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The β-1–6-linked poly-N-acetylglucosamine (PNAG) polymer is a conserved surface polysaccharide produced by many bacteria, fungi, and protozoan (and even filarial) parasites. This wide-ranging expression makes PNAG an attractive target for vaccine development, as it potentially encompasses a broad range of microorganisms. Significant progress has been made in discovering important properties of the biology of PNAG expression in recent years. The molecular characterization and regulation of operons for the production of PNAG biosynthetic proteins and enzymes have been studied in many bacteria. In addition, the physiological function of PNAG has been further elucidated. PNAG-based vaccines and PNAG-targeting antibodies have shown great efficacy in preclinical research. Furthermore, clinical tests for both vaccines and antibodies have been carried out in humans and economically important animals, and the results are promising. Although it is not destined to be a smooth road, we are optimistic about new vaccines and immunotherapeutics targeting PNAG becoming validated and eventually licensed for clinical use against multiple infectious agents.

Abstract The influence of precipitated nanophases on the mechanical properties of Fe-based amorphous nanocrystalline alloys is an urgent issue to be explored. Two amorphous nanocrystalline alloys, i.e., (Fe0.9Ni0.1)86B14 and (Fe0.7Ni0.3)86B14 containing nanophase of the body-centered cubic and face-centered cubic structures, respectively, were selected to investigate the effect of the structure and volume fraction of nanophase on their mechanical properties. The results of nanoindentation experiments and the calculation of the volume and size of the shear transition zone reveal that the two alloys show different mechanical properties. When the volume fraction of the nanophase in (Fe0.9Ni0.1)86B14 is larger than 50%, the elastic modulus is increased suddenly and the volume and size of the shear transition zone is decreased dramatically, while no dramatic change occurs in (Fe0.7Ni0.3)86B14. Moreover, it was found by using molecular dynamics simulations that the main reason for these abnormal mechanical properties is the change of cluster type in the system due to the incorporation of nanophases with different structures.

Abstract Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25–0.5 μg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

The effect of the volume fraction of nanocrystals on the macroscopic mechanical properties and microscopic atomic structure of Fe-based nanocrystalline alloys, as well as the relationship between the two, is an urgent issue to be explored. Seven nanocrystalline alloys with different volume fractions of nanocrystals were formed by annealing treatment of (Fe0·9Ni0.1)86B14 amorphous precursor. Through hardness, flat plate bending, and nanoindentation experiments, it is found that when the volume fraction of nanocrystals reaches the range of 45–55 %, there is an abrupt change in the macroscopic mechanical properties. Specifically, when the volume fraction is less than this range, the properties inherit the amorphous matrix, however, larger than this range, the properties are dominated by precipitated nanocrystalline phases. Meanwhile, based on the molecular dynamics simulation method, seven Fe90Ni10 amorphous nanocrystalline models with different volume fractions of body-centered cubic nanocrystals are established, and the deformation mechanism of models and the evolution of their microstructures during the nanoindentation process are obtained intuitively. Moreover, it is further revealed that the significant changes in the Voronoi polyhedral index, which represents the microscopic atomic structure in this range of nanocrystal volume fractions, are the main reason for the abrupt changes in the mechanical properties at the macroscopic level.

Background: Glycoprotein non-metastatic melanoma B (GPNMB)/osteoactivin was first identified in the human melanoma cell lines. GPNMB plays a key role in the anti-inflammatory and antioxidative functions as well as osteoblast differentiation, cancer progression, and tissue regeneration. Recently, GPNMB was used as an anti-aging vaccine for mice. The present study aimed to investigate the potential of biofluid GPNMB as an aging biomarker in humans using serum and urine samples from an aging Chinese population. Methods: We analyzed RNA-sequencing data (GSE132040) from 17 murine organs across different ages to assess the gene expression of potential ageing biomarkers. Spearman's correlation coefficients were used to evaluate the relationship between gene expression and age. Meanwhile, a cross-sectional population study was conducted, which included 473 participants (aged 25–91 years), a representative subset of participants from the Peng Zu Study on Healthy Ageing in China (Peng Zu Cohort). Biofluid GPNMB levels were measured by ELISA. The associations of serum and urine GPNMB levels with various clinical and anthropometrical indices were assessed using ANOVA, Kruskal-Wallis H test, and univariate and multivariate linear regression analyses. Results: In mice, the Gpnmb mRNA expression levels showed a significant positive association with age in multiple organs in mice (P

Abstract Objective The preoperative identification of tumor grade in chondrosarcoma (CS) is crucial for devising effective treatment strategies and predicting outcomes. The study aims to build and validate a CT-based radiomics nomogram (RN) for the preoperative identification of tumor grade in CS, and to evaluate the correlation between the RN-predicted tumor grade and postoperative outcome. Methods A total of 196 patients (139 in the training cohort and 57 in the external validation cohort) were derived from three different centers. A clinical model, radiomics signature (RS) and RN (which combines significant clinical factors and RS) were developed and validated to assess their ability to distinguish low-grade from high-grade CS with area under the curve (AUC). Additionally, Kaplan-Meier survival analysis was applied to examine the association between RN-predicted tumor grade and recurrence-free survival (RFS) of CS. The predictive accuracy of the RN was evaluated using Harrell’s concordance index (C-index), hazard ratio (HR) and AUC. Results Size, endosteal scalloping and active periostitis were selected to build the clinical model. Three radiomics features, based on CT images, were selected to construct the RS. Both the RN (AUC, 0.842) and RS (AUC, 0.835) were superior to the clinical model (AUC, 0.776) in the validation set (P = 0.003, 0.040, respectively). A correlation between Nomogram score (Nomo-score, derived from RN) and RFS was observed through Kaplan-Meier survival analysis in the training and test cohorts (log-rank P

BackgroundCatastrophic Antiphospholipid Syndrome (CAPS), a severe systemic autoimmune disorder, predominantly causes life-threatening multi-organ failure, with a high mortality rate. It primarily affects small vessels, seldom impacting large vessels. Notably, acute massive pulmonary embolism (PE) with bilateral atrial thrombosis is an exceptional occurrence in CAPS. Acute pulmonary embolism (PE) is a common cardiovascular disease that progresses rapidly and has a high mortality rate. Acute massive PE combined with bilateral atrial thrombosis has an even higher mortality rate. PE treatments primarily include pharmaceuticals, catheter interventions, and surgical measures, with integrated treatment strategies demonstrating promising outcomes in clinical practice. Extracorporeal membrane oxygenation (ECMO) can provide cardiopulmonary support for the treatment of high-risk PE patients and is a proven therapeutic measure.MethodsThis report presents the case of a 52-year-old male admitted due to fever and sudden onset of impaired consciousness, with cardiac ultrasound and pulmonary artery CT angiography revealing an acute large-scale pulmonary embolism accompanied by bilateral atrial thrombosis, with the condition rapidly worsening and manifesting severe respiratory and circulatory failure. With ECMO support, the patient underwent a thrombectomy using an AngioJet intervention. The diagnosis of CAPS was confirmed through clinical presentation and laboratory examination, and treatment was adjusted accordingly.ResultsThe patient made a successful recovery and was subsequently discharged from the hospital.ConclusionIn CAPS patients, the rare instance of acute massive PE accompanied by bilateral atrial thrombosis significantly risks severe respiratory and circulatory failure, adversely affecting prognosis. Early initiation of ECMO therapy is crucial, offering a vital opportunity to address the root cause. In this case report the patient was successfully treated with an AngioJet thrombectomy supported by ECMO.

Barth syndrome (BTHS) is a mitochondrial lipid disorder caused by mutations in TAFAZZIN (TAZ), required for cardiolipin (CL) remodeling. Cardiomyopathy is a major clinical feature, with no curative therapy. Linoleic acid (LA) supplementation is proposed to ameliorate BTHS cardiomyopathy by enhancing linoleoyl group incorporation into CL. While the beneficial effect of dietary LA supplementation in delaying the development of BTHS cardiomyopathy has been recently tested, its potential to reverse established BTHS cardiomyopathy remains unclear. Our study revealed that LA supplementation cannot rescue established BTHS cardiomyopathy in mice, highlighting the importance of early initiation of LA supplementation for maximum benefits.

The amorphous alloy transformer with three-dimensional wound core (TDWC) is a new type of transformer structure. Compared with the traditional three-phase five-column transformer with planar wound core (PWC), the TDWC structure exhibits a fully symmetrical magnetic circuit, resulting in enhanced short-circuit withstand capability. However, the vibration noise of the core becomes a significant engineering challenge in the design and manufacturing process due to the larger magnetostrictive coefficient of the amorphous alloy. This study establishes a magnetic-mechanical coupling mathematical model for amorphous alloy TDWC considering the magnetostrictive effect. Three-dimensional finite element analysis (FEA) is adopted to calculate the flux and vibration displacement distribution of the TDWC. Additionally, an experimental validation is conducted on a 200kVA amorphous alloy TDWC prototype to verify the accuracy of the model. Furthermore, a comparison with the PWC prototype demonstrates that the TDWC structure can effectively reduce surface vibrations, and the dominant frequency distribution law of vibration displacement at different positions of the TDWC structure is revealed, providing a foundation for the design of vibration reduction and noise control for TDWC.

The primary atomization process is simulated by Volume of Fluid (VOF) model and dynamic adaptive mesh method. The influence of melt mass flow rate and atomization pressure on the breakup process is investigated, and the effect of hot gas atomization is also evaluated. The results show that the breakup is insufficient when the melt mass flow rate is larger than 0.075 kg s−1, while the liquid film breakup inducing the nozzle clogging occurs when the melt mass flow rate is too low (0.025 kg s−1). The backflow of droplets occurs at low atomization pressure (1.0 MPa), and various defects (satellite powders, hollow powders and needle-shaped powders) appear when the atomization pressure is larger than 3.0 MPa. Although the breakup efficiency can be significantly improved by increasing the gas temperature, severe deformation of the gas-liquid interface is induced due to the Kelvin–Helmholtz wave and gas-liquid interaction, easily leading to the formation of hollow powders. Besides, the gas-to-melt ratio (GMR) is identified as a simple criterion for predicting primary atomization breakup modes, with liquid film breakup occurring when GMR≥4.4 and ''fountain'' breakup occurring when GMR≤4.3. In this work, not only the gas-liquid interaction is systematically analyzed by establishing a flow-heat transfer-VOF coupling model, but also the GMR is proposed to predict the breakup mode in the industrial production, which can provide theoretical and methodological guidance for the optimization of atomization operational parameters.

Abstract Background Leptospirosis is an infectious disease caused by pathogenic Leptospira spp., which could result in severe illnesses. Indirect contact with these pathogens is more common. Individuals could contract this disease through contact with contaminated water or during floods. In this case, we present the details of a 40-year-old male pig farmer who suffered from severe pulmonary hemorrhagic leptospirosis and multiple organ failure. The diagnosis of leptospirosis was confirmed through metagenomics next-generation sequencing (mNGS) while the patient received extracorporeal membrane oxygenation (ECMO) support, and antibiotic treatment was adjusted accordingly. The patient underwent comprehensive treatment and rehabilitation in the intensive care unit. Conclusion This case illustrates the importance of early diagnosis and treatment of leptospirosis. While obtaining the epidemiological history, second-generation metagenomics sequencing was utilized to confirm the etiology. The prompt initiation of ECMO therapy provided a crucial window of opportunity for addressing the underlying cause. This case report offers valuable insights for diagnosing patients with similar symptoms.

Using a high-dimensional time-varying parameter vector autoregression framework, we propose a volatility spillover network to analyze risk contagion direction, path, and intensity under supply-demand relationships when important events break out in the real estate market. We characterize daily return volatility spillovers across firms from January 2010 to April 2022 and find a high correlation among these firms because the real linkage based on industrial chain structure strengthened. Meanwhile, the outbreak of essential events in the real estate market corresponds to several peak values of return volatility. The empirical results show that excessive correlation induces risk contagion across the network, and spillover effects are significant under extreme market conditions, manifesting as cross-industry contagion and intersectoral diffusion. The volatility spillover effects within real estate firms are higher than spillover effects across markets. In addition, the industrial chain structure better explains the mechanism of cross-industry risk contagion, firms located upstream of the real estate industry chain are risk receivers, and those located downstream are risk spillovers. Real estate firms mainly spread risks to financial institutions and firms that provide production goods. Our findings are of constructive significance to the related policies by regulatory authorities and provide multi-angle empirical evidence support for the risk supervision theory of “too connected to fail.”

Objectives: Individuals with familial hypercholesterolemia (FH) are at an increased risk for coronary artery disease (CAD). While prior research has shown variability in coronary artery calcification (CAC) among those with FH, studies with small sample sizes and single-center recruitment have been limited in their ability to characterize CAC and plaque burden in subgroups based on age and sex. Understanding the spectrum of atherosclerosis may result in personalized risk assessment and tailored allocation of costly add-on, non-statin lipid-lowering therapies. We aimed to characterize the presence and burden of CAC and coronary plaque on computed tomography angiography (CTA) across age- and sex-stratified subgroups of individuals with FH who were without CAD at baseline. Methods: We pooled 1,011 patients from six cohorts across Brazil, France, the Netherlands, Spain, and Australia. Our main measures of subclinical atherosclerosis included CAC ranges (i.e., 0, 1–100, 101–400, >400) and CTA-derived plaque burden (i.e., no plaque, non-obstructive CAD, obstructive CAD). Results: Ninety-five percent of individuals with FH (mean age: 48 years; 54% female; treated LDL-C: 154 mg/dL) had a molecular diagnosis and 899 (89%) were on statin therapy. Overall, 423 (42%) had CAC=0, 329 (33%) had CAC 1–100, 160 (16%) had CAC 101–400, and 99 (10%) had CAC >400. Compared to males, female patients were more likely to have CAC=0 (48% [n = 262] vs 35% [n = 161]) and no plaque on CTA (39% [n = 215] vs 26% [n = 120]). Among patients with CAC=0, 85 (20%) had non-obstructive CAD. Females also had a lower prevalence of obstructive CAD in CAC 1–100 (8% [n = 15] vs 18% [n = 26]), CAC 101–400 (32% [n = 22] vs 40% [n = 36]), and CAC >400 (52% [n = 16] vs 65% [n = 44]). Female patients aged 50–59 years were less likely to have obstructive CAD in CAC >400 (55% [n = 6] vs 70% [n = 19]). Conclusion: In this large, multi-national study, we found substantial age- and sex-based heterogeneity in CAC and plaque burden in a cohort of predominantly statin-treated individuals with FH, with evidence for a less pronounced increase in atherosclerosis among female patients. Future studies should examine the predictors of resilience to and long-term implications of the differential burden of subclinical coronary atherosclerosis in this higher risk population.

A two-way coupling Discrete Phase Model (DPM) is applied to calculate the secondary atomization process. The particle flight and cooling processes are studied under different process parameters. The results show that the average particle size (d50) depends on the gas-liquid interaction and decreases with increasing gas-to-melt ratio (GMR). The standard deviation of the particle size (d84/d50) increases as the melt mass flow rate increases, and both high and low atomization pressures result in a high d84/d50. The average cooling rate of particles can be improved by reducing the melt mass flow rate and increasing the atomization pressure. By increasing the gas temperature to 400 K, the d50 can be significantly reduced and the average cooling rate can be approximately increased two times, indicating that the hot gas atomization technique can effectively improve the yield of fine amorphous powders. However, excessive gas temperature not only has a limited effect on improving the cooling rate, but also significantly increases the d84/d50 and defective particles, suggesting that the gas temperature must be matched to the atomization process to achieve ideal effects. The powders produced at 2.0 MPa and 0.075 kg·s−1 exhibit good circularity with a d50 of 58.9 μm, which is in good agreement with the simulation analysis. Moreover, the powders with sizes less than 50 μm exhibit high amorphous fraction (96.6%) and outstanding soft magnetic properties. In this work, a flow-heat transfer-DPM coupling model is established to provide theoretical guidance for the production of high-performance Fe-based amorphous powders.

Aluminum alloy frame is a novel structure system developed in recent years. In this article, the load-bearing performance of the beam-beam joint of the aluminum alloy frame is studied through numerical analysis and experiment and a safety monitoring method is developed. The impacts of the arch angle and bolt diameter on the beam-beam joint mechanical characteristics are explored through experiments under vertical load. When the diameter of the bolt was increased, the load-bearing performance of such joint displayed a pattern of first increasing and then decreasing. As the arch angle increased, the load-bearing performance on the joint gradually improved. Based on the experiments, numerical analysis models varying in arch angle were established, and the impacts of arch angles on the stiffness during the yield stage, ultimate load, and elastic stiffness of the aluminum alloy portal frame (AAPF) beam-beam joints were further explored through numerical simulation of the structure under vertical and horizontal loads. When the arching angle was increased, the elastic stiffness and yield stiffness of the beam-beam joint under vertical load showed a pattern of first increasing and then decreasing. When the arching angle was increased, the elastic stiffness and yield stiffness of the beam-beam joint under horizontal load significantly decreased. Based on the mechanical properties, a safety monitoring method for AAPF beam-beam joints based on displacement monitoring and frequency monitoring is proposed.

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4–512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Abstract Background The World Health Organization (WHO) has proposed healthy aging framework, supposing that intrinsic capacity (IC), environment and their interaction may have influence on functional ability (FA). It was still unclear how the IC level and age-friendly living environment impact on FA. This study aims to confirm the relationship between the IC level and age-friendly living environment with FA, especially in older adults with low IC. Methods Four hundred eighty-five community-dwelling residents aged ≥ 60 years were enrolled. IC constructed by locomotion, cognition, psychological, vitality, and sensory domains was assessed using full assessment tools recommended by WHO. Age-friendly living environment was measured with 12 questions adapted from the spatial indicators framework of age-friendly cities. FA was assessed using activities of daily living (ADL) and one question about mobile payment ability. Multivariate logistic regression was used to explore the association between IC, environment and FA. The influence of the environment on electronic payment and ADL under the IC layer was assessed. Results Of 485 respondents, 89 (18.4%) had ADL impairment, and 166 (34.2%) had mobile payment function impairment. Limited IC (odds ratio [OR] = 0.783, 95% confidence interval [CI] = 0.621–0.988) and poor environment (OR = 0.839, 95% CI = 0.733–0.960) were associated with mobile payment ability impairment. Our results suggested that a supportive age-friendly living environment influenced FA was more prominent in older adults with poor IC (OR = 0.650, 95% CI = 0.491–0.861). Conclusions Our results confirmed IC and the environment had an impact on mobile payment ability. The relationship between environment and FA showed differences according to IC level. These findings suggest that an age-friendly living environment is important to maintain and enhance elders’ FA, especially in those with poor IC.

BackgroundSome bacteria enter the viable but non-culturable (VBNC) state to survive harsh environmental conditions and external stresses. This alters cell physiology and has implications for the food industry as some bacteria, such as lactobacilli, undergo similar changes during food processing.MethodsThis study aimed to investigate the transcriptomic changes of a probiotic strain, Lacticaseibacillus paracasei Zhang (L. paracasei Zhang), upon transition to the VBNC state using high throughput RNA sequencing (RNA-seq).ResultsBacteria were inoculated into the de Man, Rogosa, and Sharpe medium and maintained at low temperature and pH to induce cell transition to the VBNC state. Cells were harvested for analysis at five stages of VBNC induction: 0, 3, 30, and 180 days after induction and 210 days when the cells entered the VBNC state. Our results showed that the expression of 2,617, 2,642, 2,577, 2,829, and 2,840 genes was altered at these five different stages. The function of differentially expressed genes (DEGs, compared to healthy cells collected at day 0) and their encoded pathways were analyzed by the Gene Ontology Consortium and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A total of 10 DEGs were identified in cells that entered the VBNC state: five continuously upregulated (LCAZH_0621, LCAZH_1986, LCAZH_2038, LCAZH_2040, and LCAZH_2174) and five continuously downregulated (LCAZH_0024, LCAZH_0210, LCAZH_0339, LCAZH_0621, and LCAZH_0754).ConclusionsThis study proposes a molecular model of the VBNC mechanism in L. paracasei Zhang, highlighting that changes in cell metabolism improve substrate utilization efficiency, thereby enhancing bacterial survival under adverse conditions. These data may be useful for improving the survival of probiotics in industrial food processing.

Background and objectivesNationwide data were used to explore factors associated with physical function in order to identify interventions that could improve and maintain physical function in the older people.MethodsThe physical function was assessed by gait speed (GS). We selected 2,677 male and 2,668 female older adults (aged ≥60) who could perform the GS test as study subjects. GS was measured by having subjects walk across and back a 10-m course. A gait speed less than 20% that of a reference population (

BackgroundAny form of physical activity is recommended for the older adults to maintain their physical function; however, the effect of daily activities on muscle function still needs to be investigated. Humans always use one dominant hand to perform tasks, providing a natural situation for research on the effect of daily activities on muscle function.MethodsFive hundred and twenty-six healthy adults were recruited from the community in Beijing. Muscle strength was assessed using a handgrip dynamometer, lean mass, fat mass, bone area and bone mineral content of upper limbs were assessed using dual-energy X ray-absorptiometry. The results were compared between the dominant and non-dominant upper limbs.ResultsThe dominant upper limb had better muscle strength, lean mass, bone area and bone mineral content than the non-dominant side. The difference in muscle strength and lean mass between the two upper limbs decreased with the advanced age. In older age, fat mass of upper limbs increased in men, but not in women.ConclusionDaily activities can maintain better muscle function in the dominant upper limb than in the non-dominant side; however, the delaying effect on age-related decline in muscle function was limited.

Abstract Background Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes. Objective In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT’s effects. Methods: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140–160 mg/dL, 200–230 mg/dL or 350–450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined. Results Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group. Conclusion LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.

Close-coupled gas atomization is extensively used in the industrial production of alloy powders due to the advantages of high efficiency, low cost and excellent powder properties. In order to investigate the complex gas-liquid interaction during atomization, primary atomization was simulated through the VOF (Volume of Fluid) model and the dynamic adaptive mesh method, and a two-way coupling DPM (Discrete Particle Model) was used to simulate secondary atomization. The results showed that under the low melt mass flow rate of 0.0050 kg s−1, the flow separation and droplet backflow occurred at the atomization pressure of 1 MPa, while gas-liquid interfaces deformed and rotated drastically when the atomization pressure is above 3 MPa, which led to the formation of hollow powders. When the melt mass flow rate was 0.0150 kg s−1, the d50 decreased from 40.7 to 38.4 μm as the atomization pressure increased from 2 to 3 MPa. However, the chance of collision between particles increased due to the decrease in the spray cone angle, and both the standard deviation of particle size and atomization efficiency deteriorated, which indicated that 2 MPa was the optimum atomization pressure. As the mass flow rate increased from 0.0050 to 0.0150 kg s−1, the gas to melt ratio decreased, but the d50 only increased from 32.3 to 40.7 μm, indicating that the mass flow rate of 0.0150 kg s−1 did not significantly affect the particle size distribution, but also contributed to improve the production efficiency and avoided the risk of the nozzle freeze-off. The d50 of the spherical FeSiAl powders produced by the industrial tests at 2 MPa and 0.0150 kg s−1 was 44.7 ± 2.1 μm, which was basically consistent with the simulation results, indicating that the parameter optimization by the coupling model developed in this study could provide theoretical and practical guidance for the preparation of high-performance alloy powders by gas atomization.

Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) infection, currently lacks specific preventive and therapeutic interventions. Here, we demonstrated that Pien Tze Huang (PZH) could dose-dependently inhibit EV-A71 replication at the cellular level, resulting in significant reductions in EV-A71 virus protein 1 (VP1) expression and viral yields in Vero and human rhabdomyosarcoma cells. More importantly, we confirmed that PZH could protect mice from EV-A71 infection for the first time, with Ribavirin serving as a positive control. PZH treatment reduced EV-A71 VP1 protein expression, viral yields in infected muscles, and improved muscle pathology. Additionally, we conducted a preliminary mechanism study using quantitative proteomics. The results suggested that the suppression of the PI3K/AKT/mTOR and NF-κB signaling pathways may contribute to the anti-EV-A71 activity of PZH. These findings provide strong evidence supporting the potential therapeutic application of PZH for EV-A71 infection management.

This paper deals with fractal Van der Pol damped nonlinear oscillators equation having nonlinearity. By combining the techniques of the Laplace transform and the variational iteration method, we establish approximate periodic solutions for the fractal damped nonlinear systems. In this simple way, nonlinear differential equations can be easily converted into linear differential equations. Illustrative examples including the Van der Pol damped nonlinear oscillator reveal that this method is very effective and convenient for solving fractal nonlinear differential equations. Finally, comparison of the obtained results with those of the other achieved method, also reveals that this coupling method not only suggests an easier method due to the Lagrange multiplier but also can be easily extended to other nonlinear systems.

BackgroundApolipoprotein E (APOE) ε2 and APOE ε4 are the most distinct alleles among the three APOE alleles, both structurally and functionally. However, differences in cognition, brain function, and brain structure between the two alleles have not been comprehensively reported in the literature, especially in non-demented elderly individuals.MethodsA neuropsychological test battery was used to evaluate the differences in cognitive performance in five cognitive domains. Independent component analysis (ICA) and voxel-based morphometry (VBM) were used separately to analyze resting-state functional magnetic resonance imaging (rs-fMRI) data and the structure MRI data between the two groups. Finally, correlations between differential brain regions and neuropsychological tests were calculated.ResultsAPOE ε2 carriers had better cognitive performance in general cognitive, memory, attention, and executive function than APOE ε4 carriers (all p

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC50: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 µM) and f14 (IC50: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4–8 µg/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 µM), and metabolically stable (t1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.

Perfluoroalkyl substances (PFASs) are a classic environmental endocrine disruptor with carcinogenic risk. Epidemiological studies have shown that PFASs contamination is associated with breast cancer development, but the mechanism remains largely unknown. This study first obtained complex biological information about PFASs-induced breast cancer through the comparative toxicogenomics database (CTD). The Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were utilized to investigate molecular pathways. The ESR1 and GPER expression levels at different pathological stages and the prognosis of Breast Cancer patients were confirmed using the Cancer Genome Atlas (TCGA) database. Furthermore, we verified this by cellular experiments and the results showed breast cancer cell migration and invasion were promoted by PFOA. Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression.

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap.

Chemical investigation of Penicillium sp. GDGJ-N37, a Sophora tonkinensis-associated fungus, yielded two new azaphilone derivatives, N-isoamylsclerotiorinamine (1) and 7-methoxyl-N-isoamylsclerotiorinamine (2), and four known azaphilones (3–6), together with two new chromone derivatives, penithochromones X and Y (7 and 8). Their structures were elucidated based on spectroscopic data, CD spectrum, and semi-synthesis. Sclerotioramine (3) showed significant antibacterial activities against B. subtilis and S. dysentery, and it also showed most potent anti-plant pathogenic fungi activities against P. theae, C. miyabeanus, and E. turcicum.

The HIsmelt process is well suited for smelting vanadium-titanium magnetite and has significant potential. In this paper, the vanadium and titanium distribution behavior at 1450 °C in the basicity range of 0.3–1.2 during HIsmelt smelting vanadium titano-magnetite was investigated experimentally for the first time. According to thermodynamic calculations combined with experimental validation, lower C content increases the activity coefficients of vanadium and titanium in the metal. Higher basicity decreases the activity coefficients of TiO2 and SiO2 in the slag, improves the distribution ratio of vanadium and titanium. Increasing C content and reducing basicity could increase the content of vanadium in the metal and TiO2 in the slag, which is favorable to vanadium extraction and titanium recovery. Furthermore, the V and Ti content in the hot metal increased significantly with rising smelting temperature. Higher smelting temperatures promote vanadium distribution into hot metal but not titanium distribution into slag. Finally, The Si and Ti distribution ratios have a positive connection according to the fitted models.

Introduction Heterozygous familial hypercholesterolaemia (heFH) is the most common monogenic cause of premature atherosclerotic cardiovascular disease. The precise diagnosis of heFH is established by genetic testing. This systematic review will investigate the risk factors that predict cardiovascular events in patients with a genetic diagnosis of heFH.Methods and analysis Our literature search will cover publications from database inception until June 2023. We will undertake a search of CINAHL (trial), clinicalKey, Cochrane Library, DynaMed, Embase, Espacenet, Experiments (trial), Fisterra, ÍnDICEs CSIC, LILACS, LISTA, Medline, Micromedex, NEJM Resident 360, OpenDissertations, PEDro, Trip Database, PubPsych, Scopus, TESEO, UpToDate, Web of Science and the grey literature for eligible studies. We will screen the title, abstract and full-text papers for potential inclusion and assess the risk of bias. We will employ the Cochrane tool for randomised controlled trials and non-randomised clinical studies and the Newcastle–Ottawa Scale for assessing the risk of bias in observational studies. We will include full-text peer-reviewed publications, reports of a cohort/registry, case–control and cross-sectional studies, case report/series and surveys related to adults (≥18 years of age) with a genetic diagnostic heFH. The language of the searched studies will be restricted to English or Spanish. The Grading of Recommendations, Assessment, Development and Evaluation approach will be used to assess the quality of the evidence. Based on the data available, the authors will determine whether the data can be pooled in meta-analyses.Ethics and dissemination All data will be extracted from published literature. Hence, ethical approval and patient informed consent are not required. The findings of the systematic review will be submitted for publication in a peer-reviewed journal and presentation at international conferences.PROSPERO registration number CRD42022304273.

BackgroundDiabetes mellitus (DM), a metabolic disease that has attracted significant research and clinical attention over the years, can affect the eye structure and induce cataract in patients diagnosed with DM. Recent studies have indicated the relationship between glycoprotein non-metastatic melanoma protein B (GPNMB) and DM and DM-related renal dysfunction. However, the role of circulating GPNMB in DM-associated cataract is still unknown. In this study, we explored the potential of serum GPNMB as a biomarker for DM and DM-associated cataract.MethodsA total of 406 subjects were enrolled, including 60 and 346 subjects with and without DM, respectively. The presence of cataract was evaluated and serum GPNMB levels were measured using a commercial enzyme-linked immunosorbent assay kit.ResultsSerum GPNMB levels were higher in diabetic individuals and subjects with cataract than in those without DM or cataract. Subjects in the highest GPNMB tertile group were more likely to have metabolic disorder, cataract, and DM. Analysis performed in subjects with DM elucidated the correlation between serum GPNMB levels and cataract. Receiver operating characteristic (ROC) curve analysis also indicated that GPNMB could be used to diagnose DM and cataract. Multivariable logistic regression analysis illustrated that GPNMB levels were independently associated with DM and cataract. DM was also found to be an independent risk factor for cataract. Further surveys revealed the combination of serum GPNMB levels and presence of DM was associated with a more precise identification of cataract than either factor alone.ConclusionsIncreased circulating GPNMB levels are associated with DM and cataract and can be used as a biomarker of DM-associated cataract.

ABSTRACT Enterococci can cause various infectious diseases, including urinary tract infection, wound infection, and life-threatening endocarditis and meningitis. The emergence and transmission of vancomycin-resistant enterococci (VRE) have presented a challenge to clinical treatment. There is an urgent need to develop new strategies to fight against this pathogen. This study investigated the antibacterial and anti-biofilm activity of celastrol (CEL), a natural product originating from Tripterygium wilfordii Hook F, against enterococci, and its adjuvant capacity of restoring the susceptibility of VRE to vancomycin in vitro and in vivo. CEL inhibited all enterococcus strains tested, with MICs ranging from 0.5 to 4 μg/mL. More than 50% of biofilm was eliminated by CEL at 16 μg/mL after 24 h of exposure. The combination of CEL and vancomycin showed a synergistic effect against all 23 strains tested in checkerboard assays. The combination of sub-MIC levels of CEL and vancomycin showed a synergistic effect in a time-kill assay and exhibited significant protective efficacy in Galleria mellonella larval infection model compared with either drug used alone. The underlying mechanisms of CEL were explored by conducting biomolecular binding interactions and an enzyme inhibition assay of CEL on bacterial cell-division protein FtsZ. CEL presented strong binding and suppression ability to FtsZ, with Kd and IC50 values of 2.454 μM and 1.04 ± 0.17 μg/mL, respectively. CEL exhibits a significant antibacterial and synergic activity against VRE in vitro and in vivo and has the potential to be a new antibacterial agent or adjuvant to vancomycin as a therapeutic option in combating VRE. IMPORTANCE The emergence and transmission of VRE pose a significant medical and public health challenge. CEL, well-known for a wide range of biological activities, has not previously been investigated for its synergistic effect with vancomycin against VRE. In the present study, CEL exhibited antibacterial activity against enterococci, including VRE strains, and restored the activity of vancomycin against VRE in vitro and in vivo. Hence, CEL has the potential to be a new antibacterial adjuvant to vancomycin and could provide a promising therapeutic option in combating VRE.

In the article, the semi-permanent aluminum alloy portal frame is used as the research background, beam-column joints are used as the research object, and experimental and numerical analyses are carried out. The influence of different bolt diameters and arch angles on the mechanical properties of beam-column joints under vertical load was analyzed using five sets of experiments. The experimental results show that the load–displacement curves of different bolt diameters in the elastic stage are basically consistent. After entering the plastic stage, the ultimate load first increases and then decreases, and the ultimate displacement is basically consistent. According to the experiment, there is no significant difference in the load–displacement curve when the arch angle increases from 90 degrees to 108 degrees. When the arch angle increases to 126 degrees, the stiffness and ultimate bearing capacity of the node under vertical load significantly increase. Then, a numerical analysis model was established to analyze the mechanical performance of beam-column joints under horizontal loads. The numerical analysis results indicate that under horizontal load, as the diameter of the bolt increases, the yield load, yield displacement, ultimate load, and ultimate displacement of the beam-column node exhibit no significant changes, and the change amplitude is minimal. When the beam-column node is subjected to horizontal loads, as the arch angle increases, the yield and ultimate displacement increase by 2.14 times and 2.78 times, respectively, and the yield and ultimate load decrease by 58% and 48%, respectively. Finally, a simplified design method for beam-column joints was proposed based on experiments and numerical analysis.

At present, the measurement of tillage depth is mainly based on manual measurement, but the manual raking method results in low measurement accuracy and high labor intensity. Due to the complexity of soil, theoretical research on tillage depth is relatively scarce. In order to provide a new research direction and research idea for soil stratification, topsoil was taken as the research object of this paper. The correlation between penetration resistance and penetration depth of a probe in a cultivated soil was studied, and a mathematical model was established. There is a certain similarity between the process of spherical cavity expansion and the process of probe penetration, so we introduced the theory of spherical cavity expansion into the modeling of penetration resistance of the cultivated soil. In this paper, the spherical cavity expansion theory of unsaturated soil was used as the basis for solving the penetration resistance. And the unified strength criterion was employed as a yield condition of the soil to set a stress solution and a displacement solutionin into of the probe penetrating into the elasto-plastic zone of the cultivated soil to determine the model of expansion force. We have carried out indoor tests to revise the expansion force model. Firstly, according to the range of soil density and water content in the field, the soil densities were classified into 1.1×103kg/m3, 1.2×103kg/m3 and 1.3×103kg/m3, and the water contents were divided into 10%, 15% and 20%. In addition, the orthogonal tests were performed at different levels. The soil was put into the barrel, and the probe was inserted into the soil in the barrel at the speed of 8mm/s to determine the test values of the change of the probe penetration resistance with depth. Finally, the expansion force model was fitted with the results of the indoor test, and coefficient B was introduced to express the influence degree of density and water content on the resistance. Coefficient B was substituted into the expansion force model to obtain the penetration resistance model of the cultivated soil. Through the goodness of fit analysis of the penetration resistance model, the results show that the overall average goodness of fit of the penetration resistance modelat was up to 0.871 at different water contents and densities, which was a good fit and could present novel insights into the study relating to soil stratification theory.

In this paper, the Mohand transform-based homotopy perturbation method is proposed to solve two-dimensional linear and non-linear shallow water wave equations. This approach has been proved suitable for a broad variety of non-linear differential equations in science and engineering. The variation trend of the water surface elevation at different time levels and depths are given by some graphs. Moreover, the obtained solutions are compared with the existing results, which show higher efficiency and fewer computations than other approaches studied in the literature.

Antivirulence strategy has been developed as a nontraditional therapy which would engender a lower evolutionary pressure toward the development of antimicrobial resistance. However, the majority of the antivirulence agents currently in development could not meet clinical needs due to their narrow antibacterial spectrum and limited indications. Therefore, our main purpose is to develop broad-spectrum antivirulence agents that could target on both Gram-positive and Gram-negative pathogens. We discovered ML364, a novel scaffold compound, could inhibit the productions of both pyocyanin of Pseudomonas aeruginosa and staphyloxanthin of Staphylococcus aureus. Further transcriptome sequencing and enrichment analysis showed that the quorum sensing (QS) system of pathogens was mainly disrupted by ML364 treatment. To date, autoinducer-2 (AI-2) of the QS system is the only non-species-specific signaling molecule that responsible for the cross-talk between Gram-negative and Gram-positive species. And further investigation showed that ML364 treatment could significantly inhibit the sensing of AI-2 or its nonborated form DPD signaling in Vibrio campbellii MM32 and attenuate the biofilm formation across multi-species pathogens including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. The results of molecular docking and MM/GBSA free energy prediction showed that ML364 might have higher affinity with the receptors of DPD/AI-2, when compared with DPD molecule. Finally, the in vivo study showed that ML364 could significantly improve the survival rates of systemically infected mice and attenuate bacterial loads in the organs of mice. Overall, ML364 might interfere with AI-2 quorum sensing system to exert broad-spectrum antivirulence effect both in vitro and in vivo.

Ribonucleoside monophosphates are inevitably misincorporated into the DNA genome inside cells, and they need to be excised to avoid chromosome instability. Ribonucleases H (RNases H) are enzymes that specifically hydrolyze the RNA strand of RNA/DNA hybrids or the RNA moiety from DNA containing a stretch of RNA, they therefore are required for DNA integrity. Extensive studies have drawn a mostly clear picture of the mechanisms of RNase H catalysis, but some questions are still lacking definitive answers. This review summarizes three alternative models of RNase H catalysis. The two-metal model is prevalent, but a three-metal model suggests the involvement of a third cation in catalysis. Apparently, the mechanisms underlying metal-dependent hydrolyzation are more complicated than initially thought. We also discuss the metal choices of RNases H and analyze how chemically similar cations function differently. Substrate and cleavage-site specificities vary among RNases H, and this is explicated in detail. An intriguing phenomenon is that organisms have diverse RNase H combinations, which may provide important hints to how rnh genes were transferred during evolution. Whether RNase H is essential for cellular growth, a key question in the study of in vivo functions, is also discussed. This article may aid in understanding the mechanisms underlying RNase H and in developing potentially promising applications of it.

Abstract Extrachromosomal circular DNA (eccDNA) refers to a type of circular DNA that originate from but are likely independent of chromosomes. Due to technological advancements, eccDNAs have recently emerged as multifunctional molecules with numerous characteristics. The unique topological structure and genetic characteristics of eccDNAs shed new light on the monitoring, early diagnosis, treatment, and prediction of cancer. EccDNAs are commonly observed in both normal and cancer cells and function via different mechanisms in the stress response to exogenous and endogenous stimuli, aging, and carcinogenesis and in drug resistance during cancer treatment. The structural diversity of eccDNAs contributes to the function and numerical diversity of eccDNAs and thereby endows eccDNAs with powerful roles in evolution and in cancer initiation and progression by driving genetic plasticity and heterogeneity from extrachromosomal sites, which has been an ignored function in evolution in recent decades. EccDNAs show great potential in cancer, and we summarize the features, biogenesis, evaluated functions, functional mechanisms, related methods, and clinical utility of eccDNAs with a focus on their role in evolution and cancer.

Abstract Background Giant cell tumors of the mobile spine invasion of the adjacent vertebrae are an ignored imaging finding. Methods Nine patients with giant cell tumors of the mobile spine with invasion of the adjacent vertebrae confirmed by pathology were enrolled. Eight patients had pure giant cell tumors (GCTs), while one patient also had an aneurysmal bone cyst. All patients underwent conventional computed tomography, three-dimensional reconstruction, and conventional magnetic resonance imaging, while seven patients also underwent post-contrast magnetic resonance imaging. Results All patients showed GCTs of the mobile spine that arose from the vertebral body and extended to the vertebral arch. The tumors showed soft-tissue attenuation with no evidence of a mineralized matrix. Pathological fracture was seen in five patients. The margin of the original tumor showed partial sclerosis in four patients and involved an adjacent vertebral body with a sclerotic rim in two patients. The tumors showed a homogeneous and similar signal intensity to the normal spinal cord on T1WI (T1-weighted image) in five patients. The cystic area of the tumors was hyperintense on T2WI in the remaining four patients, while one patient showed hemorrhage that was hyperintense on T1WI. The solid components of the GCTs show marked enhancement in all cases, while the cystic area of the tumors was observed without enhancement on contrast-enhanced images in four patients. Bone destruction of the adjacent vertebral body showed a homogeneous signal on T1WI and T2WI and marked enhancement on contrast-enhanced images. Conclusions Giant cell tumors of the mobile spine with invasion into adjacent vertebrae are an unusual imaging finding. Radiologists should be familiar with this imaging characteristic.

Green merger and acquisition (Green M&A) is one of the ways of corporate environmental investment, which is vital for their green transformation and sustainable development. With the implementation of the newly revised Environmental Protection Law in 2015, this paper investigates the impact of environmental regulation on corporate green M&A using the Difference-in-Difference method with a sample of Chinese listed companies from 2007 to 2020. We found that firms’ green M&A increases significantly after the implementation of the new Environmental Protection Law. The promotion effect is more pronounced when the firm is state-owned or faces lower financing constraints. Further analysis reveals that green M&A significantly reduces firms’ environmental management costs, enhances green innovation, and has no effect on market performance. This result confirms that after the implementation of the new Environmental Protection Law, companies engage in green M&A for cost and innovation motives rather than market motives.

BackgroundCommensal microbiota have been proven to colonize the mammary gland, but whether their composition is altered in patients with breast cancer (BC) remains elusive. This study intends to explore the breast microbiome differences between benign and malignant diseases and to investigate the impact of neoadjuvant chemotherapy (NAC) on the breast microbiota in patients with BC.MethodsBreast normal adipose tissues (NATs) were collected from 79 patients with BC and 15 controls between July 2019 and November 2021. The BC group consisted of 29 patients who had received NAC and 50 who were non-NAC patients. Participants diagnosed with benign breast disease were recruited as controls. 16S rRNA gene sequencing was used to analyze the bacterial diversity of NATs.ResultsThe community structure of the NAT microbiome was significantly different between the BC and control groups. Proteobacteria decreased (47.40% versus 39.74%), whereas Firmicutes increased (15.71% versus 25.33%) in patients with BC when compared with that in control tissues. Nine genera were enriched in BC NATs, and four genera levels increased in the control group. The associations between differential bacterial genera and breast tumor grade were calculated by Spearman’s correlation. The results showed that tumor grade was positively associated with the relative abundance of Streptococcus and negatively related to Vibrio, Pseudoalteromonas, RB41, and Photobacterium. Moreover, menopause was associated with the microbiota composition change of non-NAC BC patients and related to the significant reduction in the abundance level of Pseudoalteromonas, Veillonella, and Alcaligenes. In addition, NAC was related to the beta diversity of patients with BC and associated with the decrease of Clostridium_sensu_stricto_7 and Clostridium_sensu_stricto_2 in postmenopausal patients. Of note, Tax4Fun functional prediction analysis revealed that the metabolic state was more exuberant in the BC group with upregulating of multiple metabolism-related pathways.ConclusionOur results offer new insight into the relationship between NAC and breast microbiota and help to better characterize the breast microbial dysbiosis that occurs in patients with BC. Further epidemiological studies with larger sample size and well-designed animal experiments are required to elucidate the role of breast microbiota in the therapeutic outcome of BC.

Objective: Elevated lipoprotein(a) [Lp(a)] is a common inherited condition associated with cardiovascular disease. This study investigated whether cascade testing for Lp(a) was effective in detecting new cases of elevated Lp(a) in families. Methods: Relatives from adult probands with Lp(a) concentration ≥100 mg/dL were tested for elevated Lp(a) (≥50 mg/dL) via a cascade testing program in a tertiary hospital setting. The prevalence and yield of detecting new cases of elevated Lp(a) among the relatives were assessed. Results: Of the 83 probands, 43.4% had familial combined hyperlipidemia (FCHL) and 34.9% common hypercholesterolemia (CH). Among 182 relatives tested (151 adults and 31 children), elevated Lp(a) was found in 68.1%, with 32.9% having Lp(a) between 50 and 99 mg/dL and 35.2% having Lp(a) ≥100 mg/dL. One new case of elevated Lp(a) ≥50 mg/dL was identified for every 1.5 relatives tested and 1 new case of elevated Lp(a) ≥100 mg/dL for every 2.8 relatives tested. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) >150 mg/dL compared with those with Lp(a) between 100 and 150 mg/dL (81.1% vs. 55.5%; P = 0.001). The concordance rates (kappa coefficient) for the detection of elevated Lp(a) with FCHL and CH were 34.8% (0.026) and 53.2% (0.099), respectively. Conclusion: Cascade testing for elevated Lp(a) from affected probands with phenotypic dyslipidemia is highly effective in identifying new cases of high Lp(a) in families. The yield of detecting elevated Lp(a) is greater when probands have higher levels of Lp(a) and exceeds the detection of relatives with FCHL and CH.

The increasing spread of drug-resistant bacterial strains presents great challenges to clinical antibacterial treatment and public health, particularly with regard to β-lactamase-producing Enterobacteriaceae. A rapid and accurate detection method that can expedite precise clinical diagnostics and rational administration of antibiotics is urgently needed. Targeted proteomics, a technique involving selected reaction monitoring or multiple reaction monitoring, has been developed for detecting specific peptides. In the present study, a rapid single-colony-processing procedure combined with an improved parallel reaction monitoring (PRM) workflow based on HRAM Orbitrap MS was developed to detect carbapenemases (Klebsiella pneumoniae carbapenemase, KPC; imipenemase, IMP; Verona integron-encoded metallo-β-lactamase, VIM; New Delhi metallo-β-lactamase, NDM; and oxacillinase, OXA), extended spectrum β-lactamases (TEM and CTX-M), and AmpC (CMY-2) produced by Enterobacteriaceae. Specific peptides were selected and validated, and their coefficients of variation and stability were evaluated. In total, 188 Enterobacteriaceae strains were screened using the workflow. Fourteen out of total 19 peptides have 100% specificity; three peptides have specificity >95% and two peptides have specificity ranged from 74∼85%. On the sensitivity, only nine peptides have 95∼100% sensitivity. The other 10 peptides have sensitivity ranged from 27∼94%. Thus, a screening method based on peptide groups was developed for the first time. Taken together, this study described a rapid extraction and detection workflow for widespread β-lactamases, including KPC, IMP, VIM, NDM, OXA, CMY, CTX-M, and TEM, using single colonies of Enterobacteriaceae strains. PRM-targeted proteomics was proven to be a promising approach for the detection of drug-resistant enzymes.

At present, the solution and qualitative analysis of nonlinear partial differential equations occupy a very important position in the study of dynamics. In this paper, the bilinear Bäcklund transformation of the (2+1)-dimensional variable-coefficient Gardner−KP(GKP) equation is deduced by virtue of Hirota bilinear form, which consists of seven bilinear equations and involves ten arbitrary parameters. On the basis of the bilinear Bäcklund transformation, the traveling wave solution of the equation is obtained. Then the test function of the interaction solution of the positive quadratic function and exponential function of the (2+1)-dimensional variable-coefficient GKP equation is constructed, and then the test function of the positive quadratic function, hyperbolic cosine function and the interaction solution of the cosine function is constructed. With the help of mathematical symbol software Maple and Mathematica, the solitary wave solutions of (2+1)-dimensional variable-coefficient GKP equation is obtained by using Maple and Mathematica, and the interaction phenomena between a Lump wave and a Kink wave, a Lump wave and Multi-Kink waves are discussed.

Abstract Background MicroRNAs play an important role in many fundamental biological and pathological processes. Defining the microRNAs profile underlying the processes by beneficial and detrimental lifestyles, including caloric restriction (CR), exercise and high-fat diet (HF), is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We used the microarray to detect microRNAs expression in livers from CR, EX and HF mice models. After predicted potential target genes of differentially expressed microRNAs with four algorithms, we applied GO and KEGG to analyze the function of predicted microRNA targets. Results We describe the overall microRNAs expression pattern, and identified 84 differentially expressed microRNAs changed by one or two or even all the three lifestyle modifications. The common and different enriched categories of gene function and main biochemical and signal transduction pathways were presented. Conclusions We provided for the first time a comprehensive and thorough comparison of microRNAs expression profiles in liver among these lifestyle modifications. With this knowledge, our findings provide us with an overall vision of microRNAs in the molecular impact of lifestyle on health as well as useful clues for future and thorough research of the role of microRNAs.

FeSiAl is a commonly used soft magnetic material because of its high resistivity, low core loss, and low cost. In order to systematically study the effect of epoxy resin (EP) on the insulated coating and pressing effect of FeSiAl magnetic powders, six groups of composite powders and their corresponding soft magnetic powder cores (SMPCs) were prepared by changing the content of EP, and the soft magnetic properties of the powders and SMPCs were characterized. The results showed that FeSiAl powders exhibited good sphericity and morphology. The Ms of FeSiAl/EP composite powders was between 117.4–124.8 emu·g−1 after adding (0.3, 0.5, 0.7, 1, 1.5, and 2 wt. %) EP. The permeability μe of SMPCs increased first and then decreased with the increase in EP content. Among them, when the EP content was 1 wt. %, the corresponding SMPCs had the highest μe and excellent DC bias performance (63%, 100 Oe). In the whole test frequency range (50~1000 kHz), SMPCs with 1 wt. % EP content had the lowest core loss (1733.9 mW·cm−3 at 20 mT and 1000 kHz). After that, the loss separation study in the low-frequency range (50~250 kHz) was conducted, and the hysteresis loss and eddy current loss of SMPCs with 1 wt. % EP content were also the lowest. In addition, SMPCs also exhibited the best overall performance when the EP content was 1 wt. %. The results of this study can guide the design of composite insulation coating schemes and promote the development of soft magnetic materials for medium and high frequency applications.

MvaT and MvaU are global transcriptional regulators belonging to the H-NS family, and pyocyanin is an important virulence factor produced by Pseudomonas aeruginosa. mvaT mvaU double knockout mutant of P. aeruginosa PAO1 demonstrated pyocyanin abolishment in the previous study. Here, we further explored the mechanism. Two main directions were studied: pyocyanin biosynthesis pathway and QS system. The effect on the expression of the pyocyanin biosynthesis genes was evaluated by promoter strength determination and Real-Time PCR assay, and significant changes leading to low pyocyanin production were found. The effect on the QS system was studied by signal molecule quantification using LC-MS/MS and related gene expression measurements using Real-Time PCR. In mvaT mvaU double knockout, the production of 3-oxo-C12-HSL obviously increased, while those of C4-HSL and PQS obviously decreased, and the changes can be recovered by mvaT or mvaU complementation. The expressions of transcriptional activator genes binding with QS system signal molecules were all decreased, resulting in decreased formation of signal-transcriptional activator complexes. And the decreased expression of rhlR and pqsE also led to the lower expression of phzA1 and phzA2. Further exploration found that QS system downregulation may be related to QsrO, a QS system repressor, which was highly upregulated with mvaT mvaU double knockout. Hence, the synthesis of pyocyanin was suffocated and the biofilm formation ability was decreased. These results were also confirmed by transcriptome analysis, which demonstrated similar gene expression changes of the aforementioned genes together with decreased expression of other virulence factor genes regulated by QS system.

A nonlinear oscillator with zero initial conditions is considered, which makes some effective methods, for example, the variational iteration method and the homotopy perturbation method, invalid. To solve the bottleneck, this paper suggests a simple transform to convert the problem into a traditional case so that He’s frequency formulation can be effectively used to solve its approximate solution. An microelectromechanical system (MEMS) oscillator is used as example to show the solution process, and a good result is obtained.