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Abstract This study introduces a method to predict the remaining useful life (RUL) of plain bearings operating under stationary, wear-critical conditions. In this method, the transient wear data of a coupled elastohydrodynamic lubrication (mixed-EHL) and wear simulation approach is used to parametrize a statistical, linear degradation model. The method incorporates Bayesian inference to update the linear degradation model throughout the runtime and thereby consider the transient, system-dependent wear progression within the RUL prediction. A case study is used to show the suitability of the proposed method. The results show that the method can be applied to three distinct types of post-wearing-in behavior: wearing-in with subsequent hydrodynamic, stationary wear, and progressive wear operation. While hydrodynamic operation leads to an infinite lifetime, the method is successfully applied to predict RUL in cases with stationary and progressive wear.

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described.Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642).Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population.Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.

Background: To test efficacy, HIV cure-related trials often require a period of intensively monitored interruption of antiretroviral therapy (ART) (analytical treatment interruption or ATI). As individuals who started ART during primary HIV-1 infection (PHI) are often recruited, we have asked people already enrolled into an observational PHI study about their willingness and concerns around participating in cure-related studies involving ATIs. Methods: People who were diagnosed with PHI and started ART, attending two London HIV clinics, provided informed consent to complete a digital survey in clinic between 21/07/21 to October 31, 2023. Questions comprised sociodemographics, motivations, concerns and practical considerations influencing willingness to participate in studies involving ATIs. Hierarchical clustering of responses was performed using the ‘pheatmap’ R statistical package and ranked from most to least concerned. Responses were cross-referenced with enrolment into an ATI study which recruited from this cohort. Results: Of 352 eligible participants, 75 completed the survey. The majority were white, cisgender men who have sex with men, 34/75 (45 %) were born outside the UK. 29 (39 %) expressed interest in joining ATI studies. Participants who were interested or unsure in joining ATI studies were primarily motivated (53/65, 82 % very or moderately interested) by an altruistic desire to help scientific research. Across all participants, onward HIV transmission was the predominant concern (67/75, 89 % very or moderately concerned), and similar levels of concerns reported if the HIV-1 viral load threshold to restarting ART was increased from 500 to 50 000 copies/mL. Most participants preferred weekly (23/65, 35 %) or fortnightly (11/65, 17 %) viral load monitoring during an ATI. Before taking part in a study involving an ATI, participants stated they would prefer to discuss this with their HIV doctor (55/65, 85 %). Conclusion: In this small survey, 39 % of respondents expressed interest in joining studies involving ATIs, primarily for altruistic reasons. Participants were more interested in joining a potential ATI study if a novel intervention was included than simply an ATI alone. The main concern expressed was risk of viral transmission. To inform practical and study design considerations for future ATI studies, unrestricted access for mitigation of transmission risk should be included, and regular, frequent viral load monitoring is preferred.

Among breast cancer subtypes, triple-negative breast cancer stands out as the most aggressive, with patients facing a 40% mortality rate within the initial five years. The limited treatment options and unfavourable prognosis for triple-negative patients necessitate the development of novel therapeutic strategies. Photodynamic therapy (PDT) is an alternative treatment that can effectively target triple-negative neoplastic cells such as MDA-MB-231. In this in vitro study, we conducted a comparative analysis of the PDT killing rate of unbound Rose Bengal (RB) in solution versus RB-encapsulated chitosan nanoparticles to determine the most effective approach for inducing cytotoxicity at low laser powers (90 mW, 50 mW, 25 mW and 10 mW) and RB concentrations (50 µg/mL, 25 µg/mL, 10 µg/mL and 5 µg/mL). Intracellular singlet oxygen production and cell uptake were also determined for both treatment modalities. Dark toxicity was also assessed for normal breast cells. Despite the low laser power and concentration of nanoparticles (10 mW and 5 µg/mL), MDA-MB-231 cells experienced a substantial reduction in viability (8 ± 1%) compared to those treated with RB solution (38 ± 10%). RB nanoparticles demonstrated higher singlet oxygen production and greater uptake by cancer cells than RB solutions. Moreover, RB nanoparticles display strong cytocompatibility with normal breast cells (MCF-10A). The low activation threshold may be a crucial advantage for specifically targeting malignant cells in deep tissues.

Yan Wei,1,&ast; Jin Zhao,1,&ast; Jian Ming,1 Xuewu Zhang,2 Yingyao Chen1 1National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Department of Rheumatology, Peking University People’s Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuewu Zhang, Department of Rheumatology, Peking University People’s Hospital, Beijing, People’s Republic of China, Tel +8613681573403, Fax +86-010-88366323, Email xuewulore@163.com Yingyao Chen, National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86-21-33565183, Fax +86-21-64169552, Email yychen@shmu.edu.cnObjective: Rheumatoid arthritis (RA) is increasingly treated with biologics, which is commonly administered by injection devices. The aim of this study is to evaluate patients’ preferences for self-injection devices in RA, and to elicit their willingness to pay (WTP) for injector devices in China.Methods: RA patients were recruited from Beijing, Shanghai, Guangzhou, Chengdu, Wuhan and Xi’an in China. A discrete choice experiment (DCE) was employed to elicit patient preferences. Patients were presented with 15 choice sets that consisted of seven attributes, which were developed based on literature review and further validated by physicians. The seven attributes were as follows: operation steps, injection pain, feedback indication, needle visibility, needle protection, size and out-of-pocket costs. A mixed logit model was used to analyze the relative importance of seven attributes and to calculate the WTP for a changed attribute level.Results: Analyses included 114 adults with RA (mean age of 44.6 years old). When choosing the injection device, all attributes had significant influence. Among nonmonetary attributes, very slight injection pain was the most preferred for patients, followed by auto-injection method, thicker size, hidden needle, with needle protection and multiple feedback indication. Patients had a negative preference for increasing out-of-pocket costs. Patients were willing to pay CNY 45.26 for improving slight injection pain to very slight injection pain, CNY 13.26 for the auto-injection method, CNY 12.22 for the thicker size, CNY 10.06 for the hidden needle, CNY 9.82 for needle protection, and CNY 9.70 for multiple feedback indicators.Conclusion: The results suggested that injection pain was the most important attribute for RA patients. Meanwhile, all other enhanced attributes of self-injection devices also significantly influence patients’ selection on injection devices. Findings suggested that there is significant potential value in developing self-injection devices that could further help improve treatment adherence and promote patient-centered care in autoimmune diseases.Keywords: self-injection devices, rheumatoid arthritis, patient preferences, discrete choice experiment

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatment-dependent. In preclinical models of MM, synergy was observed in anti-tumor activity when poly (ADPribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan-sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.

Cancer, a prominent cause of death, presents treatment challenges, including high dosage requirements, drug resistance, poor tumour penetration and systemic toxicity in traditional chemotherapy. Photodynamic therapy, using photosensitizers like rose bengal (RB) with a green laser, shows promise against breast cancer cells in vitro. However, the hydrophilic RB struggles to efficiently penetrate the tumour site due to the unique clinical microenvironment, aggregating around rather than entering cancer cells. In this study, we have synthesized and characterized RB-encapsulated chitosan nanoparticles with a peak particle size of ~200 nm. These nanoparticles are readily internalized by cells and, in combination with a green laser (λ = 532 nm) killed 94–98% of cultured human breast cancer cells (MCF-7) and prostate cancer cells (PC3) at a low dosage (25 μg/mL RB-nanoparticles, fluence ~126 J/cm2, and irradiance ~0.21 W/cm2). Furthermore, these nanoparticles are not toxic to cultured human normal breast cells (MCF10A), which opens an avenue for translational applications.

Fowl adenoviruses (FAdVs) are distributed worldwide in poultry and incriminated as the etiological agents for several health problems in fowls, and are capable of crossing species barriers between domestic and wild fowls. An FAdV strain was, for the first time, isolated from black-necked crane in this study, and was designated as serotype 4 Fowl aviadenovirus C (abbreviated as BNC2021) according to the phylogenetic analysis of its DNA polymerase and hexon gene. The viral genomic sequence analysis demonstrated that the isolate possessed the ORF deletions that are present in FAdV4 strains circulating in poultry fowls in China and the amino acid mutations associated with viral pathogenicity in the hexon and fiber 2 proteins. A viral challenge experiment with mallard ducks demonstrated systemic viral infection and horizontal transmission. BNC2021 induced the typical clinical signs of hepatitis–hydropericardium syndrome (HHS) with swelling and inflammation in multiple organs and showed significant viral replication in all eight organs tested in the virus-inoculated ducks and their contactees at 6 dpi. The findings highlight the importance of surveillance of FAdVs in wild birds.

Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F. Keywords: adeno-associated virus vector, AAV vector, gene therapy, gene delivery, central nervous system, transduction efficiency, AAV capsid library

The seasonal migration of wild aquatic birds plays a critical role in the maintenance, transmission, and incursion of the avian influenza virus (AIV). AIV surveillance was performed during 2020–2021 in two national nature reserves with abundant wild bird resources in Yunnan, China. Four H5N8 AIVs isolates from the common crane were identified by next-generation sequencing. Phylogenetic analysis demonstrated that all eight gene segments of these H5N8 AIVs belonged to clade 2.3.4.4b high-pathogenic AIV (HPAIV) and shared high nucleotide sequence similarity with the strains isolated in Hubei, China, and Siberia, Russia, in 2020–2021. The H5N8 HPAIVs from common cranes were characterized by both human and avian dual-receptor specificity in the hemagglutinin (HA) protein. Moreover, possessing the substitutions contributes to overcoming transmission barriers of mammalian hosts in polymerase basic 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acid (PA), and exhibiting the long stalk in the neck region of the neuraminidase (NA) protein contributes to adaptation in wild birds. Monitoring AIVs in migratory birds, at stopover sites and in their primary habitats, i.e., breeding or wintering grounds, could provide insight into potential zoonosis caused by AIVs.

This paper presents methods for the 2019 PHM Conference Data Challenge developed by the team named "Angler". This Challenge aims to estimate the fatigue crack length of a type of aluminum structure using ultrasonic signals at the current load cycle and to predict the crack length at multiple future load cycles (multiple-step-ahead prediction) as accurately as possible. For estimating crack length, four crack-sensitive features are extracted from ultrasonic signals, namely, the first peak value, root mean square value, logarithm of kurtosis, and correlation coefficient. An ensemble linear regression model is presented to map these features and their second-order interactions with the crack length. The Best Subset Selection method is employed to select the optimal features. For predicting crack length, variations of the Paris’ law are derived to describe the relationships between the crack length and the number of load cycles. The material parameters and stress range of Paris’ law are learned using the Genetic Algorithm. These parameters will be updated based on the previous-step predicted crack length. After that, the crack length corresponding to a future load cycle number for either the constant amplitude load case or variable amplitude load case is predicted. The presented methods achieved a score of 16.14 based on the score-calculation rule provided by the Data Challenge committees, and was ranked third best among all participating teams.

Bifan Zhu,1 Yanfang Wang,2 Jian Ming,3 Wen Chen,4 Luying Zhang4 1Shanghai Health Development Research Center, Shanghai Medical Information Center, Shanghai, China; 2The First Affiliated Hospital of Wannan Medical College, Wuhu, China; 3IQVIA, Shanghai, China; 4School of Public Health, Fudan University, Shanghai, China Abstract: Chronic obstructive pulmonary disease (COPD) is one of the main contributors to the global burden of disease. The aim of this systematic review was to quantify the disease burden of COPD in China and to determine the risk factors of the disease. The number of studies included in the review was 47 with an average quality assessment score of 7.70 out of 10. Reported COPD prevalence varied between 1.20% and 8.87% in different provinces/cities across China. The prevalence rate of COPD was higher among men (7.76%) than women (4.07%). The disease was more prevalent in rural areas (7.62%) than in urban areas (6.09%). The diagnostic rate of COPD patients in China varied from 23.61% to 30.00%. The percentage of COPD patients receiving outpatient treatment was around 50%, while the admission rate ranged between 8.78% and 35.60%. Tobacco exposure and biomass fuel/solid fuel usage were documented as two important risk factors of COPD. COPD ranked among the top three leading causes of death in China. The direct medical cost of COPD ranged from 72 to 3,565 USD per capita per year, accounting for 33.33% to 118.09% of local average annual income. The most commonly used scales for the assessment of quality of life (QoL) included Saint George Respiratory Questionnaire, Airways Questionnaire 20, SF-36, and their revised versions. The status of QoL was worse among COPD patients than in non-COPD patients, and COPD patients were at higher risks of depression. The COPD burden in China was high in terms of economic burden and QoL. In view of the high smoking rate and considerable concerns related to air pollution and smog in China, countermeasures need to be taken to improve disease prevention and management to reduce disease burdens raised by COPD. Keywords: COPD, burden of disease, systematic review

Xinghuai Sun,1,2 Mingkai Lin,3 Xuanchu Duan,4 Chun Zhang,5 Jian Ming6 1Eye, Ear, Nose and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, 2Key Laboratory of Myopia, Ministry of Health (Fudan University), and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, 3Zhongshan Ophthalmic Center, Guangzhou, 4The Second Xiangya Hospital of Central South University, Changsha, 5Peking University Third Hospital, Beijing, 6Allergan plc, Shanghai, People’s Republic of China Background: Poor adherence to treatment is a problem in glaucoma, and patient dissatisfaction with topical glaucoma medication is a barrier to adherence. The objective of this study was to evaluate glaucoma patients’ satisfaction with fixed-combination bimatoprost/timolol ophthalmic solution (BTFC). Methods: This observational, multicenter study was conducted in China in adults with glaucoma treated with BTFC for 1–3 months. Five hundred patients answered a questionnaire concerning their demographic characteristics, history of glaucoma and topical glaucoma treatment, and use of BTFC. The primary endpoint was patient satisfaction with BTFC assessed on a 10-point scale (1= very dissatisfied, 10= very satisfied).Results: Patients received BTFC alone (65%) or with other treatments (35%), most commonly a carbonic anhydrase inhibitor. Most patients (87%) used BTFC as a replacement for other medication, usually a β-blocker or prostaglandin analog; 13% received BTFC as add-on treatment. Key reasons for initiating BTFC therapy were poor efficacy of previous treatment (72% of patients) and side effects of previous treatment (32% of patients). Most patients agreed or very much agreed that BTFC provided better control of intraocular pressure (85% of patients), had a simpler administration (87% of patients), and was associated with better tolerance and comfort (82% of patients) compared with their previous treatment. Mean satisfaction scores were significantly higher for BTFC than for previous treatments among all patients (7.8 versus 6.0; P

Effective signal processing methods are essential for machinery fault diagnosis. Most conventional signal processing methods lack adaptability, thus being unable to well extract the embedded meaningful information. Adaptive mode decomposition methods have excellent adaptability and high flexibility in describing arbitrary complicated signals, and are free from the limitations imposed by conventional basis expansion, thus being able to adapt to the signal characteristics, extract rich characteristic information, and therefore reveal the underlying physical nature. This paper presents a systematic and up-to-date review on adaptive mode decomposition in two major topics, i.e., mono-component decomposition algorithms (such as empirical mode composition, local mean decomposition, intrinsic time-scale decomposition, local characteristic scale decomposition, Hilbert vibration decomposition, empirical wavelet transform, variational mode decomposition, nonlinear mode decomposition, and adaptive local iterative filtering) and instantaneous frequency estimation approaches (including Hilbert-transform-based analytic signal, direct quadrature, and normalized Hilbert transform based on empirical AM-FM decomposition, as well as generalized zero-crossing and energy separation) reported in more than 80 representative articles published since 1998. Their fundamental principles, advantages and disadvantages, and applications to signal analysis in machinery fault diagnosis, are examined. Examples are provided to illustrate their performance.

Batten disease, or juvenile NCL, is a fatal neurodegenerative disorder that occurs due to mutations in the CLN3 gene. Because the function of CLN3 remains unclear, experimental therapies for JNCL have largely concentrated upon the targeting of downstream pathomechanisms. Neuron loss is preceded by localized glial activation, and in this proof-of-concept study we have investigated whether targeting this innate immune response with ibuprofen in combination with the neuroprotective agent lamotrigine improves the previously documented beneficial effects of immunosuppressants alone. Drugs were administered daily to symptomatic Cln3−/− mice over a 3 month period, starting at 6 months of age, and their impact was assessed using both behavioral and neuropathological outcome measures. During the treatment period, the combination of ibuprofen and lamotrigine significantly improved the performance of Cln3−/− mice on the vertical pole test, slowing the disease-associated decline, but had less of an impact upon their rotarod performance. There were also moderate and regionally dependent effects upon astrocyte activation that were most pronounced for ibuprofen alone, but there was no overt effect upon microglial activation. Administering such treatments for longer periods will enable testing for any impact upon the neuron loss that occurs later in disease progression. Given the partial efficacy of these treatments, it will be important to test further drugs of this type in order to find more effective combinations.

Abstract Background Alport syndrome (AS) is a hereditary disease caused by mutations in COL4A3‐5 genes. Recently, comprehensive genetic analysis has become the first‐line diagnostic tool for AS. However, no reports comparing mutation identification rates between conventional sequencing and comprehensive screening have been published. Methods In this study, 441 patients clinically suspected of having AS were divided into two groups and compared. The initial mutational analysis method involved targeted exome sequencing using next‐generation sequencing (NGS) (n = 147, NGS group) or Sanger sequencing for COL4A3/COL4A4/COL4A5 (n = 294, Sanger group). Results In the NGS group, 126 patients (86%) were diagnosed with AS by NGS, while two had pathogenic mutations in other genes, NPHS1 and EYA1. Further, 239 patients (81%) were diagnosed with AS by initial analysis in the Sanger group. Thirteen patients who were negative for mutation detection in the Sanger group were analyzed by NGS; three were diagnosed with AS. Two had mutations in CLCN5 or LAMB2. The final variant detection rate was 90%. Discussion Our results reveal that Sanger sequencing and targeted exome sequencing have high diagnostic ability. NGS also has the advantage of detecting other inherited kidney diseases and pathogenic mutations missed by Sanger sequencing.

Planetary gearbox systems are critical mechanical components in heavy machinery such as wind turbines. They may suffer from various failure modes, due to the harsh working environment. Dynamic modeling is a useful method to support early fault detection for enhancing reliability and reducing maintenance costs. However, reported studies have not considered the sun gear tooth crack and bearing clearance simultaneously to analyze their combined effect on vibration characteristics of planetary gearboxes. In this paper, a dynamic model is developed for planetary gearboxes considering the clearance of planet gear, sun gear, and carrier bearings, as well as sun gear tooth crack levels. Bearing forces are calculated considering bearing clearance, and the dynamic model equations are updated accordingly. The results reveal that the combination of bearing clearances can affect the vibration response with sun gear tooth crack by increasing the kurtosis. It is found that the effect of planet gear bearing clearance is very small, while the sun gear and carrier bearing clearance has clear impact on the vibration responses. These findings suggest that the incorporation of bearing clearance is important for planetary gearbox dynamic modeling.

Vasculoprotective endothelium glycocalyx (GCX) shedding plays a critical role in vascular disease. Previous work demonstrated that GCX degradation disrupts endothelial cell (EC) gap junction connexin (Cx) proteins, likely blocking interendothelial molecular transport that maintains EC and vascular tissue homeostasis to resist disease. Here, we focused on GCX regeneration and tested the hypothesis that vasculoprotective EC function can be stimulated via replacement of GCX when it is shed. We used EC with [i] intact heparan sulfate (HS), the most abundant GCX component; [ii] degraded HS; or [iii] HS that was restored after enzyme degradation, by cellular self-recovery or artificially. Artificial HS restoration was achieved via treatment with exogenous HS, with or without the GCX regenerator and protector sphingosine 1- phosphate (S1P). In these cells we immunocytochemically examined expression of Cx isotype 43 (Cx43) at EC borders and characterized Cx-containing gap junction activity by measuring interendothelial spread of gap junction permeable Lucifer Yellow dye. With intact HS, 60% of EC borders expressed Cx43 and dye spread to 2.88 ± 0.09 neighboring cells. HS degradation decreased Cx43 expression to 30% and reduced dye spread to 1.87± 0.06 cells. Cellular self-recovery of HS restored baseline levels of Cx43 and dye transfer. Artificial HS recovery with exogenous HS partially restored Cx43 expression to 46% and yielded dye spread to only 1.03 ± 0.07 cells. Treatment with both HS and S1P, recovered HS and restored Cx43 to 56% with significant dye transfer to 3.96 ± 0.23 cells. This is the first evidence of GCX regeneration in a manner that effectively restores vasculoprotective EC communication.

Maintenance optimization has received special attention among the wind energy research community over the past two decades. This is mainly because of the high degree of uncertainties involved in the execution of operation and maintenance (O&M) activities throughout the lifecycle of wind farms. The increasing complexity in offshore maintenance execution demands applied research and brings forth a need to develop problem-specific maintenance decision-making models. In this paper, a mathematical model is proposed to assist wind farm stakeholders in making critical resource- related decisions for corrective maintenance at offshore wind farms (OWFs), considering uncertainties in turbine failure information.

Patients and a mouse model of Batten disease, the juvenile form of neuronal ceroid lipofuscinosis (JNCL), raise autoantibodies against GAD65 and other brain-directed antigens. Here we investigate the adaptive component of the neuroimmune response. Cln3−/− mice have autoantibodies to GAD65 in their cerebrospinal fluid and elevated levels of brain bound immunoglobulin G (IgG). IgG deposition was found within human JNCL autopsy material, a feature that became more evident with increased age in Cln3−/− mice. The lymphocyte infiltration present in human and murine JNCL occurred late in disease progression, and was not capable of central/intrathecal IgG production. In contrast, we found evidence for an early systemic immune dysregulation in Cln3−/− mice. In addition evidence for a size-selective breach in the blood–brain barrier integrity in these mice suggests that systemically produced autoantibodies can access the JNCL central nervous system and contribute to a progressive inflammatory response.

Gears are widely used in gearbox to transmit power from one shaft to another. Gear crack is one of the most frequent gear fault modes found in industry. Identification of different gear crack levels is beneficial in preventing any unexpected machine breakdown and reducing economic loss because gear crack leads to gear tooth breakage. In this paper, an intelligent fault diagnosis method for identification of different gear crack levels under different working conditions is proposed. First, superhigh-dimensional statistical features are extracted from continuous wavelet transform at different scales. The number of the statistical features extracted by using the proposed method is 920 so that the extracted statistical features are superhigh dimensional. To reduce the dimensionality of the extracted statistical features and generate new significant low-dimensional statistical features, a simple and effective method called principal component analysis is used. To further improve identification accuracies of different gear crack levels under different working conditions, support vector machine is employed. Three experiments are investigated to show the superiority of the proposed method. Comparisons with other existing gear crack level identification methods are conducted. The results show that the proposed method has the highest identification accuracies among all existing methods.

The structural changes which occur during the swelling of Wyoming Na montmorillonite have been investigated by adsorption and desorption of water, simulation of XRD powder patterns, immersion microcalorimetry, and small-angle X-ray scattering in 10 to the power of (-3) N NaCl solutions. The progressive changes of the water concentration in the interlamellar space, and the mechanisms of water adsorption were followed from dry state to relative pressures up to 0. 9. The microstructure of Na montmorillonite corresponding to high water contents appears to be a network of quasi-crystals containing pores of about 1 µm in size. The tactoids were found to consist of a few layers and the water was mainly located in the layers inside the tactoids. Les changements de structure qui se produisent durant le gonflement de la montmorillonite Na du Wyoming ont été étudiés par différents procédés : adsorption et désorption d'eau, simulation de diagrammes de diffraction, microcalorimétrie d'immersion, et diffusion aux petits angles des rayons X dans des solutions de 10 puissance (-3) N NaCI. Les modifications progressives de la concentration d'eau dans l'espace interfoliaire, et les mécanismes de l'adsorption d'eau ont été suivis de l'état sec jusqu'à des pressions relatives atteignant 0,9. Pour de fortes teneurs en eau, la microstructure de la montmorillonite Na semble être un réseau de quasi-cristaux avec des pores d'environ 1 µm. On a constaté que les tactoïdes se composent de quelques feuillets, à l'intérieur desquels l'eau était principalement concentrée.

Planetary gearbox vibration signals have strong modulation features due to the amplitude modulation and frequency modulation (AM-FM) effect of gear faults, as well as the amplitude modulation (AM) effect of time-varying vibration transfer paths, on gear meshing vibrations. This results in an involute sidebands structure in Fourier spectrum, possibly misleading fault diagnosis. The modulating frequency of both amplitude modulation (AM) and frequency modulation (FM) parts is closely related to the gear fault characteristic frequency. This inspires the idea of joint amplitude and frequency demodulation analysis, thus addressing the complex sidebands issue inherent in Fourier spectrum. Demodulation analysis requires mono-component signals for accurate estimation of instantaneous frequency, and proper selection of an AM-FM component sensitive to gear fault. To this end, we firstly decompose the complex signal into intrinsic mode functions (IMFs) via variational mode decomposition (VMD), by exploiting its capability in decomposing complex modulated signal into constituent AM-FM components. For effective application of VMD in complex planetary gearbox signal analysis, we propose a method to determine a key parameter in VMD, i.e. the number of IMFs to be separated. For accurate instantaneous frequency estimation, we decompose IMFs via empirical AM-FM decomposition, to remove the influence of AM on instantaneous frequency estimation. Then, we select the sensitive IMF that contains the main gear fault information for further demodulation analysis. In order to properly select the sensitive IMF, we propose a criterion based on the gear vibration characteristics and the VMD properties. Finally, we obtain the amplitude and frequency demodulated spectra by applying Fourier transform to the amplitude envelope and instantaneous frequency of the selected sensitive IMF. According to the characteristics exhibited in the demodulated spectra, we can detect planetary gearbox fault. The proposed method is illustrated via a numerical simulated planetary gearbox vibration signal, and is further validated using lab experimental vibration signals of a planetary gearbox. Faults on all the three types of gear (sun, planet and ring) are successfully identified.

The pleiotropic serine/threonine protein kinase CK2 was the first kinase discovered. It is renowned for its role in cell proliferation and anti-apoptosis. The complexity of this kinase is well reflected by the findings of past decades in terms of its heterotetrameric structure, subcellular location, constitutive activity and the extensive catalogue of substrates. With the advent of non-biased high-throughput functional genomics such as genome-wide deletion mutant screening, novel aspects of CK2 functionality have been revealed. Our recent discoveries using the model organism Saccharomyces cerevisiae and mammalian cells demonstrate that CK2 regulates metal toxicity. Extensive literature search reveals that there are few but elegant works on the role of CK2 in regulating the sodium and zinc channels. As both CK2 and metal ions are key players in cell biology and oncogenesis, understanding the details of CK2’s regulation of metal ion homeostasis has a direct bearing on cancer research. In this review, we aim to garner the recent data and gain insights into the role of CK2 in metal ion transport.

To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain.A nationally representative cross-sectional study survey of children (1102) aged 4-18 years (999 white, 570 male) living in private households (January 1997-1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0-2.4]).We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.

To explore fracturing technology for vertical wells in ultra-shallow shale gas reservoirs, a coupled thermo-hydro-mechanical-damage (THM-D) fracturing and production integration model is established in this study. In addition, a new coupled hydro-mechanical damage model is established to calculate fracture evolution. These two models are validated through theoretical models and field data, respectively. Based on these models, the quality of fracturing under different geological parameters, fracturing parameters, and fracturing technology is compared and analyzed. The results show that the distribution of natural fractures significantly influences fracturing and production. In addition, due to the high leak-off in the ultra-shallow shale reservoir, the total fracture length and cumulative production after 720 days of carbon dioxide fracturing are only 70.35% and 77.26% of the values achieved by hydraulic fracturing, respectively. Therefore, it is necessary to consider reducing carbon dioxide leak-off in the design of carbon dioxide fracturing in ultra-shallow shale reservoirs. Fracturing efficiency also should be considered when designing fracturing time. When the injection rate is 5 m3/min, the efficiency drops sharply if the fracturing time exceeds 67.45 min. The production of hydraulic fracturing and carbon dioxide fractured wells has also been studied when fracturing methods without proppant are used. This study found that a satisfactory production rate can also be achieved in ultra-shallow shale gas reservoirs when fracturing without proppant.

Abstract Background Transient hypotension is a common occurrence during the implantation of bone cement. This placebo-controlled randomized clinical trial study investigated the effect of prophylactic infusion of norepinephrine on the incidence of hypotension in senior patients who underwent vertebroplasty. Methods The trial recruited patients who were greater than or equal to 65 years of age, had an American Society of Anesthesiologist physical status classification of I to III, and underwent vertebroplasty from August 2020 to August 2021 at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine in China. The patients were randomly grouped according to whether they received either a norepinephrine infusion of 0.05 µg/kg/min or an equivalent volume of saline 10 min before implantation of bone cement. Intraoperative hemodynamics were monitored continuously by the MostCare system at the following 7 time points: 10 min before implantation of bone cement and immediately, 30 s, 1, 3, 5, and 10 min after implantation of bone cement. We also recorded the number of hypotensive episodes and the total number of vasopressors after implantation of bone cement. Multivariable logistic regression was used to assess the risk factors associated with hypotension after implantation of bone cement. Results A total of 63 patients were randomized to the control group (n = 31; median [IQR] age, 74 [69–79] years) and the norepinephrine group (n = 32; median [IQR] age, 75 [71–79] years). The incidence of hypotension in the norepinephrine group was significantly lower than that in the control group after implantation of bone cement (12.5% vs. 45.2%; relative risk [RR], 3.61 [95% CI, 1.13–15.07]; P = 0.005). Moreover, the median (IQR) number of hypotensive episodes (0 [0–0] vs. 0 [0–2]; P = 0.005) and the total number of vasopressors (0 [0–0] vs. 0 [0–1]; P = 0.004) in the norepinephrine group were significantly lower than those in the control group. Furthermore, compared with the baseline, the MAP significantly decreased at 1 min (P = 0.007) and 3 min (P

Abstract In recent years, defending against adversarial examples has gained significant importance, leading to a growing body of research in this area. Among these studies, pre-processing defense approaches have emerged as a prominent research direction. However, existing adversarial example pre-processing techniques often employ a single pre-processing model to counter different types of adversarial attacks. Such a strategy may miss the nuances between different types of attacks, limiting the comprehensiveness and effectiveness of the defense strategy. To address this issue, we propose a divide-and-conquer reconstruction pre-processing algorithm via multi-classification and multi-network training to more effectively defend against different types of mainstream adversarial attacks. The premise and challenge of the divide-and-conquer reconstruction defense is to distinguish between multiple types of adversarial attacks. Our method designs an adversarial attack classification module that exploits the high-frequency information differences between different types of adversarial examples for their multi-classification, which can hardly be achieved by existing adversarial example detection methods. In addition, we construct a divide-and-conquer reconstruction module that utilizes different trained image reconstruction models for each type of adversarial attack, ensuring optimal defense effectiveness. Extensive experiments show that our proposed divide-and-conquer defense algorithm exhibits superior performance compared to state-of-the-art pre-processing methods.

Abstract The activation of nuclear factor erythroid 2–related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.

Background: Postoperative delirium (POD) is an acute postoperative syndrome of the central nervous system that seriously affects the prognosis of patients. Many vital advances have been made in the study of the management of POD. We conducted a bibliometric analysis of research on the prevention and treatment of POD over the past 20 years to consolidate current research focal points and emerging trends in this domain. Methods: We searched the Web of Science Core Collection database for literature published between 2004 and 2023. VOSviewer, CiteSpace, Microsoft Excel, Scimago Graphica, and the R tool “bibliometrix” were used to analyze and visualize annual publications, countries, organizations, journals, authors, keywords, and references. Results: A total of 1848 eligible publications were identified, with a general uptrend observed in both annual publications and citations. The USA was the most profitable country, ranking first in total publications. The most active institution was Harvard Medical School. Inouye, Sharon K was the most prolific scholar due to her numerous publications and citations. According to the co-occurrence network, the strongest citation bursts and co-cited references analysis fresh hot topics included “dexmedetomidine,” “neuroinflammation,” “haloperidol prophylaxis,” and “guideline.” Conclusions: Research on prevention and treatment of POD is gaining significant momentum worldwide. Current hot spots include early perioperative prevention strategies and integrated multi-method treatments. Effective drugs for it is one of the directions in the future. The management of pediatric patients with POD has caused concern in recent years. This bibliometric analysis is poised to guide future research trajectories in this field.

Abstract Coherent optics has profoundly impacted diverse applications ranging from communications, LiDAR to quantum computations. However, developing coherent systems in integrated photonics comes at great expense in hardware integration and energy efficiency. Here we demonstrate a high-coherence parallelization strategy for advanced integrated coherent systems at minimal cost. By using a self-injection locked microcomb to injection lock distributed feedback lasers, we achieve a record high on-chip gain of 60 dB with no degradation in coherence. This strategy enables highly coherent channels with linewidths down to 10 Hz and power over 20 dBm. The overall electrical-to-optical efficiency reaches 19%, comparable to that of advanced semiconductor lasers. This method supports a silicon photonic communication link with an unprecedented data rate beyond 60 Tbit/s and reduces phase-related DSP consumption by 99.99999% compared to traditional III-V laser pump schemes. This work paves the way for realizing scalable, high-performance coherent integrated photonic systems, potentially benefiting numerous applications.

To evaluate the effects of dietary supplementation with succinic acid on growth performance, flesh quality, glucose, and lipid metabolism of Nile tilapia (Oreochromis niloticus) fed a high-carbohydrate diet (HCD), five iso-nitrogenous and iso-lipidic diets were prepared as follows: HCD (control group) consisting of 55% corn starch and HCD supplemented with 0.5%, 1.0%, 2.0%, and 4.0% succinic acid, respectively. Tilapia with an initial body weight of 204.90 ± 1.23 g randomly assigned to 15 tanks with 3 replicates per group and 10 fish per tank fed for 8 weeks. Increasing dietary succinic acid supplementation resulted in significant second-order polynomial relationship in the weight gain rate (WGR), specific growth rate (SGR), feed conversion ratio (FCR), protein efficiency rate (PER), viscerosomatic index, condition factor, and contents of muscular crude lipid and glycogen (P

The interpenetrating connection of icosahedra network (ICOIN) was termed as structural skeleton, which could quantify the strength and ductility of MGs. The impact of different rejuvenation methods on medium-range order (MRO) alterations was rarely studied. This work employed molecular dynamics simulations to examine the difference in MRO evolution of metallic glasses treated by recovery annealing and thermal-pressure treatment during uniaxial tension. All of the specimens obtain enhanced ductility due to improved potential energy. During tension, ICOI of all rejuvenated specimens exhibits an increased destruction rate and a decreased transformation rate. However, there are some converse characteristics in the specimens under different rejuvenation methods. The rejuvenated specimens treated by recovery annealing exhibit increased free volume and decreased ICOIN density. After thermal-pressure treatment, the rejuvenated specimens demonstrated decreased free volume and enhanced ICOIN density. During tension, the enhancement of icosahedral free volume in specimens treated by thermal pressure largely decreased the ICOIN density, thereby increasing the ductility. After tension, the rejuvenated specimens under high pressure have a significant reduction in ICOIN density compared to those under recovery annealing. The significance of this work is to accurately regulate the ICOIN density of rejuvenated specimens.

Extracellular vesicles (EVs) have garnered significant attention in biomedical applications. However, the rapid, efficient, and unbiased separation of EVs from complex biological fluids remains a challenge due to their heterogeneity and low abundance in biofluids. Herein, we report a novel approach to reconfigure and modify an artificial insertion peptide for the unbiased and rapid isolation of EVs in 20 min with ∼80% recovery in neutral conditions. Moreover, the approach demonstrates exceptional anti-interference capability and achieves a high purity of EVs comparable to standard ultracentrifugation and other methods. Importantly, the isolated EVs could be directly applied for downstream protein and nucleic acid analyses, including proteomics analysis, exome sequencing analysis, as well as the detection of both epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) gene mutation in clinical plasma samples. Our approach offers great possibilities for utilizing EVs in liquid biopsy, as well as in various other biomedical applications.

Therapeutic antibodies are an important class of biopharmaceuticals. With the rapid development of deep learning methods and the increasing amount of antibody data, antibody generative models have made great progress recently. They aim to solve the antibody space searching problems and are widely incorporated into the antibody development process. Therefore, a comprehensive introduction to the development methods in this field is imperative. Here, we collected 34 representative antibody generative models published recently and all generative models can be divided into three categories: sequence-generating models, structure-generating models, and hybrid models, based on their principles and algorithms. We further studied their performance and contributions to antibody sequence prediction, structure optimization, and affinity enhancement. Our manuscript will provide a comprehensive overview of the status of antibody generative models and also offer guidance for selecting different approaches.

Sesame is a labor intensive crop with limited mechanized harvesting mainly due to the seed shattering (SS) trait. In this study, we performed a genetic analysis of the seed-shattering resistance (SR) trait with a SR sesame mutant 12M07. Unlike the SS type, the parenchyma cells in the abscission zone of the 12M07 mutant are arranged loosely but adhere to the seed coat. Inheritance analysis of six generations derived from 12M07 (SR)×Xiangcheng Dazibai (SS) showed that the SR trait is recessive and controlled by a single gene pair. Association mapping of the F2 population with 888,619 variants (single-nucleotide polymorphisms (SNPs) and insertion-deletion (InDels)) and 31,884 structural variations (SVs) determined that only SV12002 in the 5´ upstream region of gene Sindi0765000 (named SiHEC3) in Chr.3 was significantly associated with the SR trait. SiHEC3 encodes the bHLH transcription factor. A 1,049 bp deletion occurred in the 5´ UTR of Sihec3 in 12M07. SiHEC3 is mainly expressed in developing placental tissues, with the expression peaking in capsules at 45 days after pollination. A dual-luciferase reporter assay in tobacco confirmed that the promoter activity of Sihec3 was reduced because of the deletion of the 1,049 bp promoter sequence. Protein–protein interaction network analysis showed that HEC3 is co-expressed with nine key proteins, such as SHATTERPROOF1 (SHP1) and SEEDSTICK (STK) which participate in the secondary wall biosynthesis of the abscission layer in plants. The findings of this study show the important function of Sihec3 corresponding with the SR trait and supply the genetic information for breeding new varieties that are amenable to mechanized harvesting in sesame and other crops.

Abstract The encapsulation of lunar samples is a core research area in the third phase of the Chinese Lunar Exploration Program. The seal assembly, opening and closing mechanism (OCM), and locking mechanism are the core components of the encapsulation device of the lunar samples, and the requirements of a tight seal, lightweight, and low power make the design of these core components difficult. In this study, a combined sealing assembly, OCM, and locking mechanism were investigated for the device. The sealing architecture consists of rubber and an Ag-In alloy, and a theory was built to analyze the seal. Experiments of the electroplate Au coating on the knife-edge revealed that the hermetic seal can be significantly improved. The driving principle for coaxial double-helical pairs was investigated and used to design the OCM. Moreover, a locking mechanism was created using an electric initiating explosive device with orifice damping. By optimizing the design, the output parameters were adjusted to meet the requirements of the lunar explorer. The experimental results showed that the helium leak rate of the test pieces were not more than 5 × 10−11 Pa·m3·s−1, the minimum power of the OCM was 0.3 W, and the total weight of the principle prototype was 2.9 kg. The explosive driven locking mechanism has low impact. This investigation solved the difficulties in achieving tight seal, light weight, and low power for the lunar explorer, and the results can also be used to explore other extraterrestrial objects in the future.

Abstract Duchenne muscular dystrophy (DMD) affecting 1 in 3500–5000 live male newborns is the frequently fatal genetic disease resulted from various mutations in DMD gene encoding dystrophin protein. About 70% of DMD-causing mutations are exon deletion leading to frameshift of open reading frame and dystrophin deficiency. To facilitate translating human DMD-targeting CRISPR therapeutics into patients, we herein establish a genetically humanized mouse model of DMD by replacing exon 50 and 51 of mouse Dmd gene with human exon 50 sequence. This humanized mouse model recapitulats patient’s DMD phenotypes of dystrophin deficiency and muscle dysfunction. Furthermore, we target splicing sites in human exon 50 with adenine base editor to induce exon skipping and robustly restored dystrophin expression in heart, tibialis anterior and diaphragm muscles. Importantly, systemic delivery of base editor via adeno-associated virus in the humanized male mouse model improves the muscle function of DMD mice to the similar level of wildtype ones, indicating the therapeutic efficacy of base editing strategy in treating most of DMD types with exon deletion or point mutations via exon-skipping induction.

Abstract Background With recent advances in gene sequencing technology, more than 60 genetic mutations associated with very early onset inflammatory bowel disease (VEO-IBD) have been reported. Most of the genes are associated with immune deficiencies. The Myosin 5B (MYO5B) gene is primarily involved in cell motility and material transport which is associated with congenital intractable diarrhea and cholestasis. No studies have examined the relationship between the MYO5B gene and VEO-IBD. We report a case of a child with a mutation in the MYO5B gene who was diagnosed with VEO-IBD, then we investigated the association between the MYO5B gene and VEO-IBD. Case presentation A 7-month-old baby girl with a chief complaint of “blood in the stool for more than 4 months and vaginal pus and blood discharge for 3 weeks” was diagnosed with VEO-IBD, and her symptoms improved after treatment with mesalazine. The whole-exome sequencing was performed with peripheral blood. Immunohistochemistry was performed on the terminal ileal tissue. Western blotting, quantitative polymerase chain reaction (Q-PCR) and immunofluorescence were performed with cultured organoid tissue from the terminal ileum. Whole-exome sequencing identified heterozygous missense of MYO5B variant of unknown significance (p. [I769N]; [T1546M]). Immunohistochemistry revealed a significant decrease in the expression of MYO5B protein in the terminal ileum of the child with MYO5B mutation; Q-PCR revealed a decrease in the mRNA levels of occludin and ZO-1 and both the mRNA levels and protein levels of MYO5B was downregulated in the patient. Immunofluorescence images showed that MYO5B gene mutation disrupted the apical delivery of transporters SGLT1, NHE3 and AQP7. Conclusions MYO5B gene mutation leading to the downregulation of MYO5B protein may promote the occurrence of VEO-IBD by decreasing mRNA and protein levels of intestinal tight junction genes and dislocating the apical transporters.

Abstract Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10–19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.

Abstract The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients’ immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.

Abstract Background Evaluation publications typically summarize the results of studies to demonstrate the effectiveness of an intervention, but little is shared concerning any changes implemented during the study. We present a process evaluation protocol of a home-based gait, balance, and resistance exercise intervention to ameliorate persistent taxane-induced neuropathy study according to 7 key elements of process evaluation. Methods The process evaluation is conducted parallel to the longitudinal, randomized control clinical trial examining the effects of the home-based gait, balance, and resistance exercise program for women with persistent peripheral neuropathy following treatment with taxanes for breast cancer (IRB approval: Pro00040035). The flowcharts clarify how the intervention should be implemented in comparable settings, fidelity procedures help to ensure the participants are comfortable and identify their individual needs, and the process evaluation allows for the individual attention tailoring and focus of the research to avoid protocol deviation. Conclusions The publication of the evaluation protocol plan adds transparency to the findings of clinical trials and favors process replication in future studies. The process evaluation enables the team to systematically register information and procedures applied during recruitment and factors that impact the implementation of the intervention, thereby allowing proactive approaches to prevent deviations from the protocol. When tracking an intervention continuously, positive or negative intervention effects are revealed early on in the study, giving valuable insight into inconsistent results. Furthermore, a process evaluation adds a participant-centered element to the research protocols, which allows a patient-centered approach to be applied to data collection. Trial registration ClinicalTrials.gov NCT04621721, November 9, 2020, registered prospectively. Protocol version: April 27, 2020, v2.

Abstract Background The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, and IGF2BP3) are known to be involved in tumorigenesis, metastasis, prognosis, and cancer immunity in various human cancers, including non-small cell lung cancer (NSCLC). However, the literature on NSCLC largely omits the specific context of lung squamous cell carcinoma (LUSC), an oversight we aim to address. Methods Our study evaluated the differential expression of IGF2BP family members in tumors and normal tissues. Meta-analyses were conducted to assess the prognostic value of IGF2BPs in lung adenocarcinoma (LUAD) and LUSC. Additionally, correlations between IGF2BPs and tumor immune cell infiltration, mutation characteristics, chemotherapy sensitivity, and tumor mutation burden (TMB) were investigated. GSEA was utilized to delineate biological processes and pathways associated with IGF2BPs. Results IGF2BP2 and IGF2BP3 expression were found to be upregulated in LUSC patients. IGF2BP2 mRNA levels were correlated with cancer immunity in both LUSC and LUAD patients. A higher frequency of gene mutations was observed in different IGF2BP1/2/3 expression groups in LUAD compared to LUSC. Meta-analyses revealed a significant negative correlation between overall survival (OS) and IGF2BP2/3 expression in LUAD patients but not in LUSC patients. GSEA indicated a positive association between VEGF and IGF2BP family genes in LUAD, while matrix metallopeptidase activity was inversely correlated with IGF2BP family genes in LUSC. Several chemotherapy drugs showed significantly lower IC50 values in high IGF2BP expression groups in both LUAD and LUSC. Conclusion Our findings indicated that IGF2BPs play different roles in LUAD and LUSC. This divergence highlights the need for tailored therapeutic strategies and prognostic tools, cognizant of the unique molecular profiles of LUAD and LUSC.

Abstract To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that “extracellular matrix organization” ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMP s expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation.

Abstract DNA base editors enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here we develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants. By several rounds of structure-informed rational mutagenesis on UNG in cultured human cells, we obtain gTBE and gCBE with high activity of T-to-S (i.e., T-to-C or T-to-G) and C-to-G conversions, respectively. Furthermore, we conduct parallel comparison of gTBE/gCBE with those recently developed using other protein engineering strategies, and find gTBE/gCBE show the outperformance. Thus, we provide several base editors, gTBEs and gCBEs, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

The present study aimed to compare the nutritional effects of cholesterol, bile acids, and combination of cholesterol with bile acids in plant-based diets on juvenile genetically improved farmed tilapia (GIFT; Oreochromis niloticus). The isonitrogenous (321 g/kg crude protein) and isolipidic (76 g/kg crude fat) diets (Con diet) were based on plant protein sources, which included corn gluten meal, soybean meal, cottonseed meal and rapeseed meal. The Con diet was supplemented with 12 g/kg cholesterol (CHO diet), 0.2 g/kg bile acids (BAs diet), a combination of 12 g/kg cholesterol and 0.2 g/kg bile acids (CHO–BAs diet), respectively. Each diet was fed to three tanks in an indoor recirculating aquaculture system for 9 weeks. Results showed that compared to the Con group, fish had a higher weight gain rate, hepatosomatic index, and a lower feed conversion ratio in the CHO–BAs group. The highest levels of whole-fish fat and ash were found in the Con group. Serum parameters, including activities of alanine aminotransferase (ALT) and aspartate transaminase (AST), along with levels of glucose (GLU) and triglyceride (TG) except for total cholesterol (TCHO), were lower in the CHO, BAs, and CHO–BAs groups than those in the Con group (P < 0.001). Histological examination revealed that fish in the Con group exhibited severe hepatocyte vacuolization and diminished hepatocyte proliferation. Gene expression analysis indicated that the transcriptional levels of bile acid metabolism-related genes (including fxr, fgf19, bsep) were up-regulated in the CHO–BAs group (P < 0.05), whereas cholesterol metabolism-related genes (acly and hmgcr) were down-regulated in both CHO and CHO–BAs groups (P < 0.001). Moreover, UPLC-MS/MS analysis revealed that the higher taurine-conjugated bile acids (T-BAs), followed by free bile acids (Free-BAs) and glycine (G-BAs) were determined in tilapia bile. Among these, taurochenodeoxycholic bile acid was the predominant bile acid. Dietary bile acids supplementation also increased the proportion of T-BAs (tauro β-muricholic acid and taurodehydrocholic acid) while decreasing Free-BAs in the fish bile. In conclusion, the incorporation of cholesterol with bile acids into plant-based diets can effectively reduce cholesterol uptake, suppress bile acids synthesis, enhance bile acids efflux, and promote hepatocyte proliferation, which is helpful for maintaining the normal liver morphology in tilapia, and thus improving its growth performance.

The United Nations Convention on the Law of the Sea (UNCLOS) is a widely ratified multilateral treaty that defines and codifies the standards and principles of international law for the governance and management of the oceans. One of its key features is the facilitation of the peaceful settlement of disputes on maritime affairs. Article 281 constitutes an equality test by which the courts or tribunals can distinguish voluntary procedures from compulsory proceedings. Existing cases under Part XV did not provide a clear routine what circumstances might make a treaty under Article 281 “unequal”. Article 311 deals with the tension between prioritizing the regional arrangements and maintaining UNCLOS as a closed, self-contained system. This research aims to provide insights into the proper application of these two articles in future UNCLOS disputes, as the Timor Sea Conciliation (Timor-Leste v. Australia) is the first instance of the conciliation mechanism under UNCLOS. Through the methods of doctrinal research and comparing the different argumentations in previous cases, the research found that the recent Timor Sea Conciliation was decided on the basis of a controversial understanding of UNCLOS Articles 281 and 311; that a treaty featuring specific and feasible arrangements for dispute settlement would be easier in passing Article 281’s test; and that Article 311 favors UNCLOS’s integrity and considers the permitted derogations as exceptions. It is suggested that the courts or tribunals under UNCLOS Part XV interpret Articles 281 and 311 in a systematic manner, which is believed to benefit the development of voluntary dispute settlement mechanism under UNCLOS in the long run.

Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.

Abstract A variety of abnormal epithelial cells and immature and mature immune cells in thymic epithelial tumors (TETs) affect histopathological features, the degree of malignancy, and the response to treatment. Here, gene expression, trajectory inference, and T cell antigen receptor (TCR)‐based lineage tracking are profiled in TETs at single‐cell resolution. An original subpopulation of KRT14+ progenitor cells with a spindle cell phenotype is shown. An abnormal infiltration of immature T cells with a TCR hyper‐rearrangement state is revealed, due to the lack of CCL21+ medullary epithelial cells. For thymic carcinoma, the novel biomarkers of MSLN, CCL20, and SLC1A5 are identified and observed an elevated expression of LAG3 and HAVCR2 in malignant tumorn‐infiltrating mature T cells. These common features based on the single‐cell populations may inform pathological reclassification of TETs. Meanwhile, it is found that macrophages (MACs) attract thymic tumor cells through the LGALS9‐SLC1A5 axis, providing them with glutamine to elicit metabolic reprogramming. This MAC‐based metabolic pattern can promote malignancy progression. Additionally, an interactive immune environment in TETs is identified that correlates with the infiltration of abnormal FOXI1+ CFTR− ionocytes. Collectively, the data broaden the knowledge of TET cellular ecosystems, providing a basis for tackling histopathological diagnosis and related treatment.

Mineral forecasting is of great significance for social development. As an important aspect of geological exploration, its importance lies not only in its direct contribution to economic growth but also in how it employs precise technical methods for mineral exploration. This study utilizes a geological factor analysis method that combines various complex geological observation factors into a few dominant comprehensive factors, followed by causal research and multivariate statistical analysis for classification. Based on this, the study applies principles and methods of elemental geochemistry to identify the dispersion and concentration patterns of associated elements from the distribution characteristics of ordered accompanying factors, providing a scientific basis for mineralization forecasting. Using geochemical experimental data, geological survey comprehensive profiles, and factor score contour maps, this paper analyzes the southern extension segment of the Jiaojia gold mine mineralization belt through geological factor analysis. It was found that the anomalous distribution of chemical elements F4 (Hg, Au, Pb) exhibits certain regularities, which significantly indicate mineralization information and suggest the presence of two main longitudinal mineralization belts.