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The surging demand for advanced fluorine corrosion-resistant materials underscores their significance in ensuring operational safety and reliability across various industries. This study investigates the corrosion behavior of the FeCoNiCrMo high-entropy alloy (HEA) via a series of 28-day immersion tests in hydrofluoric acid (HF) solutions. The results demonstrate the FeCoNiCrMo HEA's superior corrosion-resistant performance in HF environments, exhibiting remarkably low corrosion rates of 0.179 mm/y, 0.276 mm/y, and 0.352 mm/y in 20 vol%, 30 vol%, and 40 vol% HF solutions, respectively. Comprehensive phase and microstructural characterizations were conducted on samples exposed to the 40 vol% HF solution to elucidate the corrosion mechanisms. The study revealed that localized pitting corrosion preferentially initiates within the interdendritic regions of the HEA matrix upon HF exposure. During the intermediate stage, micro-galvanic corrosion occurs between the dendritic arms and interdendritic regions, leading to the formation of a uniform and compact corrosion product film on the alloy surface. This film, enriched with Mo, Cr, and O, provides temporary protection. However, as corrosion progresses, the partial detachment of particulate corrosion products compromises the integrity of the film, resulting in increased dissolution within the interdendritic regions and the formation of irregular corrosion grooves in the later stage. These insights significantly enhance the understanding of the corrosion mechanisms of FeCoNiCrMo HEA in HF environments and provide valuable guidance for developing innovative protective materials designed for fluorine-rich engineering applications.

Abstract Introduction Constipation may be linked to cognitive decline and a higher risk of Alzheimer’s disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Methods Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Results Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with less Tau burden evaluated by 18F-MK6240 PET Braak stages. Conclusion Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

Abstract Background Ophiocordyceps sinensis (O. sinensis) is the dominant bacterium in the asexual stage of Chinese cordyceps, and its growth usually suffers from water stress. Thus, simulating its ecological growth environment is crucial for artificial cultivation. This study aimed to reveal the mechanism underlying the water stress tolerance of Ophiocordyceps sinensis (O. sinensis) by combining metabolomic and transcriptome analyses to identify crucial pathways related to differentially expressed genes (DEGs) and metabolites (DEMs) involved in the response to water stress. Results Gene coexpression analysis revealed that many genes related to ‘betalain biosynthesis’, ‘tyrosine metabolism’, ‘linoleic acid metabolism’, ‘fructose and mannose metabolism’, and ‘starch and sucrose metabolism’ were highly upregulated after 20d-water stress. Metabolomic analysis revealed that many metabolites regulated by these genes in these metabolic pathways were markedly decreased. On the one hand, we surmised that carbohydrate metabolism and the β-oxidation pathway worked cooperatively to generate enough acyl-CoA and then entered the TCA cycle to provide energy when exposed to water stress. On the other hand, the betalain biosynthesis and tyrosine metabolism pathway might play crucial roles in response to water stress in O. sinensis by enhancing cell osmotic potential and producing osmoregulatory substances (betaine) and antioxidant pigments (eumelanin). Conclusions Overall, our findings provide important information for further exploration of the mechanism underlying the water stress tolerance of O. sinensis for the industrialization of artificial cultivation of Chinese cordyceps.

Abstract Magnetic kagome materials provide a fascinating playground for exploring the interplay of magnetism, correlation and topology. Many magnetic kagome systems have been reported including the binary Fe m X n (X = Sn, Ge; m:n = 3:1, 3:2, 1:1) family and the rare earth RMn6Sn6 (R = rare earth) family, where their kagome flat bands are calculated to be near the Fermi level in the paramagnetic phase. While partially filling a kagome flat band is predicted to give rise to a Stoner-type ferromagnetism, experimental visualization of the magnetic splitting across the ordering temperature has not been reported for any of these systems due to the high ordering temperatures, hence leaving the nature of magnetism in kagome magnets an open question. Here, we probe the electronic structure with angle-resolved photoemission spectroscopy in a kagome magnet thin film FeSn synthesized using molecular beam epitaxy. We identify the exchange-split kagome flat bands, whose splitting persists above the magnetic ordering temperature, indicative of a local moment picture. Such local moments in the presence of the topological flat band are consistent with the compact molecular orbitals predicted in theory. We further observe a large spin-orbital selective band renormalization in the Fe $${{{{\rm{d}}}}}_{{xy}}+{{{{\rm{d}}}}}_{{x}^{2}-{y}^{2}}$$ d x y + d x 2 − y 2 spin majority channel reminiscent of the orbital selective correlation effects in the iron-based superconductors. Our discovery of the coexistence of local moments with topological flat bands in a kagome system echoes similar findings in magic-angle twisted bilayer graphene, and provides a basis for theoretical effort towards modeling correlation effects in magnetic flat band systems.

Abstract Background Root nodule symbiosis (RNS) is a fascinating evolutionary event. Given that limited genes conferring the evolution of RNS in Leguminosae have been functionally validated, the genetic basis of the evolution of RNS remains largely unknown. Identifying the genes involved in the evolution of RNS will help to reveal the mystery. Results Here, we investigate the gene loss event during the evolution of RNS in Leguminosae through phylogenomic and synteny analyses in 48 species including 16 Leguminosae species. We reveal that loss of the Lateral suppressor gene, a member of the GRAS-domain protein family, is associated with the evolution of RNS in Leguminosae. Ectopic expression of the Lateral suppressor (Ls) gene from tomato and its homolog MONOCULM 1 (MOC1) and Os7 from rice in soybean and Medicago truncatula result in almost completely lost nodulation capability. Further investigation shows that Lateral suppressor protein, Ls, MOC1, and Os7 might function through an interaction with NODULATION SIGNALING PATHWAY 2 (NSP2) and CYCLOPS to repress the transcription of NODULE INCEPTION (NIN) to inhibit the nodulation in Leguminosae. Additionally, we find that the cathepsin H (CTSH), a conserved protein, could interact with Lateral suppressor protein, Ls, MOC1, and Os7 and affect the nodulation. Conclusions This study sheds light on uncovering the genetic basis of the evolution of RNS in Leguminosae and suggests that gene loss plays an essential role.

Abstract Brain disease diagnosis using multiple imaging modalities has shown superior performance compared to using single modality, yet multi-modal data is not easily available in clinical routine due to cost or radiation risk. Here we propose a synthesis-empowered uncertainty-aware classification framework for brain disease diagnosis. To synthesize disease-relevant features effectively, a two-stage framework is proposed including multi-modal feature representation learning and representation transfer based on hierarchical similarity matching. Besides, the synthesized and acquired modality features are integrated based on evidential learning, which provides diagnosis decision and also diagnosis uncertainty. Our framework is extensively evaluated on five datasets containing 3758 subjects for three brain diseases including Alzheimer’s disease (AD), subcortical vascular mild cognitive impairment (MCI), and O[6]-methylguanine-DNA methyltransferase promoter methylation status for glioblastoma, achieving 0.950 and 0.806 in area under the ROC curve on ADNI dataset for discriminating AD patients from normal controls and progressive MCI from static MCI, respectively. Our framework not only achieves quasi-multimodal performance although using single-modal input, but also provides reliable diagnosis uncertainty.

Abstract Flat electronic bands are expected to show proportionally enhanced electron correlations, which may generate a plethora of novel quantum phases and unusual low-energy excitations. They are increasingly being pursued in d-electron-based systems with crystalline lattices that feature destructive electronic interference, where they are often topological. Such flat bands, though, are generically located far away from the Fermi energy, which limits their capacity to partake in the low-energy physics. Here we show that electron correlations produce emergent flat bands that are pinned to the Fermi energy. We demonstrate this effect within a Hubbard model, in the regime described by Wannier orbitals where an effective Kondo description arises through orbital-selective Mott correlations. Moreover, the correlation effect cooperates with symmetry constraints to produce a topological Kondo semimetal. Our results motivate a novel design principle for Weyl Kondo semimetals in a new setting, viz. d-electron-based materials on suitable crystal lattices, and uncover interconnections among seemingly disparate systems that may inspire fresh understandings and realizations of correlated topological effects in quantum materials and beyond.

The Sommerfeld effect is a phenomenon in which a non-ideal prime mover fails to provide enough energy around the resonance speed in a vibration system, resulting in resonance capture and a nonlinear jump. This study discusses the successful techniques for attenuating the Sommerfeld effect in a vibration system with four degrees of freedom (DOFs) driven by a non-ideal induction motor. The kinetic equations of the system are derived using the Lagrange function. Additionally, the mean rotational speed and stability of a non-ideal motor are studied by energy balance and perturbation analysis method. Then, the relationship between electromagnetic torque and motor speed in the Sommerfeld effect is analyzed. The Sommerfeld effect exists near the natural frequencies (NFs) with electrical frequency increased or decreased. The main reason is that the gradually increasing mechanical load power of the vibrating system near the NFs contradicts the finite electromagnetic output power of the non-ideal induction motor. Moreover, the validity of the proposed methods is demonstrated through numerical analysis and simulation. The Sommerfeld effect can be effectively mitigated by appropriately increasing the damping coefficient, reducing the installation distance, and minimizing both the eccentric mass and eccentricity radius of the rotor.

AML is a malignant tumor derived from the hematopoietic system, which has a poor prognosis and its incidence is increasing recent years. LncRNAs bind to miRNAs as competitive endogenous RNAs to regulate the occurrence and progression of AML， with IL-6R playing a crucial role in hematological malignancies. However, the mechanism by which noncoding RNAs regulate IL6R expression in AML remains unclear. This study found that the AC010247.2/miR-125b-5p axis promotes AML progression by regulating IL-6R expression. Specifically, knocking down or inhibiting AC010247.2 and miR-125b-5p affected IL6R and its downstream genes. Mechanistically, AC010247.2 acts as a ceRNA for miR-125b-5p, influencing IL-6R expression. Additionally, AC010247.2's regulation of AML progression partially depends on miR-125b-5p. Notably, the AC010247.2/miR-125b-5p/IL6R axis serves as a better polygenic diagnostic marker for AML. Our study identifies a key ceRNA regulatory axis that modulates IL6R expression in AML, providing a reliable multigene diagnostic method and potential therapeutic target.

With the targets of carbon peaking and carbon neutrality, carbon emission reduction measures have become significant issues in new-type power systems. Distribution networks (DNs), which multiple power sources and flexible loads access to, play an essential role in exploiting the potential of reducing carbon emissions on the demand side. To achieve a global carbon emission reduction considering the carbon quota of each customer, shared photovoltaics (PVs) and energy storage systems (ESSs) are allocated with a centralized calculation and optimization conducted by DNs. To solve two key points in demand-side planning of shared PVs and ESSs in distribution networks, i.e., the accuracy of carbon emission flow (CEF) calculation and carbon quota-oriented optimization planning, this paper proposes a low-carbon oriented planning method for shared PVs and ESSs via CEF tracing. Firstly, a novel CEF calculation method is proposed based on the forward current sweep and backward voltage sweep algorithm, which considers the tracing of reactive power and power losses. Next, carbon emission index and economic index of allocating shared PVs and ESSs are defined. Subsequently, a bi-level optimization model is presented, considering the excess carbon emissions of each load based on carbon accounting and carbon quotas. Finally, the superiority of the proposed method is verified through a modified IEEE 33-node distribution network, and the effects of various investment constraints and carbon quotas are discussed.

Abstract In this study, a small phase angle resonant controller (SPARC) is designed to suppress the current harmonics in a permanent magnet synchronous motor (PMSM). First, the analytical model of the PMSM is established. Second, a SPARC is designed to improve the problem of the overly large phase angle of the resonant controller at the resonant frequency. Third, the frequency error caused by the SPARC discretisation is compensated online. Finally, an experimental platform is built for the PMSM harmonic suppression, and the effectiveness and feasibility of the proposed method are verified through a comparison with the method of motor control using quasi‐resonant controller.

Abstract The metabolic implications in Alzheimer’s disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-β deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

Abstract Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.

Titanium alloys have excellent properties and are widely used in aerospace, medicine, chemical industry, and other fields. With the rapid development of the powder metallurgy and 3D printing industries, the demand for ultra-fine titanium alloy powders has increased significantly. It should be noted that the particle size of titanium alloy powders determines the application process. However, the high melting point of titanium and titanium alloys and the limitation of many factors, such as the prepared powders being easily contaminated by secondary pollution, make the preparation cost higher, which restricts their promotion and application. In this study, the research progress of micro and nano titanium alloy powder preparation process is described, and the existing problems of various processes are analyzed and discussed, and it is proposed that the direct reduction in TiO2 to obtain micro and nano titanium alloy powder is the key research direction in the future. In particular, the preparation of micro and nano titanium alloy powder by “calciothermic self-propagation process” has great industrial potential.

Abstract Legume-rhizobia root-nodule symbioses involve the recognition of rhizobial Nod factor (NF) signals by NF receptors, triggering both nodule organogenesis and rhizobial infection. RinRK1 is induced by NF signaling and is essential for infection thread (IT) formation in Lotus japonicus. However, the precise mechanism underlying this process remains unknown. Here, we show that RinRK1 interacts with the extracellular domains of NF receptors (NFR1 and NFR5) to promote their accumulation at root hair tips in response to rhizobia or NFs. Furthermore, Flotillin 1 (Flot1), a nanodomain-organizing protein, associates with the kinase domains of NFR1, NFR5 and RinRK1. RinRK1 promotes the interactions between Flot1 and NF receptors and both RinRK1 and Flot1 are necessary for the accumulation of NF receptors at root hair tips upon NF stimulation. Our study shows that RinRK1 and Flot1 play a crucial role in NF receptor complex assembly within localized plasma membrane signaling centers to promote symbiotic infection.

Abstract Background Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. Methods The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice. Results Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia. Conclusions We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders.

Abstract This retrospective study aimed to investigate the impact of lumbar disc herniation (LDH) on vertebral axial rotation (VAR) in the lumbar spine, focusing on both close and distant neighboring vertebrae. A total of 516 patients with LDH and an equal number of healthy individuals were included in the study, matched for age and gender. The degree of axial rotation for each lumbar spine vertebra was assessed using the Nash–Moe index. The results revealed that the prevalence of VAR in the lumbar spine was significantly higher in the LDH group compared to the Control group (65.7% vs 46.7%, P

Abstract Background To evaluate the postoperative morbidity and mortality of patients undergoing cardiovascular surgery during the 2022 nationwide Omicron variant infection wave in China. Methods This retrospective cohort study included 403 patients who underwent cardiovascular surgery for the first time during the 2022 wave of the pandemic within 1 month. Among them, 328 patients were preoperatively diagnosed with COVID-19 Omicron variant infection during the pandemic, and 75 patients were negative. The association between Omicron variant exposure and postoperative prognosis was explored by comparing patients with and without COVID-19 exposure. The primary outcome was in-hospital death after cardiovascular surgery. The secondary outcomes were major postoperative morbidity, including myocardial infarction (MI), acute kidney injury (AKI), postoperative mechanical ventilation hours, ICU stay hours, and postoperative length of stay. The data were analyzed using inverse probability of treatment weighting (IPTW) to minimize bias. Results We identified 403 patients who underwent cardiovascular surgery, 328 (81.39%) had Omicron variant infections. In total, 10 patients died in the hospital. Omicron variant infection was associated with a much greater risk of death during cardiovascular surgery after adjustment for IPTW (2.8% vs. 1.3%, adjusted OR 2.185, 95%CI = 1.193 to 10.251, P = 0.041). For major postoperative morbidity, there were no significant differences in terms of myocardial infarction between the two groups (adjusted OR = 0.861, 95%CI = 0.444 to 1.657, P = 0.653), acute kidney injury (adjusted OR = 1.157, 95%CI = 0.287 to 5.155, P = 0.820), postoperative mechanical ventilation hours (B -0.375, 95%CI=-8.438 to 7.808, P = 0.939), ICU stay hours (B 2.452, 95%CI=-13.269 to 8.419, P = 0.660) or postoperative stay (B -1.118, 95%CI=-2.237 to 1.154, P = 0.259) between the two groups. Conclusion Perioperative COVID-19 infection was associated with an increased risk of in-hospital death among patients who underwent cardiovascular surgery during the Omicron variant wave of the pandemic.

Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.

Lattice symmetries are central to the characterization of electronic topology. Recently, it was shown that Green's function eigenvectors form a representation of the space group. This formulation has allowed the identification of gapless topological states even when quasiparticles are absent. Here we demonstrate the profundity of the framework in the extreme case, when interactions lead to a Mott insulator, through a solvable model with long-range interactions. We find that both Mott poles and zeros are subject to the symmetry constraints, and relate the symmetry-enforced spectral crossings to degeneracies of the original noninteracting eigenstates. Our results lead to new understandings of topological quantum materials and highlight the utility of interacting Green's functions toward their symmetry-based design.

This patient was an elderly patient with abdominal distension and shortness of breath. According to relevant examinations, his condition was initially considered to be related to cirrhosis, but pathological biopsy confirmed the diagnosis of noncirrhotic portal hypertension of unknown etiology. The portal vein pressure was significantly reduced after transjugular intrahepatic portosystemic shunt (TIPS). Nevertheless, the relief of the hydrothorax and ascites was not significant, and the numbness in both lower limbs gradually worsened. POEMS syndrome was ultimately diagnosed following a comprehensive examination. After two courses of bortezomib combined with dexamethasone, the patient died due to a systemic infection. The clinical symptoms of the patient were atypical, as was the presence of portal hypertension, which hindered the diagnosis of POEMS. Due to the patient’s advanced age, the diagnosis was delayed, and the prognosis was poor. This case reminds clinicians that POEMS patients can also have portal hypertension as the main manifestation.

The stimulator of interferon genes (STING), an integral adaptor protein in the DNA-sensing pathway, plays a pivotal role in the innate immune response against infections. Additionally, it presents a valuable therapeutic target for infectious diseases and cancer. We observed that fangchinoline (Fan), a bis-benzylisoquinoline alkaloid (BBA), effectively impedes the replication of vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), influenza A virus (H1N1), and herpes simplex virus-1 (HSV-1) in vitro. Fan treatment significantly reduced the viral load, attenuated tissue inflammation, and improved survival in a viral sepsis mouse model. Mechanistically, Fan activates the antiviral response in a STING-dependent manner, leading to increased expression of interferon (IFN) and interferon-stimulated genes (ISGs) for potent antiviral effects in vivo and in vitro. Notably, Fan interacts with STING, preventing its degradation and thereby extending the activation of IFN-based antiviral responses. Collectively, our findings highlight the potential of Fan, which elicits antiviral immunity by suppressing STING degradation, as a promising candidate for antiviral therapy.

During the COVID-19 pandemic, quarantines effectively prevented the spread of COVID-19 but also caused people to develop mental health problems. We thus aimed to verify the impact of social support and resilience on mental health and to uncover the moderating role played by time in isolation during the post-pandemic era. We administered a cross-sectional survey to 510 college students. The results found that social support directly and negatively predicted mental health problems, and this relationship was mediated by resilience. Through multigroup analysis, resilience partially mediated the relationship between social support and mental health during period of isolation 1 (PI1) and fully mediated this relationship during period of isolation 2 (PI2) and period of isolation 3 (PI3). Moreover, the path coefficient of resilience to mental health at T3 was significantly higher than that at T2. Thus, the effect of resilience on mental health increases with the duration of time in isolation.

Summary: The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

Despite the widespread interest in starch-based nanogels due to their excellent swelling capacity and biocompatibility, there is a lack of in-depth analysis in the existing literature on the effects of their preparation methods, internal structure, and physicochemical properties on the release, retention, and protection of bioactive when used as delivery systems. In addition, there is a lack of systematic integration and discussion on the theoretical basis of how to design starch-based nanogels with specific structures and functions and the specific functions of these nanogels in oral-gastrointestinal digestive delivery systems. In this review, the preparation methods, characterization, and functions of starch-based nanogels are discussed in association with the delivery process to further understand the influence that the preparation method, as well as the structural and physicochemical characteristics have on the construction of the nanogel. This review aims to offer a theoretical foundation for designing starch-based nanogels with specific structures and functions. Summarizing functions of starch-based nanogels in an oral–gastrointestinal digestive delivery system can lay the foundation for the further development of starch-based nanogels as delivery systems. Furthermore, it can also deliver valuable insights and direct the development of healthy food items in an industrial setting.

Abstract Background Domesticated pigs serve as an ideal animal model for biomedical research and also provide the majority of meat for human consumption in China. Porcine intramuscular fat content associates with human health and diseases and is essential in pork quality. The molecular mechanisms controlling lipid metabolism and intramuscular fat accretion across tissues in pigs, and how these changes in response to pig breeds, remain largely unknown. Results We surveyed the tissue-resident cell types of the porcine jejunum, colon, liver, and longissimus dorsi muscle between Lantang and Landrace breeds by single-cell RNA sequencing. Combining lipidomics and metagenomics approaches, we also characterized gene signatures and determined key discriminating markers of lipid digestibility, absorption, conversion, and deposition across tissues in two pig breeds. In Landrace, lean-meat swine mainly exhibited breed-specific advantages in lipid absorption and oxidation for energy supply in small and large intestinal epitheliums, nascent high-density lipoprotein synthesis for reverse cholesterol transport in enterocytes and hepatocytes, bile acid formation, and secretion for fat emulsification in hepatocytes, as well as intestinal-microbiota gene expression involved in lipid accumulation product. In Lantang, obese-meat swine showed a higher synthesis capacity of chylomicrons responsible for high serum triacylglycerol levels in small intestinal epitheliums, the predominant characteristics of lipid absorption in muscle tissue, and greater intramuscular adipcytogenesis potentials from muscular fibro-adipogenic progenitor subpopulation. Conclusions The findings enhanced our understanding of the cellular biology of lipid metabolism and opened new avenues to improve animal production and human diseases. Video Abstract

Abstract. Background:. Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. Methods:. In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl4), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. Results:. We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. Conclusion:. We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Abstract Background Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the initial pathophysiological mechanism of Alzheimer’s disease (AD). The study aims to investigate the association between mGluR5 availability and AD’s biomarkers and cognitive function. Methods We examined 35 individuals with mGluR5 tracer [18F]PSS232 to assess mGluR5 availability, and with [18F]Florbetapir PET to assess global amyloid deposition, and [18F]FDG PET to assess glucose metabolism. The plasma neurofilament light (NfL) and p-tau181 levels in a subset of individuals were measured (n = 27). The difference in mGluR5 availability between the AD and normal control (NC) groups was explored. The associations of mGluR5 availability with amyloid deposition, glucose metabolism, gray matter volume (GMV), neuropsychological assessment scores, and plasma biomarkers were analyzed. Results The mGluR5 availability was significantly reduced in AD patients’ hippocampus and parahippocampal gyrus compared to NCs. Global amyloid deposition was positively associated with mGluR5 availability in the AD group and reversely associated in the NC group. The mGluR5 availability was positively correlated with regional glucose metabolism in the overall and stratified analyses. The availability of mGluR5 in the hippocampus and parahippocampal gyrus demonstrated a strong relationship with the GMV of the medial temporal lobe, plasma p-tau181 or NfL levels, and global cognitive performance. Conclusions [18F]PSS232 PET can quantify the changes of mGluR5 availability in the progression of AD. mGluR5 availability correlated not only with neuropathological biomarkers of AD but also with neurodegenerative biomarkers and cognitive performance. mGluR5 may be a novel neurodegenerative biomarker, and whether mGluR5 could be a potential therapeutic target for AD needs to be further studied.

AIM: To investigate the preoperative ocular symptoms and the characteristics of asymptomatic ocular surface abnormalities in hospitalized patients with primary pterygium.METHODS: Cross-sectional study. Hospitalized patients diagnosed with primary pterygium and scheduled to receive pterygium excision surgery at the Xiamen Eye Center of Xiamen University from August 2022 to October 2022 were enrolled. Ocular surface disease index questionnaire(OSDI), six examinations including non-invasive tear film break-up time, Schirmer I test, tear meniscus height, lid margin abnormality, meibomian gland dropout and tear film lipid layer thickness, and anterior segment optical coherence tomography(AS-OCT)were performed and statistically analyzed.RESULTS: A total of 178 cases(178 eyes), with a mean age of 54.39±10.75 years old, were recruited, including 75 males(42.1%)and 103 females(57.9%). The average values of ocular surface parameters in these patients included OSDI: 11.47±9.69, tear film break-up time: 7.10±3.86 s; tear meniscus height: 0.16±0.07 mm, Schirmer I test values: 14.39±7.29 mm/5 min, and pterygium thickness: 504.74±175.87 μm. Totally 161 eyes(90.4%)presented with abnormal lid margin, 44 eyes(24.7%)presented with meibomian gland dropout score ≥4, 52 eyes(29.2%)presented with low lipid layer thickness. In the 6 objective examinations, abnormalities in at least 4 of these tests were found in 85.4% of eyes. Pterygium morphology was classified into four grades: 10 eyes(5.6%)of grade Ⅰ, 93 eyes(52.2%)of grade Ⅱ, 60 eyes(33.7%)of grade Ⅲ, and 15 eyes(8.4%)of grade Ⅳ. In patients with a higher grade of pterygium, the tear film break-up time was lower, and the proportion of abnormal lid margin was also significantly higher(P

Abstract Background Studies have shown that the wet suction technique in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) generates better histological diagnostic accuracy and specimen quality than the dry suction technique. However, conclusions of wet suction on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) are still controversial. Besides, the optimal number of passes for EUS-FNB has not been determined. We aimed to design a large multicenter randomized trial to compare the diagnostic accuracy of dry suction versus wet suction technique in solid pancreatic lesions (SPLs) using 22G Franseen needles and determine the optimal number of passes required for EUS-FNB. Methods This is a multi-center open-label, randomized controlled non-inferiority trial with two parallel groups. Two hundred patients with SPLs will undergo EUS-FNB using 22G Franseen needles in 4 tertiary hospitals in China and will be randomly assigned to the dry suction group and wet suction group in a ratio of 1:1. The primary endpoint is diagnostic accuracy. Secondary endpoints include the optimal number of needle passes, sensitivity, specificity, specimen quality, cytological diagnoses, time of the procedure, and incidence of complications. Discussion This study has been designed to determine (i) whether EUS-FNB using 22G Franseen needle with dry suction is non-inferior to wet suction in terms of diagnostic accuracy and (ii) the optimal number of passes during EUS-FNB of SPLs using 22G Franseen needle. Trial registration ClinicalTrials.gov NCT05549856. Registered on September 22, 2022.

Understanding the effects of bacteria and enzyme addition on mixed crop silage is imperative for dairy producers to make informed decisions. The current study evaluated the chemical changes in silage prepared from different ramie and elephant grass ratios (30:70, 50:50, 70:30, and 100:0) in response to bacteria (0, 100, 200, and 300 mg/kg) and enzyme addition (0, 10, 20, and 30 mg/kg) in a complete randomized design. The results indicated that the proportion of ramie in silage (p < 0.01), level of bacteria (p < 0.05), and level of enzyme added (p = 0.05) affected the CP, fiber, volatile fatty acids, and lactic acid contents and pH of silage. By comprehensive analysis, low lignin content and pH of silage with high lactic acid content was observed with a 30% ramie proportion. High CP and lactic acid contents with low ADF, lignin, and pH values were observed with the addition of bacteria (p < 0.05). High lactic acid with low ADF content was observed with the addition of enzyme in silage (p ≤ 0.05). The optimum quality of silage was observed when the ramie, bacteria, and enzymes were added at the levels of 30%, 200 mg/kg, and 20 mg/kg, respectively, in ramie and elephant grass mixed silage.

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK–delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK–delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK–delta8 rather than wild-type CENPK, underscoring the role of CENPK–delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine.

There is extensive current interest in electronic topology in correlated settings. In strongly correlated systems, contours of Green's function zeros may develop in frequency-momentum space, and their role in correlated topology has increasingly been recognized. However, whether and how the zeros contribute to electronic properties is a matter of uncertainty. Here we address the issue in an exactly solvable model for a Mott insulator. We show that the Green's function zeros contribute to several physically measurable correlation functions in a way that does not run into inconsistencies. In particular, the physical properties remain robust to chemical potential variations up to the Mott gap, as it should be based on general considerations. Our work sets the stage for further understandings of the rich interplay among topology, symmetry, and strong correlations.

Flax powdery mildew (PM), caused by Oidium lini, is a globally distributed fungal disease of flax, and seriously impairs its yield and quality. To data, only three resistance genes and a few putative quantitative trait loci (QTL) have been reported for flax PM resistance. To dissect the resistance mechanism against PM and identify resistant genetic regions, based on four years of phenotypic datasets (2017, 2019 to 2021), a genome-wide association study (GWAS) was performed on 200 flax core accessions using 674,074 SNPs and 7 models. A total of 434 unique quantitative trait nucleotides (QTNs) associated with 331 QTL were detected. Sixty-four loci shared in at least two datasets were found to be significant in haplotype analyses, and 20 of these sites were shared by multiple models. Simultaneously, a large-effect locus (qDI 11.2) was detected repeatedly, which was present in the mapping study of flax pasmo resistance loci. Oil flax had more QTL with positive-effect or favorable alleles (PQTL) and showed higher PM resistance than fiber flax, indicating that effects of these QTL were mainly additive. Furthermore, an excellent resistant variety C120 was identified and can be used to promote planting. Based on 331 QTLs identified through GWAS and the statistical model GBLUP, a genomic selection (GS) model related to flax PM resistance was constructed, and the prediction accuracy rate was 0.96. Our results provide valuable insights into the genetic basis of resistance and contribute to the advancement of breeding programs.

Background The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors immunotherapy landscape.Methods By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).Results While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.Conclusions We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.Trial registration number NCT06165874.

Introduction Urinary incontinence (UI) is one of the most common chronic diseases among women, which can endanger their physical and mental health and incur a heavy financial burden on both individuals and society. Web-based interventions (WBIs) have been applied to manage women’s UI, but their effectiveness has remained inconclusive. This systematic review and meta-analysis aims to explore the effectiveness of WBIs on self-reported symptom severity, condition-specific quality of life, adherence to pelvic floor muscle training (primary outcomes) and other extensive secondary outcomes among women with UI. We also aimed to investigate whether intervention characteristics (format, interactivity and main technology) have impacts on the effectiveness of primary outcomes.Methods and analysis This systematic review protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. 10 electronic databases will be comprehensively searched from their inception to 1 May 2024, along with grey literature searches and manual reviews of relevant reference lists to identify eligible randomised controlled trials. The methodological quality of the included studies will be assessed by two reviewers based on the Cochrane Risk of Bias Tool. Meta-analyses will be conducted via Stata V.12.0. Leave-one-out sensitivity analyses will be performed, and publication bias will be evaluated using funnel plots and Egger’s test. Subgroup analyses regarding intervention format, interactivity and main technology will be carried out.Ethics and dissemination No ethics approval is needed for this review since no primary data are to be collected. The results of this review will help develop an optimal WBI for women with UI, thereby providing them with maximum benefits. The findings will be disseminated via a peer-reviewed journal or conference presentation.PROSPERO registration number CRD42023435047.

Purpose: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. Methods: Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-β), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. Results: Reduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. Conclusion: These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.

Summary: Life cycle Human System Integration (HSI) practices are crucial for optimizing human system performance, reducing costs, and ensuring safety. To address the limited HSI practices under typical Human Readiness Levels (HRLs), our study proposes an HSI theoretical framework and applies it to the design of human-machine interfaces (HMIs) for special vehicles. A stakeholder survey evaluates effectiveness of the framework and its application. Conclusions: (1) The framework, based on the input-process-output model, covers HSI processes and their support across HRLs. (2) The case study of HMI design in HRLs 4–6 identifies key processes and their specific support, contributing to the refinement of the framework. (3) The stakeholder survey underscores the importance and effectiveness of HSI processes and their support in the case study for life cycle human factor practices, suggesting areas for improvement in structuring and operability. The study offers insights into HSI practices under typical HRLs, merging theoretical and case study perspectives.

Abstract Creeping fat is a typical feature of Crohn’s disease. It refers to the expansion of mesenteric adipose tissue around inflamed and fibrotic intestines and is associated with stricture formation and intestinal obstruction. In this study, we characterize creeping fat as pro-adipogenic and pro-fibrotic. Lipidomics analysis of Crohn’s disease patients (sixteen males, six females) and healthy controls (five males, ten females) reveals abnormal lipid metabolism in creeping fat. Through scRNA-seq analysis on mesenteric adipose tissue from patients (five males, one female) and healthy controls (two females), we identify a CCL2+DPP4+ subset of mesenchymal stem cells that expands in creeping fat and expedites adipogenic differentiation into dystrophic adipocytes in response to CCL20+CD14+ monocytes and IL-6, leading to the formation of creeping fat. Ex vivo experiments (tissues from five males, one female) confirm that both CCL20+CD14+ monocytes and IL-6 activate DPP4+ mesenchymal stem cells towards a pro-adipogenic phenotype. This study provides a comprehensive investigation of creeping fat formation and offers a conceptual framework for discovering therapeutic targets for treatment of Crohn’s disease.

Abstract Chinese cordyceps was one of most valuable traditional Chinese medicine fungi. To elucidate the molecular mechanisms related to energy supply mechanism involved in the initiation and formation of primordium in Chinese cordyceps, we performed the integrated metabolomic and transcriptomic analyses of it at pre-primordium period, primordium germination period and after-primordium period, respectively. Transcriptome analysis showed that many genes related to ‘starch and sucrose metabolism’, ‘fructose and mannose metabolism’, ‘linoleic acid metabolism’, ‘fatty acids degradation’ and ‘glycerophospholipid metabolism’ were highly up-regulated at primordium germination period. Metabolomic analysis showed many metabolites regulated by these genes in these metabolism pathways were also markedly accumulated at this period. Consequently, we inferred that carbohydrate metabolism and β-oxidation pathway of palmitic acid and linoleic acid worked cooperatively to generate enough acyl-CoA, and then entered TCA cycle to provide energy for fruiting body initiation. Overall, our finding provided important information for further exploring the energy metabolic mechanisms of realizing the industrialization of Chinese cordyceps artificial cultivation.

The Chinese caterpillar mushroom, Ophiocordyceps sinensis (O. sinensis), is a rarely medicinal fungus in traditional chinese herbal medicine due to its unique medicinal values, and the expression stability of reference genes is essential to normalize its gene expression analysis. In this study, BestKeeper, NormFinder and geNorm, three authoritative statistical arithmetics, were applied to evaluate the expression stability of sixteen candidate reference genes (CRGs) in O. sinensis under different stress [low temperature (4°C), light treatment (300 lx), NaCl (3.8%)] and different development stages (mycelia, primordia and fruit bodies) and formation of morphologic mycelium (aeriasubstrate, hyphae knot mycelium). The paired variation values indicated that two genes could be enough to accurate standardization exposed to different conditions of O.sinensis. Among these sixteen CRGs, 18S ribosomal RNA (18S rRNA) and beta-Tubulin (β-TUB) showed the topmost expression stability in O.sinensis exposed to all conditions, while glutathione hydrolase proenzym (GGT) and Phosphoglucose isomerase (PGI) showed the least expression stability. The optimal reference gene in different conditions was various. β-TUB and Ubiquitin (UBQ) were identified as the two most stable genes in different primordia developmental stage, while phosphoglucomutase (PGM) with elongation factor 1-alpha (EF1-α) and 18S rRNA with UBQ were the most stably expressed for differentially morphologic mycelium stages and different stresses, respectively. These results will contribute to more accurate evaluation of the gene relative expression levels in O.sinensis under different conditions using the optimal reference gene in real-time quantitative PCR (RT-qPCR) analysis.

Antibiotic resistance in Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus remains a major public health concern worldwide. Furthermore, these microbes frequently co-exist in biofilm-associated infections, largely nullifying antibiotic-based therapy. Therefore, it is imperative to develop an efficient therapeutic strategy for combating infections caused by polymicrobial biofilms. In this study, we investigated the antibacterial and antibiofilm activity of the bacteriophage endolysin Ply113 in vitro. Ply113 exhibited high and rapid lytic activity against E. faecium, E. faecalis, and S. aureus, including vancomycin-resistant Enterococcus and methicillin-resistant S. aureus isolates. Transmission electron microscopy revealed that Ply113 treatment led to the detachment of bacterial cell walls and considerable cell lysis. Ply113 maintained stable lytic activity over a temperature range of 4–45°C, over a pH range of 5.0–8.0, and in the presence of 0–400 mM NaCl. Ply113 treatment effectively eliminated the mono-species biofilms formed by E. faecium, E. faecalis, and S. aureus in a dose-dependent manner. Ply113 was also able to eliminate the dual-species biofilms of E. faecium–S. aureus and E. faecalis–S. aureus. Additionally, Ply113 exerted potent antibacterial efficacy in vivo, distinctly decreasing the bacterial loads in a murine peritoneal septicemia model. Our findings suggest that the bacteriophage endolysin Ply113 is a promising antimicrobial agent for the treatment of polymicrobial infections.

ABSTRACTStreptococcus suis is a zoonotic Gram-positive bacterium that causes invasive infections such as sepsis and meningitis, threatening public health worldwide. For successful establishment of infection, the bacterium should subvert the innate effectors of immune defence, including the cathelicidin family of host-defence peptides that combat pathogenic bacteria by directly disrupting cell membranes and coordinating immune responses. Here, our study shows that an extracellular endopeptidase O (PepO) of S. suis contributes to assisting the bacterium to resist cathelicidin-mediated killing, as the deletion of the pepO gene makes S. suis more sensitive to the human cathelicidin LL-37, as well as its mouse equivalent, mCRAMP. This protease targets and cleaves both LL-37 and mCRAMP, degrading them into shorter peptides with only a few amino acids, thereby abrogating their ability to kill S. suis. By cleaving LL-37 and mCRAMP, PepO impairs their chemotactic properties for neutrophil migration and undermines their anti-apoptosis activity, which is required for prolonging neutrophil lifespan. Also, PepO inhibits the ability of LL-37 and mCRAMP to promote lysosome development in macrophages. Moreover, the loss of PepO attenuates organ injury and decreases bacterial burdens in a murine model of S. suis bacteraemia. Taken together, these data provide novel insights into the role of the intrinsic proteolytic characteristics of PepO in S. suis-host interaction. Our findings demonstrate that S. suis utilizes the PepO protease to cleave cathelicidins, which is an immunosuppressive strategy adopted by this bacterium to facilitate pathogenesis.

Abstract For a receiver of the BeiDou Satellite Based Augmentation System (BDSBAS), the acquisition aims to coarsely estimate the pseudo‐code delays and carrier Doppler shifts of the received signals. The use of downsampling techniques to accelerate this acquisition process for weak signals has been an emerging topic. However, the acquisition probabilities of conventional algorithms with downsampling are inadequate and need to be enhanced to prevent excessive false alarms due to degradation of the peak signal‐to‐noise ratios (PSNRs) during acquisition. To improve signal acquisition performance, we introduce an enhancer function before downsampling to achieve the minimum PSNR loss during acquisition. Then, we use graphic processing unit (GPU) functions to speed up the processing loop, matrix multiplication and fast Fourier transform operations. We thus present a fast GPU‐based acquisition method by using minimum loss and downsampling techniques. Our experimental results show the remarkable effectiveness of our method for receiving weak BDSBAS signals as compared to legacy downsampling algorithms. This work seeks not only to solve the current issue of achieving fast acquisition of weak BDSBAS signals but also to inspire creative new ideas that spur further advances in this promising field in the future.

Abstract Background Accurate prediction of cerebral amyloidosis with easily available indicators is urgently needed for diagnosis and treatment of Alzheimer’s disease (AD). Methods We examined plasma Aβ42, Aβ40, T-tau, P-tau181, and NfL, with APOE genotypes, cognitive test scores and key demographics in a large Chinese cohort (N = 609, aged 40 to 84 years) covering full AD spectrum. Data-driven integrated computational models were developed to predict brain β-amyloid (Aβ) pathology. Results Our computational models accurately predict brain Aβ positivity (area under the ROC curves (AUC) = 0.94). The results are validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Particularly, the models have the highest prediction power (AUC = 0.97) in mild cognitive impairment (MCI) participants. Three levels of models are designed with different accuracies and complexities. The model which only consists of plasma biomarkers can predict Aβ positivity in amnestic MCI (aMCI) patients with AUC = 0.89. Generally the models perform better in participants without comorbidities or family histories. Conclusions The innovative integrated models provide opportunity to assess Aβ pathology in a non-invasive and cost-effective way, which might facilitate AD-drug development, early screening, clinical diagnosis and prognosis evaluation.

Abstract Antibiotic resistance and the ability to form biofilms of Enterococcus faecalis have compromised the choice of therapeutic options, which triggered the search for new therapeutic strategies, such as the use of phage endolysins and antimicrobial peptides. However, few studies have addressed the synergistic relationship between these two promising options. Here, we investigated the combination of the phage endolysin Ply2660 and the antimicrobial peptide LL-37 to target drug-resistant biofilm-producing E. faecalis. In vitro bactericidal assays were used to demonstrate the efficacy of the Ply2660–LL-37 combination against E. faecalis. Larger reductions in viable cell counts were observed when Ply2660 and LL-37 were applied together than after individual treatment with either substance. Transmission electron microscopy revealed that the Ply2660–LL-37 combination could lead to severe cell lysis of E. faecalis. The mode of action of the Ply2660–LL-37 combination against E. faecalis was that Ply2660 degrades cell wall peptidoglycan, and subsequently, LL-37 destroys the cytoplasmic membrane. Furthermore, Ply2660 and LL-37 act synergistically to inhibit the biofilm formation of E. faecalis. The Ply2660–LL-37 combination also showed a synergistic effect for the treatment of established biofilm, as biofilm killing with this combination was superior to each substance alone. In a murine peritoneal septicemia model, the Ply2660–LL-37 combination distinctly suppressed the dissemination of E. faecalis isolates and attenuated organ injury, being more effective than each treatment alone. Altogether, our findings indicate that the combination of a phage endolysin and an antimicrobial peptide may be a potential antimicrobial strategy for combating E. faecalis.