Quercetin Promotes the M1-to-M2 Macrophage Phenotypic Switch During Liver Fibrosis Treatment by Modulating the JAK2/STAT3 Signaling Pathway.

OBJECTIVE: To investigate the underlying mechanism by which quercetin (Que) regulates macrophage polarization and its subsequent therapeutic effect on liver fibrosis, an important pathological precondition for hepatocellular carcinoma (HCC). METHODS: In vitro experiments were performed on the RAW264.7 mouse macrophage line. After the induction of M1-type macrophages with LPS, the effects of Que on cell morphology, M1/M2 surface marker expression, cytokine expression, and JAK2/STAT3 expression were analyzed. In vivo, male SD rats were used as a model of CCL4-induced hepatic fibrosis, and the effects of Que on serum aminotransferase levels, the histopathological structure of liver tissues, and macrophage-associated protein expression in liver tissues were analyzed. RESULTS: In vitro experiments revealed that Que can suppress the activation of the JAK2/STAT3 signaling pathway, leading to decreases in the expression of M1 macrophage surface markers and cytokines. Additionally, Que was found to increase the expression of M2 macrophage surface markers and cytokines. In vivo, assays demonstrated that Que significantly ameliorated the development of inflammation and fibrosis in a rat liver fibrosis model. CONCLUSION: Que can inhibit hepatic fibrosis by promoting M1 to M2 macrophage polarization, which could be associated with its ability to suppress the JAK2/STAT3 signaling pathway in macrophages.

Neratinib safety evaluation: real-world adverse event analysis from the FAERS database.

Aims: Neratinib has emerged as significant theraputic option for breast cancer treatment. However, despite its approval, numerous adverse drug events (ADEs) associated to it remain unrecognized and unreported. This study aims to mine and analyze the signals of ADEs related to neratinib from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, providing insights for safe and rational clinical use of drug. Methods: All the neratinib-related ADEs data were collected from FAERS database from the third quarter (Q3) of 2017 to the fourth quarter (Q4) of 2023. After standardizing the data, 4 disproportionality methods were used to assess the correlation between neratinib and ADEs. Results: Of the 1,544 ADEs implicating neratinib as the primary suspected drug, a combined total of 48 preferred terms (PTs) and 10 system organ classes (SOCs) showed significant disproportionality accross all four algorithms simultaneously. These SOCs included gastrointestinal disorders (n = 2,564, ROR 7.14), general disorders and administration site conditions (n = 958, ROR 0.77) and injury poisoning and procedural complications (n = 474, ROR 0.58) among others. Upon comparison with the neratinib manual, 34 ADEs not documented in the manual were found at the PT level. Conclusion: Our study provide new real-world evidence for drug safety information of neratinib. While the majority of our findings were aligned with the information provided in the manual. We identified additional ADEs not previously documented. Consequently, further studies are needed to validate unreported ADEs to ensure the efficacy and safety of neratinib for patients.

Radio-Frequency Magnetometry Based on Parametric Resonances.

We propose and demonstrate a radio-frequency (rf) atomic magnetometer based on parametric resonances. Previously, most rf atomic magnetometers are based on magnetic resonances and their sensitivities are often limited by spin-exchange relaxation. Here, we introduce a novel scheme for an rf magnetometer where the rf magnetic field is measured by exciting the parametric resonances instead of magnetic resonances using parametric modulation fields. In this way, the spin-exchange relaxation is almost eliminated. Benefiting from the low spin relaxation rate, the parametric resonance scheme exhibits a narrower linewidth and stronger signal, which results in a higher sensitivity. With a 6×6×3 mm^{3} Rb atomic vapor cell, we developed an rf atomic magnetometer with a noise floor of 2 fT/Hz^{1/2}, which is about one order of magnitude higher than the sensitivity achieved in the magnetic-resonance-based scheme. The presented rf detection scheme holds promise in advancing rf atomic magnetometers and brings new insight into their various applications.

Causal association of basal metabolic rate on systemic sclerosis: a bidirectional mendelian randomization study.

Prior evidence suggests that altered energy metabolism plays a crucial role in the development of fibrotic diseases. Recent research indicates that systemic sclerosis (SSc) patients have potentially benefited from energy management, implying that basal metabolic rate (BMR), a vital energy metabolic parameter, may be related to SSc. However, the causal effect of BMR on SSc remains unknown. Thus, we aimed to elucidate the causal links between BMR and SSc. Based on summary statistics from the genome-wide association studies (GWAS) database, two-sample Mendelian randomization (MR) was applied to explore causality between BMR and SSc. The causal relationships were assessed employing inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Meanwhile, several sensitivity analyses were carried out to ensure the robustness of the findings. There was an underlying genetic association of BMR on SSc (OR = 0.505, 95% CI: 0.272-0.936, P = 0.030). Moreover, no significant causal effect between SSc and BMR was observed in the reverse MR analysis (OR = 0.999, 95% CI: 0.997-1.001, P = 0.292). According to the sensitivity analysis, the presence of heterogeneity and genetic pleiotropy was not detected. Our findings, derived from a genetic perspective, provide robust evidence of a causal connection between BMR and SSc. To verify these results and clarify the potential mechanisms, further research is warranted.

Safety assessment of neurokinin-1 receptor antagonist: real-world adverse event analysis from the FAERS database.

Background: Aprepitant, fosaprepitant, and netupitant are three common neurokinin-1 receptor antagonists (NK-1RAs) used to prevent chemotherapy-induced nausea and vomiting, following highly or moderately emetogenic chemotherapy. Understanding their different adverse event (AE) profiles may help clinicians make appropriate treatment decisions. Methods: All data collected from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023 underwent disproportionality analysis to detect, evaluate, and compare AE signals of the three NK-1RAs. Results: A total of 3,904, 1,123, and 243 AE reports related to aprepitant, fosaprepitant, and netupitant, respectively, were extracted from the FAERS database. Of these, more than 50% of respondents were female, and most of them were aged 45-65 years. General disorders and administration-site conditions, and gastrointestinal disorders were the most frequent signals in the system organ class of the three NK-1RA drugs. In addition, aprepitant was strongly associated with joint deposit (ROR = 26.27) and fosaprepitant was closely related to seizure-like phenomena (ROR = 26.90); two preferred terms (PTs) were not mentioned in the manual. Statistically, netupitant was likely to induce death (N = 63, ROR = 8.78, 95% CI: 6.75-11.42). Additionally, neutropenic colitis, colitis, and stomatitis were unique to netupitant. Furthermore, the AE profiles of the three NK-1RA drugs were different by gender. Conclusion: The AE profiles for aprepitant, fosaprepitant, and netupitant were different. In addition to paying attention to common AEs, clinicians need to pay attention to new emerging AEs, such as joint deposit, seizure-like phenomena, neutropenic colitis, colitis, and stomatitis, regarding the three NK-1RA drugs. Furthermore, the AE compositions of the three NK-1RA drugs were different in different genders, and clinicians should take these factors into account when selecting NK-1RAs for CINV treatment.

Optimizing biomagnetic sensor performance through in silico diagnostics: A novel approach with BEST (Biomagnetism Evaluation via Simulated Testing).

Advancing biomagnetic measurement capabilities requires a nuanced understanding of sensor performance beyond traditional metrics. This study introduces Biomagnetism Evaluation via Simulated Testing (BEST), a novel methodology combining a current dipole model simulating cardiac biomagnetic fields with a convolutional neural network. Our investigation reveals that optimal sensor array performance is achieved when sensors are in close proximity to the magnetic source, with a shorter effective domain. Contrary to common assumptions, the bottom edge length of the sensor has a negligible impact on array performance. BEST provides a versatile framework for exploring the influence of diverse technical indicators on biomagnetic sensor performance, offering valuable insights for sensor development and selection.

Adaptive block imaging based on compressive sensing in AFM.

Atomic force microscopy (AFM) is a kind of high-precision instrument to measure the surface morphology of various conductive or nonconductive samples. However, obtaining a high-resolution image with standard AFM scanning requires more time. Using block compressive sensing (BCS) is an effective approach to achieve rapid AFM imaging. But, the routine BCS-AFM imaging is difficult to balance the image quality of each local area. It is easy to lead to excessive sampling in some flat areas, resulting in time-consuming. At the same time, there is a lack of sampling in some areas with significant details, resulting in poor imaging quality. Thus, an innovative adaptive BCS-AFM imaging method is proposed. The overlapped block is used to eliminate blocking artifacts. Characteristic parameters (GTV, Lu, and SD) are used to predict the local morphological characteristics of the samples. Back propagation neural network is employed to acquire the appropriate sampling rate of each sub-block. Sampling points are obtained by pre-scanning and adaptive supplementary scanning. Afterward, all sub-block images are reconstructed using the TVAL3 algorithm. Each sample is capable of achieving uniform, excellent image quality. Image visual effects and evaluation indicators (PSNR and SSIM) are employed for the purpose of evaluating and analyzing the imaging effects of samples. Compared with two nonadaptive and two other adaptive imaging schemes, our proposed scheme has the characteristics of a high degree of automation, uniformly high-quality imaging, and rapid imaging speed. HIGHLIGHTS: The proposed adaptive BCS method can address the issues of uneven image quality and slow imaging speed in AFM. The appropriate sampling rate of each sub-block of the sample can be obtained by BP neural network. The introduction of GTV, Lu, and SD can effectively reveal the morphological features of AFM images. Seven samples with different morphology are used to test the performance of the proposed adaptive algorithm. Practical experiments are carried out with two samples to verify the feasibility of the proposed adaptive algorithm.

Equitable infrastructure: Achieving resilient systems and restorative justice through policy and research innovation.

Recent major investments in infrastructure in the United States and globally present a crucial opportunity to embed equity within the heart of resilient infrastructure decision-making. Yet there is a notable absence of frameworks within the engineering and scientific fields for integrating equity into planning, design, and maintenance of infrastructure. Additionally, whole-of-government approaches to infrastructure, including the Justice40 Initiative, mimic elements of process management that support exploitative rather than exploratory innovation. These and other policies risk creating innovation traps that limit analytical and engineering advances necessary to prioritize equity in decision-making, identification and disruption of mechanisms that cause or contribute to inequities, and remediation of historic harms. Here, we propose a three-tiered framework toward equitable and resilient infrastructure through restorative justice, incremental policy innovation, and exploratory research innovation. This framework aims to ensure equitable access and benefits of infrastructure, minimize risk disparities, and embrace restorative justice to repair historical and systemic inequities. We outline incremental policy innovation and exploratory research action items to address and mitigate risk disparities, emphasizing the need for community-engaged research and the development of equity metrics. Among other action items, we recommend a certification system-referred to as Social, Environmental, and Economic Development (SEED)-to train infrastructure engineers and planners and ensure attentiveness to gaps that exist within and dynamically interact across each tier of the proposed framework. Through the framework and proposed actions, we advocate for a transformative vision for equitable infrastructure that emphasizes the interconnectedness of social, environmental, and technical dimensions in infrastructure planning, design, and maintenance.

Broiler Spaghetti Meat Abnormalities: Muscle Characteristics and Metabolomic Profiles.

Spaghetti meat (SM) is a newly identified muscle abnormality that significantly affects modern broiler chickens, consequently exerting a substantial economic impact on the poultry industry worldwide. However, investigations into the meat quality and the underlying causative factors of SM in broilers remain limited. Therefore, this study was undertaken to systematically evaluate meat quality and muscle fiber characteristics of SM-affected meat. To elucidate the disparities between SM-affected and normal (NO) muscles in broiler chickens reared under identical conditions, we selected 18 SM-affected breast tissues and 18 NO breast tissues from 200 broiler chickens raised according to commercial standards under the same conditions for our study. The results showed that compared with the NO group, the muscle surface of the SM group lost integrity, similar to strip and paste. The brightness and yellowness values were significantly higher than those of the NO group. On the contrary, the shear force and protein were significantly lower in the SM group. Microscopic examination revealed that the muscle fibers in the SM group were lysed, necrotic, and separated from each other, with a large number of neutrophils diffusely distributed on the sarcolemma and endometrium. Thirty-five significantly different metabolites were observed in the breast muscles between both groups. Among them, the top differential metabolites-14,15-DiHETrE, isotretinoin, L-malic acid, and acetylcysteine-were mainly enriched in lipid metabolism and inflammatory pathways, including linoleic acid, arachidonic acid, phenylalanine, and histidine metabolism. Overall, these findings not only offer new insights into the meat quality and fiber traits of SM but also contribute to the understanding of potential mechanisms and nutritional regulators for SM myopathy.

Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

Semi-Supervised 3D Shape Segmentation via Self Refining.

3D shape segmentation is a fundamental and crucial task in the field of image processing and 3D shape analysis. To segment 3D shapes using data-driven methods, a fully labeled dataset is usually required. However, obtaining such a dataset can be a daunting task, as manual face-level labeling is both time-consuming and labor-intensive. In this paper, we present a semi-supervised framework for 3D shape segmentation that uses a small, fully labeled set of 3D shapes, as well as a weakly labeled set of 3D shapes with sparse scribble labels. Our framework first employs an auxiliary network to generate initial fully labeled segmentation labels for the sparsely labeled dataset, which helps in training the primary network. During training, the self-refine module uses increasingly accurate predictions of the primary network to improve the labels generated by the auxiliary network. Our proposed method achieves better segmentation performance than previous semi-supervised methods, as demonstrated by extensive benchmark tests, while also performing comparably to supervised methods.

G-protein-coupled estrogen receptor 1 promotes peritoneal metastasis of gastric cancer through nicotinamide adenine dinucleotide kinase 1-mediated redox modulation.

Adipose tissue is the second most important site of estrogen production, where androgens are converted into estrogen by aromatase. While gastric cancer patients often develop adipocyte-rich peritoneal metastasis, the underlying mechanism remains unclear. In this study, we identified the G-protein-coupled estrogen receptor (GPER1) as a promoter of gastric cancer peritoneal metastasis. Functional in vitro studies revealed that ß-Estradiol (E2) or the GPER1 agonist G1 inhibited anoikis in gastric cancer cells. Additionally, genetic overexpression or knockout of GPER1 significantly inhibited or enhanced gastric cancer cell anoikis in vitro and peritoneal metastasis in vivo, respectively. Mechanically, GPER1 knockout disrupted the NADPH pool and increased reactive oxygen species (ROS) generation. Conversely, overexpression of GPER1 had the opposite effects. GPER1 suppressed nicotinamide adenine dinucleotide kinase 1(NADK1) ubiquitination and promoted its phosphorylation, which were responsible for the elevated expression of NADK1 at protein levels and activity, respectively. Moreover, genetic inhibition of NADK1 disrupted NADPH and redox homeostasis, leading to high levels of ROS and significant anoikis, which inhibited lung and peritoneal metastasis in cell-based xenograft models. In summary, our study suggests that inhibiting GPER1-mediated NADK1 activity and its ubiquitination may be a promising therapeutic strategy for peritoneal metastasis of gastric cancer.

Research trends and frontiers in lupus nephritis: a bibliometric analysis from 2012 to 2022.

OBJECTIVES: Lupus nephritis is a prevalent renal manifestation of systemic lupus erythematosus (SLE) and represents a significant cause of morbidity and mortality associated with the disease. This study endeavors to undertake a meticulous bibliometric analysis of LN publications to comprehend the research hotspots and future directions. METHODS: The literature on LN was acquired from the Web of Science Core Collection (WoSCC). Co-occurrence and cooperative relationship analysis of authors, institutions, countries, journals, references and keywords in the publication was performed through CiteSpace, VOSviewer and a bibliometric online analysis platform. The knowledge graphs were created, and clustering and emergence analyses were performed. RESULTS: According to the search strategy, a total of 2077 publications related to lupus nephritis (LN) have been identified, with China being the largest contributor globally. The Ohio State University emerged as the most prolific institution. Lupus is the most cited and published journal. Jan J Weening and Brad Rovin were the most prolific and cocited authors. The current research focus revolved around the "nirp3 inflammasome," "biomarker," and "voclosporin". "international society," "thrombotic microangiopathy (TMA)," and "pathway" were identified to be future research hotpots by keyword burst analysis. CONCLUSIONS: This bibliometric analysis summarizes for the first time the progress of LN research (2012-2022), and qualitatively and quantitatively evaluates the bibliometric information of LN research. There has been a steady increase in the scientific literature on LN over the past 11 years, with an average growth rate of 7.27%. In this field, researchers are primarily based in China and the United States. The pathogenic mechanisms, management strategies and prognostic outcomes of LN are acknowledged as prospective research hotspots. Bibliometrically, the research status and trends of LN publications may greatly assist and be a significant reference for future research in the area.

Therapeutic effect of yinchenhao decoction on cholelithiasis via mucin in the gallbladder and intestine.

Cholelithiasis is a common and frequently occurring disease worldwide that belongs to the category of jaundice in traditional Chinese medicine. Yinchenhao decoction (YD) consists of Artemisia capillaris Thunb., Gardenia jasminoides J.Ellis, and Rheum palmatum L., and is traditionally used to treat jaundice, which has a significant therapeutic effect on cholelithiasis. Our study aimed to investigate the pathological mechanism of cholelithiasis and the therapeutic mechanism of YD via mucin in the gallbladder and intestine. YD was prepared and analyzed using HPLC. The supersaturation stability experiment was designed by the solvent-shift method. The cell transport experiment was conducted by coculture monolayers. The animal experiment was performed using a cholelithiasis model with a high-cholesterol diet. The related indicators were detected by automatic biochemical analyzer, PCR, western blot, or ELISA. Statistics were analyzed using χ2-tests and t-tests. As the results, in cholelithiasis, MUC5AC highly expressed in the gallbladder shortened cholesterol supersaturation and promoted cholesterol crystallization via the inflammatory cytokine signaling pathway; MUC2 highly expressed in the small intestine prolonged cholesterol supersaturation and promoted cholesterol absorption via the inflammatory cytokine signaling pathway. YD inhibited mucin expression in the gallbladder and intestine in a concentration-dependent manner for cholelithiasis treatment by inhibiting the inflammatory cytokine signaling pathway, which was attributed to the active components, including chlorogenic acid, geniposide, and rhein.

Association between Dietary Intake of Live Microbes and Chronic Constipation in Adults.

BACKGROUND: Chronic constipation (CC) is a common gut health problem, and the role of live dietary microbes in CC is unclear. OBJECTIVE: This study aimed to investigate the relationship between dietary live microbes consumption and CC. METHODS: Using the National Health and Nutrition Examination Survey data (2005-2010), 11,170 adults who completed the 24-h face-to-face dietary recall and bowel health questionnaire were identified. CC was defined by the Bristol Stool Form Scale. Dietary live microbes intake was classified as low, medium, and high. Additionally, combined medium and high categories (MedHi) were analyzed. Multivariate regression models were constructed to assess the association between dietary intake of live microbes and CC. RESULTS: In the weighted sample, the age-adjusted CC prevalence was 7.06% (95% confidence interval [CI]: 6.45, 7.67). In multivariate regression models, after controlling for potential confounders race/ethnicity, sex, body mass index, education, poverty, depression, caffeine intake, and alcohol intake, a significant inverse association between dietary live microbes consumption and CC was observed (odds ratio [OR]: 0.77, 95% CI: 0.61, 0.97, P-trend = 0.061). CONCLUSIONS: Our findings suggest that a high dietary live microbes consumption may be associated with lower odds of CC. However, further prospective studies are essential to confirm its effectiveness in reducing CC occurrence.

Genetic Diversity Analysis and Breeding of Geese Based on the Mitochondrial ND6 Gene.

To explore the differences in body-weight traits of five goose breeds and analyze their genetic diversity and historical dynamics, we collected body-weight data statistics and used Sanger sequencing to determine the mitochondrial DNA of 100 samples of five typical goose breeds in China and abroad. The results indicated that Lion-Head, Hortobagy, and Yangzhou geese have great breeding potential for body weight. Thirteen polymorphic sites were detected in the corrected 505 bp sequence of the mitochondrial DNA (mtDNA) ND6 gene, accounting for approximately 2.57% of the total number of sites. The guanine-cytosine (GC) content (51.7%) of the whole sequence was higher than the adenine-thymine (AT) content (48.3%), showing a certain GC base preference. There were 11 haplotypes among the five breeds, including one shared haplotype. We analyzed the differences in the distribution of base mismatches among the five breeds and conducted Tajima's D and Fu's Fs neutral tests on the historical dynamics of the populations. The distribution of the mismatch difference presented an unsmooth single peak and the Tajima's D value of the neutral test was negative (D < 0) and reached a significant level, which proves that the population of the three species had expanded; the Lion-Head goose population tends to be stable. The genetic diversity of Lion-Head, Zhedong White, Yangzhou, and Taihu geese was equal to the average diversity of Chinese goose breeds. The Hortobagy goose is a foreign breed with differences in mating line breeding and hybrid advantage utilization.

Enantioselective synthesis of α,α-diarylketones by sequential visible light photoactivation and phosphoric acid catalysis.

Chiral ketones and their derivatives are useful synthetic intermediates for the synthesis of biologically active natural products and medicinally relevant molecules. Nevertheless, general and broadly applicable methods for enantioenriched acyclic α,α-disubstituted ketones, especially α,α-diarylketones, remain largely underdeveloped, owing to the easy racemization. Here, we report a visible light photoactivation and phosphoric acid-catalyzed alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction using arylalkyne, benzoquinone, and Hantzsch ester for the expeditious synthesis of α,α-diarylketones with excellent yields and enantioselectivities. In the reaction, three chemical bonds, including C═O, C─C, and C─H, are formed, providing a de novo synthesis reaction for chiral α,α-diarylketones. Moreover, this protocol provides a convenient and practical method to synthesize or modify complex bioactive molecules, including efficient routes to florylpicoxamid and BRL-15572 analogs. Computational mechanistic studies revealed that C-H/π interactions, π-π interaction, and the substituents of Hantzsch ester all play crucial roles in the stereocontrol of the reaction.