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The importance of teaching the Luria-Delbrück experiment to biology students is increasingly recognized by educators, and improved pedagogical methods for teaching the classic experiment have been proposed and tested in the classroom. However, there are still obstacles that impede the proper teaching of the classic experiment. This note proposes two strategies to further improve the teaching of the classic experiment. The first strategy is to be frank with an inherent limitation of the classic experiment, and instructors should explain from a logical point of view why the classic experiment cannot be used to refute the possibility of directed mutation. The second strategy is to emphasize the pioneering work of Delbrück on developing the mutant distribution that enables researchers to estimate microbial mutation rates using data generated by fluctuation experiments, and instructors should shift their attention to the overlooked essential role of the mutant distribution.

Abstract Aiming at the problem of "crystallization" on the surface of Yuan blue and white ceramics, which causes reflections and loss of image texture, an image processing method is proposed to repair the image texture information. A multi-scale Retinex pre-processing method is proposed to enhance the contrast between the pattern and the background. A color factor is introduced to prevent color distortion. A weighted average function is constructed to enhance image details and improve texture information. The Yuan blue and white pattern can be effectively segmented from the background using a combination of multi-peak thresholding for segmentation and other techniques. The experimental results demonstrate that, in comparison to other algorithms, the multi-scale Retinex and histogram multi-peak threshold coupled segmentation method proposed in this paper exhibits the highest F1-score of 0.03067 and an accuracy of 92.67% in cross-evaluation with other algorithms. This indicates that the overall performance of the algorithm is the best. The proposed method has the potential to inform the protection of cultural relics.

Abstract Background Tall wheatgrass is a perennial salt‐tolerant bunchgrass, which is a promising candidate for establishing a “Coastal Grass Belt” in China, particularly in the coastal saline–alkaline soils surrounding the Bohai Sea. Methods Seven harvesting treatments were performed to explore the optimal harvesting time and frequency for tall wheatgrass in coastal area. The dry matter yield (DMY) and forage nutritional values were investigated for each cut. The correlation between harvesting time and frequency thereof among the investigated traits was also determined. Results The results showed that the two‐cut on June 18 and October 29 produced the highest DMY. Another two‐cut on May 26 and October 29 produced a relatively high crude protein (CP) yield. The DMY, contents of neutral detergent fiber (NDF), acid detergent fiber (ADF), and crude cellulose (CC) as well as CP yield were positively correlated to plant height, while the CP content and the relative feed value (RFV) were negatively correlated to plant height. The accumulating growing degree days, accumulated precipitation, and sunshine duration were positively correlated with plant height, DMY, contents of NDF, ADF, and CC as well as CP yield, but negatively correlated with CP content and RFV for the first cut. Conclusions The two‐cut treatment at the end of May and October may be suitable for tall wheatgrass in the “Coastal Grass Belt” targeted area.

Abstract Background Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self‐renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non‐small cell lung cancer (NSCLC) remains unclear. Methods The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β‐catenin while pcDNA3‐β‐catenin (S33Y) plasmid enhanced the expression of β‐catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real‐time PCR. Results We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β‐catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β‐catenin inhibitor or siRNA knockdown, whereas increased after β‐catenin overexpression. Furthermore, hypoxia treatment suppressed E‐cadherin expression in H520 cells and enhanced N‐cadherin and β‐catenin expression, while this effect was completely opposite in A549 cells. Conclusion The hypoxia‐EMT‐β‐catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

Abstract Backgrounds Microfibril-associated protein 2 (MFAP2) is a protein presenting in the extracellular matrix that governs the activity of microfibrils through its interaction with fibrillin. While the involvement of MFAP2 in metabolic disorders has been documented, its expression and prognostic significance in triple-negative breast cancer (TNBC) remain unexplored. Methods We acquired datasets pertaining to breast cancer (BC) from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Next, a Venn diagram was used to identify the differentially expressed genes (DEGs). The DEGs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI), immune and survival analysis. The expressions of MFAP2, PD-1 and PD-L1 were examined by immunohistochemistry and western blot and their relationship with clinical pathological parameters were analyzed by clinical specimen samples from patients with TNBC. Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ) was adopted to calculate the immune infiltration level of TNBC. The link between gene expression and tumor mutational burden (TMB) was described using Spearman’s correlation analysis. Results We identified 66 differentially expressed genes (DEGs) that were up-regulated. Among these DEGs, MFAP2 was found to be overexpressed in TNBC and was associated with a lower probability of survival. This finding was confirmed through the use of immunohistochemistry and western blot techniques. Additionally, MFAP2 was found to be related to various pathological parameters in TNBC patients. Mechanistically, gene set enrichment analysis (GSEA) revealed that MFAP2 primarily influenced cellular biological behavior in terms of epithelial mesenchymal transition, glycolysis, and apical junction. Notably, MFAP2 expression was positively correlated with the abundance of macrophages, while a negative correlation was observed with the abundance of B cells, CD4 + T cells, CD8 + T cells, neutrophils and dendritic cells through immune analysis. Furthermore, it was observed that MFAP2 displayed a negative correlation not only with tumor mutational burden (TMB), a recognized biomarker for PD-1/PD-L1 immunotherapy, but also with PD-L1 in samples of TNBC. Conclusion MFAP2 may be an important prognostic biomarker for TNBC, as well as a viable target for immunotherapy in this disease.

We de novo assembled and analysed the chloroplast genomes of Capsella bursa-pastoris, Descurainia sophia, and Lepidium apetalum of the plant family Brassicaceae. These chloroplast genomes exhibited a quadripartite structure characterised by inverted repeat regions (26,268–26,460 bp) separating large single copy (83,771–83,870 bp) and small single copy (17,570–18,014 bp) regions. Genetic analysis revealed 112 unique genes, comprising 78 protein-coding genes, 30 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. Notably, phylogenetic analysis of 21 species revealed close relationships between C. bursa-pastoris and C. orientalis, D. sophia and D. erodiifolia, and L. apetalum and L. cordatum, with 100% bootstrap support. In conclusion, the analysis of these genomes will contribute to the growing knowledge of chloroplast genomes in the Brassicaceae family and of the specific genera Capsella, Descurainia, and Lepidium.

Three-cycle minimum surface structures show excellent lightweight and energy absorption capabilities, and additive manufacturing techniques provide a unique degree of freedom for lattice structure design. Therefore, in this study, three-period minimum surface (TPMS) structures of Schwarz-P boron steel alloys were prepared by Selective Laser Melting (SLM) technique. By investigating the effect of lattice structure design, we have analyzed the deformation behavior, mechanical properties and energy absorption capacity under compression. In addition, tensile properties and fracture morphology were analyzed to gain insight into the performance characteristics of these structures, and the effect of structural design on hardness was explored. The results of the study show that the structural design has a small effect on the microstructure and hardness. Under compressive loading, the P (0.5 1) structure exhibits a uniform deformation behavior, while the other four structures show a crushing deformation pattern. In particular, the P (0.5 1) structure exhibits excellent compressive performance, with an energy absorption work per unit mass as high as 296.2 J/mm^3, and its stiffness reaches 1627 MPa. Meanwhile, the P (0.35 1) structure exhibits excellent tensile performance with the tensile strength of 687 MPa. The morphological analysis of the tensile fracture reveals that the fracture mainly occurs in the strut nodes, and it mainly exhibits ductile tensile fracture.

Highlights MXene/TiO2 hybrids are prepared by a simple calcination treatment, and their electromagnetic response is customized by in situ atomic reconstruction engineering. Based on the excellent electromagnetic response of MXene/TiO2 hybrids, a series of electromagnetic devices are constructed. Multi-spectrum stealth is realized covering visible-light, infrared radiation and GHz.

Abstract The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the β-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1, which was inhibited by NE-βAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

Abstract Atomically precise defect engineering is essential to manipulate the properties of emerging topological quantum materials for practical quantum applications. However, this remains challenging due to the obstacles in modifying the typically complex crystal lattice with atomic precision. Here, we report the atomically precise engineering of the vacancy-localized spin–orbit polarons in a kagome magnetic Weyl semimetal Co3Sn2S2, using scanning tunneling microscope. We achieve the step-by-step repair of the selected vacancies, leading to the formation of artificial sulfur vacancies with elaborate geometry. We find that that the bound states localized around these vacancies undergo a symmetry dependent energy shift towards Fermi level with increasing vacancy size. As the vacancy size increases, the localized magnetic moments of spin–orbit polarons become tunable and eventually become itinerantly negative due to spin–orbit coupling in the kagome flat band. These findings provide a platform for engineering atomic quantum states in topological quantum materials at the atomic scale.

Liver fibrosis, characterized by scar tissue formation, can ultimately result in liver failure. It's a major cause of morbidity and mortality globally, often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases. However, current treatment options are limited, highlighting the urgent need for the development of new therapies. As a reversible regulatory mechanism, epigenetic modification is implicated in many biological processes, including liver fibrosis. Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases, although the current evidence is still controversial. This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications, including DNA methylation, histone modification, and RNA modification, in liver fibrotic diseases. The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted. Finally, available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed. In summary, elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

The incompletely eliminated Treponema pallidum (T. pallidum) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.

Abstract The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis.

Abstract Background Ras gene mutation and/or overexpression are drivers in the progression of cancers, including colorectal cancer. Blocking the Ras signaling has become a significant strategy for cancer therapy. Previously, we constructed a recombinant scFv, RGD-p21Ras-scFv by linking RGD membrane-penetrating peptide gene with the anti-p21Ras scFv gene. Here, we expressed prokaryotically RGD-p21Ras-scFv on a pilot scale, then investigated the anti-tumor effect and the mechanism of blocking Ras signaling. Methods The E. coli bacteria which could highly express RGD-p21Ras-scFv was screened and grown in 100 L fermentation tank to produce RGD-p21Ras-scFv on optimized induced expression conditions. The scFv was purified from E. coli bacteria using His Ni-NTA column. ELISA was adopted to test the immunoreactivity of RGD-p21Ras-scFv against p21Ras proteins, and the IC50 of RGD-p21Ras-scFv was analyzed by CCK-8. Immunofluorescence colocalization and pull-down assays were used to determine the localization and binding between RGD-p21Ras-scFv and p21Ras. The interaction forces between RGD-p21Ras-scFv and p21Ras after binding were analyzed by molecular docking, and the stability after binding was determined by molecular dynamics simulations. p21Ras-GTP interaction was detected by Ras pull-down. Changes in the MEK-ERK /PI3K-AKT signaling paths downstream of Ras were detected by WB assays. The anti-tumor activity of RGD-p21Ras-scFv was investigated by nude mouse xenograft models. Results The technique of RGD-p21Ras-scFv expression on a pilot scale was established. The wet weight of the harvested bacteria was 31.064 g/L, and 31.6 mg RGD-p21Ras-scFv was obtained from 1 L of bacterial medium. The purity of the recombinant antibody was above 85%, we found that the prepared on a pilot scale RGD-p21Ras-scFv could penetrate the cell membrane of colon cancer cells and bind to p21Ras, then led to reduce of p21Ras-GTP (active p21Ras). The phosphorylation of downstream effectors MEK-ERK /PI3K-AKT was downregulated. In vivo antitumor activity assays showed that the RGD-p21Ras-scFv inhibited the proliferation of colorectal cancer cell lines. Conclusion RGD-p21Ras-scFv prokaryotic expressed on pilot-scale could inhibited Ras-driven colorectal cancer growth by partially blocking p21Ras-GTP and might be able to be a hidden therapeutic antibody for treating RAS-driven tumors.

Based on delay-Doppler maps (DDMs) in raw counts generated by spaceborne global navigation satellite system reflectometry (GNSS-R) receivers, retrieving ocean surface wind speeds is feasible, so several spaceborne GNSS-R missions have been carried out. However, it is currently troubled by global data latency of several hours or even more due to the bottleneck in the satellite downlink. Consequently, this article, for the first time, presents an algorithm for spaceborne GNSS-R receivers to conduct the DDM calibration in orbit and then to retrieve ocean surface wind speeds in real time, which contributes to not only lightening the burden on downloading a wealth of scientific data but also broadcasting real-time ocean surface wind speeds to users. Since there is a power correlation between direct and reflected signals from the same GNSS satellite with respect to the GNSS-R receiver, this algorithm calibrates direct signal power first, and then it estimates the real-time GNSS transmitter effective isotropic radiated power at the reflected signal according to the normalized antenna pattern of the corresponding GNSS satellite. Afterward, DDMs in raw counts are calibrated. Finally, ocean surface wind speeds are computed using pretrained geophysical model functions. Exploiting the scientific data from the GNOS-II onboard China's FY-3E satellite, this algorithm is validated carefully, and final retrieved ocean surface wind speeds against collocated European Centre for Medium-Range Weather Forecasts wind speeds have an overall root-mean-square error of 1.68 m/s and 1.50 m/s for GPS-R and BDS-R, respectively.

Abstract Salvia miltiorrhiza Bge. is a traditional Chinese medicine (TCM) that has been used for treatment of various diseases, including cancer by activating blood circulation and removing blood stasis. Tanshinone (TanIIA) and cryptotanshinone (CPT) are major lipophilic compounds extracted from the root of Salvia miltiorrhiza Bge., which are considered to be the effective compounds affecting the efficacy of the anti-tumor therapy of Salvia miltiorrhiza Bge. We have explored the mechanism of CPT and TanIIA exerting inhibition in non-small cell lung cancer (NSCLC) to provide experimental data support for guiding the translational development and clinical application of anti-tumor components of TCM. The subcutaneous tumor model and in vitro culture model of A549 cells was constructed to evaluate CPT and TanIIA's tumour-inhibitory effect respectively. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify differentially expressed genes (DEGs) and signalling pathways related to CPT and TanIIA treatment. qRT-PCR and Western blot were used to explore the mechanism of CPT and TanIIA intervention on NSCLC. Both CPT and TanIIA significantly inhibited the proliferation of A549 tumor cells and tumor growth in animal models. After intervention, the migration ability decreased and the level of apoptosis increased. RNA-seq results showed that both CPT and TanIIA could cause gene differential expression, miR-21-5p as one of the most significant gene expression differences between the two groups, and could act on cell connectivity. CPT and TanIIA play a regulatory role in regulating tight junction proteins (Occludin and ZO1), and Occludin mRNA and protein levels were reduced in an in vitro miR-21-5p overexpression A549 cell model. The mechanisms may be related to the reduction of miR-21-5p expression to increase the level of promoted tight junction protein expression for the purpose of inhibiting proliferation and invasion of NSCLC.

Objective The aim of this study was to reveal the role and regulatory mechanism of miR-188-5p in the proliferation and differentiation of goat muscle satellite cells. Methods Goat skeletal muscle satellite cells isolated in the pre-laboratory were used as the test material. First, the expression of miR-188-5p in goat muscle tissues at different developmental stages was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, miR-188-5p was transfected into goat skeletal muscle satellite cells by constructing mimics and inhibitors of miR-188-5p, respectively. The changes of differentiation marker gene expression were detected by qPCR method. Results It was highly expressed in adult goat latissimus dorsi and leg muscles, goat fetal skeletal muscle, and at the differentiation stage of muscle satellite cells. Overexpression and interference of miR-188-5p showed that miR-188-5p inhibited the proliferation and promoted the differentiation of goat muscle satellite cells. Target gene prediction and dual luciferase assays showed that miR-188-5p could target the 3′untranslated region of the calcium/calmodulin dependent protein kinase II beta (CAMK2B) gene and inhibit luciferase activity. Further functional studies revealed that CAMK2B promoted the proliferation and inhibited the differentiation of goat muscle satellite cells, whereas si-CAMK2B restored the function of miR-188-5p inhibitor. Conclusion These results suggest that miR-188-5p inhibits the proliferation and promotes the differentiation of goat muscle satellite cells by targeting CAMK2B. This study will provide a theoretical reference for future studies on the molecular mechanisms of skeletal muscle development in goats.

To solve the problems of noise coverage defect and low contrast between the defect and the background of ZrO2 ceramic bearing balls, a surface defect extraction algorithm based on shearlet transform image enhancement for ZrO2 ceramic bearing balls is proposed. According to the shape characteristics of ceramic bearing balls, the surface defect image acquisition platform is built to collect and analyze surface defect images. Gaussian filtering weakens the scatter-particle noise in the image, and the threshold corrects the coefficient generated by the shearlet transform. After shearlet transform, the relatively low-frequency and high-frequency parts appear. The low-frequency part reflects the edge information of defects, and the high-frequency part reflects the edge and texture information of defects. Thus, the integrity of the defect is ensured, and an enhanced surface defect image is obtained. The gray histogram of the enhanced image is observed. The optimal threshold is selected by the histogram threshold segmentation method, and the process of defects being completely extracted from the background is realized. Experimental results showed that the extraction rates of pits, scratches, and cracks in ZrO2 ceramic bearing balls’ surface images are 95.00%, 92.50%, and 92.50%, respectively.

Background: Influenza and COVID-19 patients share similar features and outcomes amongst adults. However, the difference between these diseases is not explored in paediatric age group especially in terms of inflammatory markers, coagulation profile and outcomes. Hence, we did this review to compare the inflammatory, coagulation features and outcomes between influenza and COVID-19 infected children. Methods: Literature search was done in PubMed Central, Scopus, EMBASE, CINAHL, Cochrane library, Google Scholar & ScienceDirect from November 2019 to May 2022. Risk of bias assessment was done through Newcastle Ottawa scale. Meta-analysis was done using random-effects model and the final pooled estimate was reported as pooled odds ratio (OR) or standardized mean difference (SMD) along with 95 % confidence interval (CI) depending on the type of outcome. Results: About 16 studies were included with most studies having higher risk of bias. Influenza paediatric patients had significantly higher erythrocyte sedimentation rate (ESR) (pooled SMD = 0.60; 95%CI: 0.30–0.91; I2 = 0 %), lactate dehydrogenase (LDH) (pooled SMD = 2.01; 95%CI: 0.37–3.66; I2 = 98.4 %) and prothrombin time (PT) (pooled SMD = 2.12; 95%CI: 0.44–3.80; I2 = 98.3 %) when compared to paediatric COVID-19 patients. There was no significant difference in terms of features like CRP, procalcitonin, serum albumin, aPTT, mortality and need for mechanical ventilation. Conclusion: Inflammatory markers like ESR, LDH and PT was significantly higher in influenza patients when compared to COVID-19 in children, while rest of the markers and adverse clinical outcomes were similar between both the groups. Identification of these biomarkers has helped in understanding the distinctness of COVID-19 and influenza virus and develop better management strategies.

ABSTRACTThe importance of teaching the Luria-Delbrück experiment to biology students is increasingly recognized by educators, and improved pedagogical methods for teaching the classic experiment have been proposed and tested in the classroom. However, there are still obstacles that impede the proper teaching of the classic experiment. This note proposes two strategies to further improve the teaching of the classic experiment. The first strategy is to be frank with an inherent limitation of the classic experiment, and instructors should explain from a logical point of view why the classic experiment cannot be used to refute the possibility of directed mutation. The second strategy is to emphasize the pioneering work of Delbrück on developing the mutant distribution that enables researchers to estimate microbial mutation rates using data generated by fluctuation experiments, and instructors should shift their attention to the overlooked essential role of the mutant distribution.

Alpha rhythm slowing is an important electroencephalogram(EEG) feature associated with (AD). This study aims to understand the correlation between alpha band deceleration and molecular changes from the perspective of neural computing. Considering the effect of Aβ amyloid deposition on the inhibitory changes in the thalamic, a thalamic cortical model coupled with Aβ amyloid is established. The results show that Aβ amyloid deposition may induce neurotoxicity in thalamic reticular nucleus neurons, which results in inhibitory changes in the thalamus and slows the alpha rhythm of EEG output from the thalamus. In order to understand the pathogenesis more intuitively, some numerical simulations are provided to illustrate the obtained theories. This research is helpful to understand the pathogenesis of AD, so as to provide theoretical basis for the intervention and control of the disease.

Licorice is extensively utilized in the food industry, and glycyrrhetinic acid is among the most critical active constituents in licorice. This ingredient has garnered increasing attention in recent years. In a previous study, we identified a new series of Glycyrrhetinic acid derivatives containing piperazine skeleton, using virtual screening techniques based on docking. In this study, we conducted further optimization of the lead compound 4c, with a focus on enhancing the hydrophobic interactions in the binding site to improve agonist efficacy for peroxisome proliferator-activated receptor γ (PPARγ). The obtained compounds were characterized using 1H NMR, 13C NMR, HRMS, and HPLC. Furthermore, these compounds were evaluated strong antitumor activity. Some compounds with potent antitumor activities were tested for their PPARγ agonist activity. Especially, compound 4f showed the most potent antitumor activity with half maximal inhibitory concentration (IC50) values of 2.382 μM against the tested tumor cell lines Siha. Docking simulation was performed to position compound 4f into the PPARγ active site to determine the probable binding conformation. Consequently, we discovered a novel PPARγ agonist 4f that demonstrated high in vitro agonist activity.

C17H13F4NO4, monoclinic, P21/n (no. 14), a = 5.470(4) Å, b = 26.141(17) Å, c = 11.689(8) Å, β = 90.01°, V = 1671.3(19) Å3, Z = 4, Rgt${R}_{\mathit{gt}}$ (F) = 0.0612, wRref$w{R}_{\mathit{ref}}$ (F2) = 0.1650, T = 296(2) K.

In this study, the flavor components of double-low fragrant rapeseed oils (cv. “Zhongyouza 19”) from nine different planting areas were qualitatively and quantitatively analyzed by headspace solid phase microextraction (HS-SPME) and gas chromatography-mass spectrometry coupled with olfactometry (GC-MS-O). The results showed that a total of 63 aroma-active compounds were identified using two columns (polar and non-polar) at a total concentration of 222.0 to 468.9 mg/kg. The total concentration of aroma compounds was highest in the Hunan sample and lowest in the Jiangxi sample. Out of the identified flavor substances, 38 had odor activity value (OAV) greater than 10. The results of partial least squares-discriminant analysis (PLS-DA) and sensory evaluation showed that 2-methylpyrazine, 2,3,5-trimethylpyrazine, and 2-methyl-3,5-diethylpyrazine were the main contributors to roasted aroma notes, 3-butenylisothiocyanate provided spicy notes, and 5-hexenenitrile and 4-methylthionitrile led to green notes. Based on variable important in the projection (VIP) values, nine key differential substances were selected, namely, methanthiol, 2-methylpyrazine, 2,3-diethyl-5-methylpyrazine, dimethyl disulfide, 5-methylthiopentonitrile, 5-hexenenitrile, (E,Z)-2,4-pentadienonitrile, hexanal and dimethyl trisulfide. They could be considered as potential flavor markers for the discrimination of double-low fragrant rapeseed oils from different planting areas. This research can provide a theoretical guide for the screening of raw materials for fragrant rapeseed oils.

The Pan-Third Pole region comprises multiple nations affected by climate vulnerability and energy inequality, wherein promoting energy transitions in rural households would provide a path to combat climate change. Identifying the factors that drive rural household energy consumption and the transition is important. This study performed a micro-survey of 1060 rural households in five countries in the Pan-Third Pole region and empirically analyzed the relationships between off-farm income, energy consumption, and energy transitions. The off-farm income of rural households was found to have a significantly positive effect (p

Muscle fibers are the main component of skeletal muscle and undergo maturation through the formation of myotubes. During early development, a population of skeletal muscle satellite cells (SSCs) proliferate into myoblasts. The myoblasts then undergo further differentiation and fusion events, leading to the development of myotubes. However, the mechanisms involved in the transition from SSCs to myotube formation remain unclear. In this study, we characterized changes in the proteomic and transcriptomic expression profiles of SSCs, myoblasts (differentiation for 2 d) and myotubes (differentiation for 10 d). Proteomic analysis identified SLMAP and STOM as potentially associated with myotube formation. In addition, some different changes in MyoD, MyoG, Myosin7 and Desmin occurred after silencing SLMAP and STOM, suggesting that they may affect changes in the myogenic marker. GO analysis indicated that the differentiation and migration factors SVIL, ENSCHIG00000026624 (AQP1) and SERPINE1 enhanced the transition from SSCs to myoblasts, accompanied by changes in the apoptotic balance. In the myoblast vs. myotube group, candidates related to cell adhesion and signal transduction were highly expressed in the myotubes. Additionally, CCN2, TGFB1, MYL2 and MYL4 were identified as hub-candidates in this group. These data enhance our existing understanding of myotube formation during early development and repair.

Abstract While it is generally accepted that holistic processing facilitates face recognition, recent studies suggest that poor recognition might also arise from imprecise perception of local features in the face. This study aimed to examine to what extent holistic and featural processing relates to individual differences in face recognition ability (FRA), during face learning (Experiment 1) and face recognition (Experiment 2). Participants performed two tasks: (1) The “Cambridge Face Memory Test-Chinese” which measured participants’ FRAs, and (2) an “old/new recognition memory test” encompassing whole faces (preserving holistic and featural processing) and faces revealed through a dynamic aperture (impairing holistic processing but preserving featural processing). Our results showed that participants recognised faces more accurately in conditions when holistic information was preserved, than when it is impaired. We also show that the better use of holistic processing during face learning and face recognition was associated with better FRAs. However, enhanced featural processing during recognition, but not during learning, was related to better FRAs. Together, our findings demonstrate that good face recognition depends on distinct roles played by holistic and featural processing at different stages of face recognition.

Abstract Differential gene expression (DGE) analysis has been widely employed to identify genes expressed differentially with respect to a trait of interest using RNA sequencing (RNA-Seq) data. Recent RNA-Seq data with large samples pose challenges to existing DGE methods, which were mainly developed for dichotomous traits and small sample sizes. Especially, existing DGE methods are likely to result in inflated false positive rates. To address this gap, we employed a linear mixed model (LMM) that has been widely used in genetic association studies for DGE analysis of quantitative traits. We first applied the LMM method to the discovery RNA-Seq data of dorsolateral prefrontal cortex (DLPFC) tissue (n = 632) with four continuous measures of Alzheimer’s Disease (AD) cognitive and neuropathologic traits. The quantile–quantile plots of p-values showed that false positive rates were well calibrated by LMM, whereas other methods not accounting for sample-specific mixed effects led to serious inflation. LMM identified 37 potentially significant genes with differential expression in DLPFC for at least one of the AD traits, 17 of which were replicated in the additional RNA-Seq data of DLPFC, supplemental motor area, spinal cord, and muscle tissues. This application study showed not only well calibrated DGE results by LMM, but also possibly shared gene regulatory mechanisms of AD traits across different relevant tissues.

Boron(B)element is often utilized to enhance mechanical properties of stainless steel due to its excellent performance. In this study, selective laser melting (SLM) was used to print 316L/B stainless steel with varying boron weight content. The effects of boron content on microstructure, nanoindentation, and mechanical properties of the printed 316L stainless steel were discussed. Fine cell dendrites and columnar crystals were found in the SLM printed stainless steel due to the rapid solidification in SLM. It was found that boron has a higher growth limiting factor in the iron system and the boron solute can provide a high component supercooling. By adding boron element to stainless steel during printing, the honeycomb and grain size after solidification are significantly reduced due to interactions between the boron element and the 316L. Tensile testing results show that the ultimate tensile strength of the SLM fabricated parts with 0.5 wt% and 1 wt% boron element addition can be increased significantly to 1071 MPa and 1174 MPa, respectively.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with gut microbiota imbalance playing a significant role. There are increasing numbers of research studies exploring treatment options involving probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), but it is still uncertain which treatment option is superior. The research was conducted on various databases and unpublished trial data (up to February 2023). Randomized controlled trials (RCTs) were screened for adult patients with IBS comparing interventions with placebo. Probiotics, prebiotics, synbiotics, and FMT were assessed for their impact using mean difference and Bayesian network meta-analysis. Out of 6528 articles, 54 were included for probiotics, 7 for prebiotics/synbiotics, and 6 for FMT. Probiotics showed improvement in IBS symptoms, particularly with Bifidobacterium and Lactobacillus strains. Prebiotics and synbiotics did not show significant improvement. Network meta-analysis indicated the favorable effects of probiotics (OR = 0.53, 95% CI, 0.48 to 0.59) and FMT (OR = 0.46, 95% CI, 0.33 to 0.64) on IBS, with no serious adverse events reported. In short, probiotics and FMT are effective for managing IBS, with Bifidobacterium and Lactobacillus being dominant strains. However, the most effective probiotic combination or strain remains unclear, while prebiotics and synbiotics did not show significant improvement.

Objective: The objective of this study was to evaluate the therapeutic efficacy of ursodeoxycholic acid (UDCA) and mesenchymal stem cells (MSCs) in patients with severe COVID-19. Methods: We included severe COVID-19 patients hospitalized at Shulan (Hangzhou) Hospital between December 2022 and June 2023. We used a logistic regression model to compare the use of UDCA and MSCs in the two distinct groups of improved and poor outcomes. It is noteworthy that the deterioration group encompassed instances of both death and abandonment of treatment. The receiver operating characteristic (ROC) curve was plotted to assess the performance of the model. The aim was to assess the therapeutic effect of UDCA and MSCs on the outcome of severe COVID-19 patients. Results: A total of 167 patients with severe COVID-19 were included in this study. The analysis revealed that out of 42 patients (25.1%), 17 patients (10.2%) had taken UDCA, and 17 patients (10.2%) had used MSCs. Following a multivariable logistic regression, the results indicated a negative association between UDCA treatment (OR = 0.38 (0.16–0.91), p = 0.029), MSCs treatment (OR = 0.21 (0.07–0.65), p = 0.007), and the risk of severe COVID-19 mortality. Additionally, age showed a positive association with the risk of mortality (OR = 1.03 (1.01–1.07), p = 0.025). Conclusions: UDCA and MSCs have shown potential in improving the prognosis of severe COVID-19 patients and could be considered as additional treatments for COVID-19 in the future.

Stout beer was selected as the research object to screen angiotensin-converting enzyme (ACE) inhibitory peptides. The peptide sequences of stout beer were identified using ultra-performance liquid chromatography-quadrupole-Orbitrap mass spectrometry with de novo, and 41 peptides were identified with high confidence. Peptide Ranker was used to score the biological activity and six peptides with a score ≥ 0.5 were screened to predict their potential ACE inhibitory (ACEI) activity. The toxicity, hydrophilicity, absorption, and excretion of these peptides were predicted. In addition, molecular docking between the peptides and ACE revealed a significant property of the peptide DLGGFFGFQR. Furthermore, molecular docking conformation and molecular dynamics simulation revealed that DLGGFFGFQR could be tightly bound to ACE through hydrogen bonding and hydrophobic interaction. Lastly, the ACEI activity of DLGGFFGFQR was confirmed using in vitro evaluation and the IC50 value was determined to be 24.45 μM.

Background: Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease characterized by unknown causes and a poor prognosis. Recent research indicates that age-related mechanisms, such as cellular senescence, may play a role in the development of this condition. However, the relationship between cellular senescence and clinical outcomes in IPF remains uncertain. Methods: Data from the GSE70867 database were meticulously analyzed in this study. The research employed differential expression analysis, as well as univariate and multivariate Cox regression analysis, to pinpoint senescence-related genes (SRGs) linked to prognosis and construct a prognostic risk model. The model’s clinical relevance and its connection to potential biological processes were systematically assessed in training and testing datasets. Additionally, the expression location of prognosis-related SRGs was identified through immunohistochemical staining, and the correlation between SRGs and immune cell infiltration was deduced using the GSE28221 dataset. Result: The prognostic risk model was constructed based on five SRGs (cellular communication network factor 1, CYR61, stratifin, SFN, megakaryocyte-associated tyrosine kinase, MATK, C-X-C motif chemokine ligand 1, CXCL1, LIM domain, and actin binding 1, LIMA1). Both Kaplan-Meier (KM) curves (p = 0.005) and time-dependent receiver operating characteristic (ROC) analysis affirmed the predictive accuracy of this model in testing datasets, with respective areas under the ROC curve at 1-, 2-, and 3-years being 0.721, 0.802, and 0.739. Furthermore, qRT-RCR analysis and immunohistochemical staining verify the differential expression of SRGs in IPF samples and controls. Moreover, patients in the high-risk group contained higher infiltration levels of neutrophils, eosinophils, and M1 macrophages in BALF, which appeared to be independent indicators of poor prognosis in IPF patients. Conclusion: Our research reveals the effectiveness of the 5 SRGs model in BALF for risk stratification and prognosis prediction in IPF patients, providing new insights into the immune infiltration of IPF progression.

The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.

Summary: Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83–0.88) in the training cohort, and 0.89 (95% CI 0.86–0.92), 0.76 (95% CI 0.73–0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).

Background: The prognosis of malignant pleural effusion (MPE) is poor. A timely and accurate diagnosis is the prerequisite for managing MPE patients. Carbohydrate antigen 72-4 (CA72-4) is a diagnostic tool for MPE. Objective: We aimed to evaluate the diagnostic accuracy of pleural fluid CA72-4 for MPE. Design: A prospective, preregistered, and double-blind diagnostic test accuracy study. Methods: We prospectively enrolled participants with undiagnosed pleural effusions from two centers in China (Hohhot and Changshu). CA72-4 concentration in pleural fluid was measured by electrochemiluminescence. Its diagnostic accuracy for MPE was evaluated by a receiver operating characteristic (ROC) curve. The net benefit of CA72-4 was determined by a decision curve analysis (DCA). Results: In all, 153 participants were enrolled in the Hohhot cohort, and 58 were enrolled in the Changshu cohort. In both cohorts, MPE patients had significantly higher CA72-4 levels than benign pleural effusion (BPE) patients. At a cutoff value of 8 U/mL, pleural fluid CA72-4 had a sensitivity, specificity, and area under the ROC curve (AUC) of 0.46, 1.00, and 0.79, respectively, in the Hohhot cohort. In the Changshu cohort, CA72-4 had a sensitivity, specificity, and AUC of 0.27, 0.94, and 0.86, respectively. DCA revealed the relatively high net benefit of CA72-4 determination. In patients with negative cytology, the AUC of CA72-4 was 0.67. Conclusion: Pleural fluid CA72-4 helps differentiate MPE and BPE in patients with undiagnosed pleural effusions.

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

ABSTRACTThe dissemination of antibiotic resistance genes (ARGs) driven by mobile genetic elements (MGEs), especially among pathogenic bacteria, is of increasing global concern. Different from other well-characterized MGEs, integrative and conjugative elements (ICEs) have been lacking a comprehensive understanding of their roles in ARG propagation across bacterial phylogenies. Through genomic study based on a large collection of bacterial complete genomes and further comparative analysis with two prominent MGEs to spread ARGs—conjugative plasmids and class 1 integrons, we, for the first time, demonstrated that ICEs are indeed overlooked “hot” vectors from the aspects of mobility and pathogenicity: (i) ICEs exhibited broader phylogenetic distribution among two dominant phyla with high ARG diversity and (ii) ARG-carrying ICEs were significantly enriched in potential human pathogens covering all the six “ESKAPE” species, of which some displayed typical co-occurrence patterns with ARGs and virulence factors. Moreover, this first genomic comparative study also deciphered the distinct ARG profiles harbored by these three essential MGE groups in terms of diversity and prevalence, with characteristic ARG preference to each MGE group. Overall, our findings concerning the MGE-specific performance for ARG transmission, in particular, the historically understudied ICEs, could shed light on control strategy optimization to antibiotic resistance crises.IMPORTANCEDifferent from other extensively studied mobile genetic elements (MGEs) whose discoveries were initiated decades ago (1950s–1980s), integrative and conjugative elements (ICEs), a diverse array of more recently identified elements that were formally termed in 2002, have aroused increasing concern for their crucial contribution to the dissemination of antibiotic resistance genes (ARGs). However, the comprehensive understanding on ICEs’ ARG profile across the bacterial tree of life is still blurred. Through a genomic study by comparison with two key MGEs, we, for the first time, systematically investigated the ARG profile as well as the host range of ICEs and also explored the MGE-specific potential to facilitate ARG propagation across phylogenetic barriers. These findings could serve as a theoretical foundation for risk assessment of ARGs mediated by distinct MGEs and further to optimize therapeutic strategies aimed at restraining antibiotic resistance crises.

Background: Lung cancer is the most common cause of malignant pleural effusion (MPE). Serum human epididymis secretory protein 4 (HE4) is a useful diagnostic marker for lung cancer. Objective: This study aimed to evaluate the diagnostic accuracy of pleural fluid HE4 for MPE. Design: A prospective, double-blind diagnostic test accuracy study. Methods: Patients with undiagnosed pleural effusion were enrolled in two cohorts (Hohhot and Changshu). Electrochemiluminescence immunoassay was used to detect pleural fluid HE4. The diagnostic accuracy of HE4 was evaluated by a receiver operating characteristic (ROC) curve, and the net benefit of HE4 was assessed by a decision curve analysis (DCA). Results: A total of 66 MPEs and 86 benign pleural effusions (BPEs) were enrolled in the Hohhot cohort. In the Changshu cohort, 26 MPEs and 32 BPEs were enrolled. In both cohorts, MPEs had significantly higher pleural fluid HE4 than BPEs. The area under the ROC curve (AUC) of HE4 was 0.73 (95% CI: 0.64–0.81) in the Hohhot cohort and 0.79 (95% CI: 0.67–0.91) in the Changshu cohort. At a threshold of 1300 pmol/L, HE4 had sensitivities of 0.44 (95% CI: 0.33–0.56) in the Hohhot cohort and 0.54 (95% CI: 0.35–0.73) in the Changshu cohort. The corresponding specificities were 0.90 (95% CI: 0.83–0.95) in the Hohhot cohort and 0.94 (95% CI: 0.84–1.00) in the Changshu cohort. In subgroup analyses, HE4 had an AUC (95% CI) of 0.78 (0.71–0.85) in exudates and an AUC of 0.69 (0.57–0.81) in patients with negative effusion cytology. The DCA revealed that HE4 determination had a net benefit in both cohorts. Conclusion: Pleural fluid HE4 has moderate diagnostic accuracy for MPE and has net benefit in pleural effusion patients with unknown etiology.