, we need to understand the limitations of LLMs. Here, we investigate the bias of AIGC produced by seven representative LLMs, including ChatGPT and LLaMA. We collect news articles from The New York Times and Reuters, both known for their dedication to provide unbiased news. We then apply each examined LLM to generate news content with headlines of these news articles as prompts, and evaluate the gender and racial biases of the AIGC produced by the LLM by comparing the AIGC and the original news articles. We further analyze the gender bias of each LLM under biased prompts by adding gender-biased messages to prompts constructed from these news headlines. Our study reveals that the AIGC produced by each examined LLM demonstrates substantial gender and racial biases. Moreover, the AIGC generated by each LLM exhibits notable discrimination against females and individuals of the Black race. Among the LLMs, the AIGC generated by ChatGPT demonstrates the lowest level of bias, and ChatGPT is the sole model capable of declining content generation when provided with biased prompts., (© 2024. The Author(s).)

Post-COVID-19 syndrome may be associated with the abnormal immune status. Compared with the unexposed age-matched elder group, PD-1 in the CD8 + T cells from recovered COVID-19 patients was significantly lower. IFN-γ in the plasma of COVID-19 convalescent patients was increased, which inhibited PD-1 expression in CD8 + T cells from COVID-19 convalescent patients. scRNA-seq bioinformatics analysis revealed that AKT/GSK3β may regulate the INF-γ/PD-1 axis in CD8 + T cells from COVID-19 convalescent patients. In parallel, an IFN-γ neutralizing antibody reduced AKT and increased GSK3β in PBMCs. An AKT agonist (SC79) significantly decreased p-GSK3β. Moreover, AKT decreased PD-1 on CD8 + T cells, and GSK3β increased PD-1 on CD8 + T cells according to flow cytometry analysis. Collectively, we demonstrated that recovered COVID-19 patients may develop long COVID. Increased IFN-γ in the plasma of recovered Wuhan COVID-19 patients contributed to PD-1 downregulation on CD8 + T cells by regulating the AKT/GSK3β signaling pathway., (© 2024. The Author(s).)

Spatial, momentum and energy separation of electronic spins in condensed-matter systems guides the development of new devices in which spin-polarized current is generated and manipulated 1-3 . Recent attention on a set of previously overlooked symmetry operations in magnetic materials 4 leads to the emergence of a new type of spin splitting, enabling giant and momentum-dependent spin polarization of energy bands on selected antiferromagnets 5-10 . Despite the ever-growing theoretical predictions, the direct spectroscopic proof of such spin splitting is still lacking. Here we provide solid spectroscopic and computational evidence for the existence of such materials. In the noncoplanar antiferromagnet manganese ditelluride (MnTe 2 ), the in-plane components of spin are found to be antisymmetric about the high-symmetry planes of the Brillouin zone, comprising a plaid-like spin texture in the antiferromagnetic (AFM) ground state. Such an unconventional spin pattern, further found to diminish at the high-temperature paramagnetic state, originates from the intrinsic AFM order instead of spin-orbit coupling (SOC). Our finding demonstrates a new type of quadratic spin texture induced by time-reversal breaking, placing AFM spintronics on a firm basis and paving the way for studying exotic quantum phenomena in related materials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Onoceroids are a rare family of triterpenes. One representative onoceroid is ambrein, which is the main component of ambergris used as a traditional medicine. We have previously identified the onoceroid synthase, BmeTC, in Bacillus megaterium and succeeded in creating ambrein synthase by introducing mutations into BmeTC. Owing to the structural similarity of ambrein to vitamin D, a molecule with diverse biological activities, we hypothesized that some of the activities of ambergris may be induced by the binding of ambrein to the vitamin D receptor (VDR). We demonstrated the VDR binding ability of ambrein. By comparing the structure-activity relationships of triterpenes with both the VDR affinity and osteoclastic differentiation-promoting activity, we observed that the activity of ambrein was not induced via the VDR. Therefore, some of the activities of ambergris, but not all, can be attributed to its VDR interaction. Additionally, six unnatural onoceroids were synthesized using the BmeTC reactions, and these compounds exhibited higher VDR affinity than that of ambrein. Enzymatic syntheses of onoceroid libraries will be valuable in creating a variety of bioactive compounds beyond ambergris., (© 2024. The Author(s).)

Unmanned Aerial Vehicles are useful tools for many applications. However, autonomous path planning for Unmanned Aerial Vehicles in unfamiliar environments is a challenging problem when facing a series of problems such as poor consistency, high influence by the native controller of the Unmanned Aerial Vehicles. In this paper, we investigate reinforcement learning-based autonomous local path planning methods for Unmanned Aerial Vehicles with high autonomous decision-making capability and locally high portability. We propose an autonomous local path planning algorithm based on the TD3 strategy to solve the problem of local obstacle avoidance and path planning in unfamiliar environments using autonomous decision-making of Unmanned Aerial Vehicles. The simulation results on Gazebo show that our method can effectively realize the autonomous local path planning task for Unmanned Aerial Vehicles, the success rate of path planning with our method can reach 93% under the interference of no obstacles, and 92% in the environment with obstacles. Finally, our method can be used for autonomous path planning of Unmanned Aerial Vehicles in unfamiliar environments., (© 2024. The Author(s).)

Uridine, a pyrimidine nucleoside, is crucial in the synthesis of metabolites. According to observational studies, a higher plasma uridine level is associated with a lower risk of atrial fibrillation (AF). However, the casual relationship between uridine and AF is still unknown. In this study, we used the Mendelian randomisation (MR) approach to explore causality. Three genetic variants associated with uridine were identified from the Metabolomics GWAS server (7824 participants); summary-level datasets associated with AF were acquired from a genome-wide association study (GWAS) meta-analysis with 1,030,836 European participants (60,620 AF cases). We duplicated the MR analyses using datasets from AF HRC studies and the FinnGen Consortium, and then conducted a meta-analysis which combined the main results. The risk of AF was significantly associated with the genetically determined plasma uridine level (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.16, 0.47; p = 2.39 × 10 -6 ). The association remained consistent in the meta-analysis of the various datasets (OR 0.27; 95% CI 0.17, 0.42; p = 1.34 × 10 -8 ). In conclusion, the plasma uridine level is inversely associated with the risk of AF. Raising the plasma uridine level may have prophylactic potential against AF., (© 2023. The Author(s).)

In the field of rare and intractable diseases, new drug development is difficult and drug repositioning (DR) is a key method to improve this situation. In this study, we present a new method for finding DR candidates utilizing virtual screening, which integrates amino acid interaction mapping into scaffold-hopping (AI-AAM). At first, we used a spleen associated tyrosine kinase inhibitor as a reference to evaluate the technique, and succeeded in scaffold-hopping maintaining the pharmacological activity. Then we applied this method to five drugs and obtained 144 compounds with diverse structures. Among these, 31 compounds were known to target the same proteins as their reference compounds and 113 compounds were known to target different proteins. We found that AI-AAM dominantly selected functionally similar compounds; thus, these selected compounds may represent improved alternatives to their reference compounds. Moreover, the latter compounds were presumed to bind to the targets of their references as well. This new "compound-target" information provided DR candidates that could be utilized for future drug development., (© 2023. The Author(s).)

Surface coal mining procedures include piercing-blasting-mining and loading-transportation-discharging, blasting link exists due to the poor blasting effect leads to low loading efficiency, blasting dust caused by environmental pollution and other problems. In this paper, from the mechanical characteristics of the water medium, we analyze in detail the transferring effect, transducing effect and bubble pulsation phenomenon of the water medium in the blasting process. The results show that when the blasting medium is water medium, the maximum principal stress is 1.53 times that of air medium; the peak energy transfer can be up to 2.73 times that of air medium. With the help of TrueGrid/LS-DYNA finite element analysis software to simulate the dynamic process of blasting, the study of the maximum principal stresses around the hole, the top of the slope, the foot of the slope on the maximum principal stress changes, the results show that the maximum principal stresses around the hole, the top of the slope, the foot of the slope unit with the increase in the water content is gradually increasing trend. Finally, combined with the actual mine production conditions for blasting field test, water-mediated blasting dust reduction rate of 75%, the use of AHP-fuzzy comprehensive evaluation method of two groups of traditional dry hole blasting and three groups of water-mediated blasting comprehensive evaluation, the results show that the water-mediated blasting scores are higher than the traditional dry hole blasting, proving that the water-mediated blasting has a certain prospect of engineering applications., (© 2023. The Author(s).)

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive 1,2 . Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy., (© 2023. The Author(s).)

Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ferroptosis among cell populations in a wave-like manner, developing the "wave of ferroptosis" causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the "wave of ferroptosis" in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the "wave of ferroptosis" propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m 6 A) RNA modification occurs in HPSCC. The expression of the m 6 A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an m 6 A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m 6 A modification, which could be recognized by the m 6 A readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for m 6 A demethylation of mRNA in HPSCC. The inhibition of m 6 A modification of ALKBH5 in HPSCC deserves further clinical investigation., (© 2023. Cell Death Differentiation Association (ADMC).)

Urogenital congenital anomalies (UCAs) is defined as "any live-birth with a urinary or genital condition" and affects millions of men and women worldwide. However, sex differences and related environmental risk factors in UCAs burden on a global scale have not been assessed. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we estimated prevalence, incidence, mortality and disability-adjusted life years (DALYs) of UCAs from 1990 to 2019 by sex, region, and socio-demographic Index (SDI) in 204 countries and territories. The disease burden of UCAs was also estimated attributable to each risk factor were estimated according to risk exposure. In 2019, UCAs caused 10,200 all-ages deaths (95% UI 7550-13,400). The combined global incidence rate was 8.38 per 1000 (95% UI 5.88-12.0) live births. The ASIR increased slightly, while the ASDR decreased from 1990 to 2019.The UCAs burden varies greatly depending on the development level and geographical location. The UCAs burden was significantly higher in men than in women, and the sex differences showed an enlarging trend. Health risks and issues, including pollution, child and maternal malnutrition, diet habits, unsafe sanitation and water source, were detected to be positively related to UCAs burden. Albeit the age-standardised prevalence, mortality, incidence, and DALYs of UCAs have decreased, they still cause a public health challenge worldwide. The high deaths and DALYs rates in low and low-middle SDI countries highlight the urgent need for improved preventive, diagnostic, and therapeutic measures. Global strategies for enhancing water safety, reducing pollution, and healthy diets are crucial steps in reducing the burden of UCAs., (© 2023. Springer Nature Limited.)

Quantitative sensory testing (QST) is useful when analysing musculoskeletal pain disorders. A handheld algometer is most commonly used for pressure pain threshold (PPT) tests. However, reference intervals for PPTs are not elucidated. We assessed reference intervals of PPTs for QST in 158 healthy adult Japanese with no history of musculoskeletal or neurological problems. A handheld algometer was used to record PPT at five different assessment sites on the body: lumbar paravertebral muscle, musculus gluteus maximus, quadriceps, tibialis anterior muscle, and anterior talofibular ligament. Multiple regression analysis was performed to explore sources of variation of PPT according to sex, age, body mass index, UCLA Activity Level Rating, and Tegner Activity Score. Reference intervals were determined parametrically by Gaussian transformation of PPT values using the two-parameter Box-Cox formula. Results of multiple regression analysis revealed that age was significantly associated with PPT of lumbar paravertebral muscle and musculus gluteus maximus. In females, body mass index showed significant positive correlation with PPT of anterior talofibular ligament, and UCLA Activity Level Rating also showed significant positive association with tibialis anterior muscle and anterior talofibular ligament. Site-specific reference intervals of PPTs for Japanese are of practical relevance in fields of pain research using a handheld algometer., (© 2023. Springer Nature Limited.)