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Abstract Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.

Abstract Background A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. Methods Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. Results Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. Conclusions The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.

Abstract Diffusion Kurtosis Imaging (DKI)-derived metrics are recognized as indicators of maturation in neonates with low-grade germinal matrix and intraventricular hemorrhage (GMH-IVH). However, it is not yet known if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire DKI-derived metrics in neonates with low-grade GMH-IVH, and to demonstrate their association with later neurodevelopmental outcomes. In this prospective study, neonates with low-grade GMH-IVH and control neonates were recruited, and DKI were performed between January 2020 and March 2021. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age. Mean kurtosis (MK), radial kurtosis (RK) and gray matter values were measured. Spearman correlation analyses were conducted for the measured values and neurodevelopmental outcome scores. Forty controls (18 males, average gestational age (GA) 30 weeks ± 1.3, corrected GA at MRI scan 38 weeks ± 1) and thirty neonates with low-grade GMH-IVH (13 males, average GA 30 weeks ± 1.5, corrected GA at MRI scan 38 weeks ± 1). Neonates with low-grade GMH-IVH exhibited lower MK and RK values in the PLIC and the thalamus (P

Abstract Volume fracturing technology is commonly used to develop tight sandstone reservoirs. During the fracturing process, it is important to not only focus on achieving a larger stimulation volume but also on creating a fracture network conductivity that is suitable for the tight reservoir. However, while there have been numerous studies on optimizing the conductivity of individual fractures, the optimization of fracture network conductivity is still incomplete. To address this issue, a reservoir numerical model is established to optimize the equivalent conductivity of the post‐fracturing fracture network, considering it as a high permeability zone, optimizing the equivalent conductivity to 9.7 μm2 cm. Utilizing the discrete element theory, a “pipe domain” discrete element model is developed to analyze fracture expansion. The findings indicate that the ratios of first‐level, second‐level, and third‐level fractures differ based on the number of clusters, such as 1:4:8 and 1:5:9 for three‐cluster and four‐cluster perforations. By applying the hydropower similarity principle, the fracture network is treated as a three‐level circuit to determine the conductivity of each fracture level. Finally, the model is fitted based on conductivity to determine the optimal fracture conductivity for different fracture number ratios, thereby enhancing the flow capability.

Abstract Biofilms produced by Candida albicans present a challenge in treatment with antifungal drug. Enhancing the sensitivity to fluconazole (FLC) is a reasonable method for treating FLC-resistant species. Moreover, several lines of evidence have demonstrated that berberine (BBR) can have antimicrobial effects. The aim of this study was to clarify the underlying mechanism of these effects. We conducted a comparative study of the inhibition of FLC-resistant strain growth by FLC treatment alone, BBR treatment alone, and the synergistic effect of combined FLC and BBR treatment. Twenty-four isolated strains showed distinct biofilm formation capabilities. The antifungal effect of combined FLC and BBR treatment in terms of the growth and biofilm formation of Candida albicans species was determined via checkerboard, time-kill, and fluorescence microscopy assays. The synergistic effect of BBR and FLC downregulated the expression of the efflux pump genes CDR1 and MDR, the hyphal gene HWP1, and the adhesion gene ALS3; however, the gene expression of the transcriptional repressor TUP1 was upregulated following treatment with this drug combination. Furthermore, the addition of BBR led to a marked reduction in cell surface hydrophobicity. To identify resistance-related genes and virulence factors through genome-wide sequencing analysis, we investigated the inhibition of related resistance gene expression by the combination of BBR and FLC, as well as the associated signaling pathways and metabolic pathways. The KEGG metabolic map showed that the metabolic genes in this strain are mainly involved in amino acid and carbon metabolism. The metabolic pathway map showed that several ergosterol (ERG) genes were involved in the synthesis of cell membrane sterols, which may be related to drug resistance. In this study, BBR + FLC combination treatment upregulated the expression of the ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes and downregulated the expression of the ERG6 and ERG9 genes compared with fluconazole treatment alone (p

Abstract Background The methylation of SHOX2 and RASSF1A shows promise as a potential biomarker for the early screening of lung cancer, offering a solution to remedy the limitations of morphological diagnosis. The aim of this study is to diagnose lung adenocarcinoma by measuring the methylation levels of SHOX2 and RASSF1A, and provide an accurate pathological diagnosis to predict the invasiveness of lung cancer prior to surgery. Material and methods The methylation levels of SHOX2 and RASSF1A were quantified using a LungMe® test kit through methylation-specific PCR (MS-PCR). The diagnostic efficacy of SHOX2 and RASSF1A and the cutoff values were validated using ROC curve analysis. The hazardous factors influencing the invasiveness of lung adenocarcinoma were calculated using multiple regression. Results: The cutoff values of SHOX2 and RASSF1A were 8.3 and 12.0, respectively. The sensitivities of LungMe® in IA, MIA and AIS patients were 71.3% (122/171), 41.7% (15/36), and 16.1% (5/31) under the specificity of 94.1% (32/34) for benign lesions. Additionally, the methylation level of SHOX2, RASSF1A and LungMe® correlated with the high invasiveness of clinicopathological features, such as age, gender, tumor size, TNM stage, pathological type, pleural invasion and STAS. The tumor size, age, CTR values and LungMe® methylation levels were identified as independent hazardous factors influencing the invasiveness of lung adenocarcinoma. Conclusion: SHOX2 and RASSF1A combined methylation can be used as an early detection indicator of lung adenocarcinoma. SHOX2 and RASSF1A combined (LungMe®) methylation is significantly correlated to age, gender, tumor size, TNM stage, pathological type, pleural invasion and STAS. The SHOX2 and RASSF1A methylation levels, tumor size and CTR values could predict the invasiveness of the tumor prior to surgery, thereby providing guidance for the surgical procedure.

AIM: To understand the current status and differences in visual acuity of children of the same age from different regions of Xi'an, and to take an effective basis for the prevention of children's myopia.METHODS: Random stratified sampling was used to select the uncorrected distance visual acuity and computed dioptric data of 41 285 children aged 6-12 from 6 towns, 10 urban and rural areas and 112 country schools screened by Xi'an Central Hospital in December 2022.RESULTS: The myopia detection rate in different regions of Xi'an is 47.16% in towns, 38.59% in urban and rural areas, and 32.29% in the country, and the total myopia rate is 37.50%. The myopia rate of 6-12 years old in towns is higher than that in urban and rural areas, and that of urban and rural areas is higher than that of country; the myopia rate of girls is higher than that of boys; myopia rate increases with age; mild myopia: the myopia rate in towns is significantly higher than that of the urban and rural areas and the country; high myopia: the myopia rate in the country is significantly higher than that of the towns and the urban and rural areas. The total rate of deficient hyperopia reserves in different regions of Xi'an is 92.08% in towns, 93.67% in urban and rural areas, and 90.92% in the country, and the total rate of deficient hyperopia reserves is 92.09%. The rate of deficient hyperopia reserves at the age of 6-12 is higher in the urban and rural areas than in the towns, and higher in the towns than in the country; the total rate of deficient hyperopia reserve is higher in girls than in boys; it is the peak period of the development of hyperopia reserve rate before the age of 8.CONCLUSION: The total myopia rate and the total vision reserve deficiency rate of 6-12 years old in different regions of Xi'an are different, and 8-9 years old is the accelerated period of myopia development, and the peak of deficient hyperopia reserve is before the age of 8 years old. With the growth of age, the myopia rate shows a certain growth trend, and the rate of deficient hyperopia reserve shows a decreasing trend after reaching the peak. The total myopia rate and insufficient acuity reserve rate of girls are higher than those of boys.

The incidence of myopia among Chinese adolescents is progressively rising, indicating a distinct trend toward younger age onset.This paper aims to comprehensively review the impact of various visual performance on myopia and its progression, with a specific emphasis on accommodative function, convergence function, and ocular position. A meticulous exploration of accommodation function, encompassing accommodative amplitude, accommodative facility, accommodative response, positive relative accommodation, and negative relative accommodation, has been undertaken to elucidate its contributory role in myopia progression. Concurrently, an exhaustive analysis of convergence function has been conducted including esotropia and exotropia, convergence insufficiency and convergence excess, fusional function vergence, divergence insufficiency, and excess, providing a nuanced understanding of convergence's implications for myopia advancement. Furthermore, the influence of ocular position on myopia progression, along with other factors affecting perceptual ocular position and intermittent exotropia, is discussed. The primary objective of this article is to unveil the multifaceted visual performance influencing myopia and its progression, elucidating the paramount significance of accommodative function, convergence function, and ocular position in this context.

Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Summary: The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ T cell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.

Background and aims Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known.Approach and results The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually.Conclusions Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

Traditionally, the ampacity of an overhead transmission line (OHTL) is a static value obtained based on adverse weather conditions, which constrains the transmission capacity. With the continuous growth of power system load, it is increasingly necessary to dynamically adjust the ampacity based on weather conditions. To this end, this paper models the heat balance relationship of the OHTL based on a BP neural network using Bayesian optimization (BO-BP). On this basis, an OHTL ampacity prediction method considering the model error is proposed. First, a two-stage current-stepping ampacity prediction model is established to obtain the initial ampacity prediction results. Then, the risk control strategy of ampacity prediction considering the model error is proposed to correct the ampacity based on the quartile of the model error to reduce the risk of the conductor overheating caused by the model error. Finally, a simulation is carried out based on the operation data of a 220-kV transmission line. The simulation results show that the accuracy of the BO-BP model is improved by more than 20% compared with the traditional heat balance equation. The proposed ampacity prediction method can improve the transmission capacity by more than 150% compared with the original static ampacity.

ABSTRACT Tuberculosis (TB) remains one of the infectious diseases with high incidence and high mortality. About a quarter of the population has been latently infected with Mycobacterium tuberculosis. At present, the available TB treatment strategies have the disadvantages of too long treatment duration and serious adverse reactions. The sustained inflammatory response leads to permanent tissue damage. Unfortunately, the current selection of treatment regimens does not consider the immunomodulatory effects of various drugs. In this study, we preliminarily evaluated the effects of commonly used anti-tuberculosis drugs on innate immunity at the cellular level. The results showed that clofazimine (CFZ) has a significant innate immunosuppressive effect. CFZ significantly inhibited cytokines and type I interferons (IFNα and IFNβ) expression under both lipopolysaccharide stimulation and CFZ-resistant strain infection. In further mechanistic studies, CFZ strongly inhibited the phosphorylation of nuclear factor kappa B (NF-κB) p65 and had no significant effect on the phosphorylation of p38. In conclusion, our study found that CFZ suppresses innate immunity against Mycobacterium tuberculosis by NF-κB, which should be considered in future regimen development.IMPORTANCEThe complete elimination of Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, from TB patients is a complicated process that takes a long time. The excessive immune inflammatory response of the host for a long time causes irreversible organic damage to the lungs and liver. Current antibiotic-based treatment options involve multiple complex drug combinations, often targeting different physiological processes of Mtb. Given the high incidence of post-tuberculosis lung disease, we should also consider the immunomodulatory properties of other drugs when selecting drug combinations.

Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the “window period” characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing (RNA-seq) and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the Ras homologue family member A (RhoA)/Rho-associated protein kinase (ROCK) signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.

Background: The Chinese herbal compound Lian-Gui-Ning-Xin-Tang (LGNXT), composed of 9 herbs, has a significant antiarrhythmic effect. Previous studies have confirmed that preventing intracellular Ca2+ overload and maintaining intracellular Ca2+ homeostasis may be the important antiarrhythmic mechanisms of LGNXT. Recent studies are focused on elucidating the mechanisms and pharmacodynamic substances of LGNXT. Purpose: 1) To investigate the antiarrhythmic mechanisms of LGNXT; 2) to explore the association of pharmacodynamics (PD) and pharmacokinetics (PK) of the potential pharmacodynamic substances in LGNXT to further verify the mechanisms of action. Methods: First, pharmacodynamic studies were conducted to determine the effect of LGNXT in arrhythmia at the electrophysiological, molecular, and tissue levels, and the “effect–time” relationship of LGNXT was further proposed. Next, an HPLC-MS/MS method was established to identify the “dose–time” relationship of the 9 potential compounds. Combining the “effect–time” and “dose–time” curves, the active ingredients closely related to the inhibition of inflammation, oxidative stress, and energy metabolism were identified to further verify the mechanisms and pharmacodynamic substances of LGNXT. Results: Pretreatment with LGNXT could delay the occurrence of arrhythmias and reduce their duration and severity. LGNXT exerted antiarrhythmic effects by inhibiting MDA, LPO, IL-6, and cAMP; restoring Cx43 coupling function; and upregulating SOD, Ca2+-ATPase, and Na+-K+-ATPase levels. PK-PD association showed that nobiletin, methylophiopogonanone A, trigonelline, cinnamic acid, liquiritin, dehydropolisic acid, berberine, and puerarin were the main pharmacodynamic substances responsible for inhibiting the inflammatory response in arrhythmia. Methylophiopogonanone A, dehydropalingic acid, nobiletin, trigonelline, berberine, and puerarin in LGNXT exerted antiarrhythmic effects by inhibiting oxidative stress. Dehydropalingic acid, berberine, cinnamic acid, liquiritin, puerarin, trigonelline, methylophiopogonanone A, nobiletin, and tetrahydropalmatine exerted antiarrhythmic effects by inhibiting the energy-metabolism process. Conclusions: LGNXT had a positive intervention effect on arrhythmias, especially ventricular tachyarrhythmias, which could inhibit inflammation, oxidative stress, and energy metabolism; positively stabilize the structure, and remodify the function of myocardial cell membranes. Additionally, the PD–PK association study revealed that methylophiopogonanone A, berberine, trigonelline, liquiritin, puerarin, tetrahydropalmatine, nobiletin, dehydropachymic acid, and cinnamic acid directly targeted inflammation, oxidative stress, and energy metabolism, which could be considered the pharmacodynamic substances of LGNXT. Thus, the antiarrhythmic mechanisms of LGNXT were further elucidated.

Mesenchymal stem cell derived extracellular vesicles (MSC EVs) are paracrine modulators of macrophage function. Scientific research has primarily focused on the immunomodulatory and regenerative properties MSC EVs derived from bone marrow. The dental pulp is also a source for MSCs, and their anatomical location and evolutionary function has primed them to be potent immunomodulators. In this study, we demonstrate that extracellular vesicles derived from dental pulp stem cells (DPSC EVs) have pronounced immunomodulatory effect on primary macrophages by regulating the NFκb pathway. Notably, the anti-inflammatory activity of DPSC-EVs is enhanced following exposure to an inflammatory stimulus (LPS). These inhibitory effects were also observed in vivo. Sequencing of the naïve and LPS preconditioned DPSC-EVs and comparison with our published results from marrow MSC EVs revealed that Naïve and LPS preconditioned DPSC-EVs are enriched with anti-inflammatory miRNAs, particularly miR-320a-3p, which appears to be unique to DPSC-EVs and regulates the NFκb pathway. Overall, our findings highlight the immunomodulatory properties of DPSC-EVs and provide vital clues that can stimulate future research into miRNA-based EV engineering as well as therapeutic approaches to inflammation control and disease treatment.

Abstract The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro‐tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF‐κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region‐specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16‐knockout reverses the pro‐tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region‐specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

The dissimilar metal welding joint is connected by the metallurgical bond of intermetallic compounds at the interface, which easily causes stress concentration at the interface and cracks continuously along the interface, resulting in low reliability in impact environments. A novel multi-layer plug and bolt connection for TC4/7A52 dissimilar metal butt joints is proposed in this manuscript and analyzes the influence mechanism of the structural design on impact toughness. The impact toughness of the Ti/Al composite butt joint is 30.3 J/cm2, which is 2.6 times that of the 7A52 BM. The layered toughening design significantly reduces stress concentrations for the butt joint at impact for the Ti/Al composite butt joint. Upon impact, the Ti/Al composite butt joint does not fracture continuously at the V-notch and exhibits significant macroscopic plastic deformation. For the microstructure of each TC4 and 7A52 layer in the impact fracture, more intragranular slip systems are activated and show a higher dislocation density. Therefore, this structural design can enable dissimilar metals to absorb more impact energy during the impact process.

Abstract Sonodynamic therapy (SDT) is demonstrated to trigger the systemic immune response of the organism and facilitate the treatment of metastatic tumors. However, SDT‐mediated neutrophil extracellular traps (NETs) formation can promote tumor cell spread, thus weakening the therapeutic effectiveness of metastatic tumors. Herein, the amorphous CoW‐layered double hydroxide (a‐CoW‐LDH) nanosheets are functionalized with a peptidyl arginine deiminase 4 (PAD4) inhibitor, i.e., YW3‐56, to construct a multifunctional nanoagent (a‐LDH@356) for synergistic SDT/immunotherapy. Specifically, a‐CoW‐LDH nanosheets can act as a sonosensitizer to generate abundant reactive oxygen species (ROS) under US irradiation. After loading with YW3‐56, a‐LDH@356 plus US irradiation not only effectively induces ROS generation and immunogenic cell death, but also inhibits the elevation of citrullinated histone H3 (H3cit) and the release of NETs, enabling a synergistic enhancement of anti‐tumor metastasis effect. Using 4T1 tumor model, it is demonstrated that combining a‐CoW‐LDH with YW3‐56 stimulates an anti‐tumor response by upregulating the proportion of immune‐activated cells and inducing polarization of M1 macrophages, and inhibits immune escape by downregulating the expression of PD‐1 on immune cells under US irradiation, which not only arrests primary tumor progression with a tumor inhibition rate of 69.5% but also prevents tumor metastasis with the least number of lung metastatic nodules.

While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.

C23H25FN2O, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 6.5011(2) Å, b = 11.2794(4) Å, c = 14.0796(6) Å, α = 110.246(4)°, β = 97.236(3)°, γ = 98.335(2)°, V = 941.01(6) Å3, Z = 2, Rgt (F) = 0.0476, wRref (F 2) = 0.1366, T = 293 K.

Abstract Background Mesenchymal stem/stromal cells (MSCs) have been acknowledged as the most important stromal cells in the bone marrow (BM) microenvironment for physiologic hematopoiesis and the concomitant hematologic malignancies. However, the systematic and detailed dissection of the biological and transcriptomic signatures of BM-MSCs in multiple myeloma (MM) are largely unknown. Methods In this study, we isolated and identified BM-MSCs from 10 primary MM patients and 10 healthy donors (HD). On the one hand, we compared the multifaceted biological characteristics of the indicated two BM-MSCs, including biomarker expression pattern, multilineage differentiation potential, stemness and karyotyping, together with the cellular vitality and immunosuppressive property. On the other hand, we took advantage of RNA-SEQ and bioinformatics analysis to verify the similarities and differences at the transcriptomic level between MM-MSCs and HD-MSCs. Results As to biological phenotypes and biofunctions, MM-MSCs revealed conservation in immunophenotype, stemness and differentiation towards adipocytes and chondrocytes with HD-MSCs, whereas with impaired osteogenic differentiation potential, cellular vitality and immunosuppressive property. As to transcriptomic properties, MM-MSCs revealed multidimensional alterations in gene expression profiling and genetic variations. Conclusions Overall, our date systematic and detailed reflected the multifaceted similarities and variations between MM-MSCs and HD-MSCs both at the cellular and molecular levels, and in particular, the alterations of immunomodulation and cellular viability of MM-MSCs, which wound benefit the further exploration of the pathogenesis and new drug application (NDA) of multiple myeloma from the view of BM-MSCs.

Abstract The prevalence of porcine reproductive and respiratory syndrome virus 1 (PRRSV1) isolates has continued to increase in Chinese swine herds in recent years. However, no effective control strategy is available for PRRSV1 infection in China. In this study, we generated the first infectious cDNA clone (rHLJB1) of a Chinese PRRSV1 isolate and subsequently used it as a backbone to construct an ORF2-6 chimeric virus (ORF2-6-CON). This virus contained a synthesized consensus sequence of the PRRSV1 ORF2-6 gene encoding all the envelope proteins. The ORF2-6 consensus sequence shared > 90% nucleotide similarity with four representative strains (Amervac, BJEU06-1, HKEU16 and NMEU09-1) of PRRSV1 in China. ORF2-6-CON had replication efficacy similar to that of the backbone rHLJB1 virus in primary alveolar macrophages (PAMs) and exhibited cell tropism in Marc-145 cells. Piglet inoculation and challenge studies indicated that ORF2-6-CON is not pathogenic to piglets and can induce enhanced cross-protection against a heterologous SD1291 isolate. Notably, ORF2-6-CON inoculation induced higher levels of heterologous neutralizing antibodies (nAbs) against SD1291 than rHLJB1 inoculation, which was concurrent with a higher percentage of T follicular helper (Tfh) cells in tracheobronchial lymph nodes (TBLNs), providing the first clue that porcine Tfh cells are correlated with heterologous PRRSV nAb responses. The number of SD1291-strain-specific IFNγ-secreting cells was similar in ORF2-6-CON-inoculated and rHLJB1-inoculated pigs. Overall, our findings support that the Marc-145-adapted ORF2-6-CON can trigger Tfh cell and heterologous nAb responses to confer improved cross-protection and may serve as a candidate strain for the development of a cross-protective PRRSV1 vaccine.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Brain functional networks derived from functional magnetic resonance imaging (fMRI) provide a promising approach to understanding cognitive processes and predicting cognitive abilities. The topological attribute parameters of global networks are taken as the features from the overall perspective. It is constrained to comprehend the subtleties and variances of brain functional networks, which fell short of thoroughly examining the complex relationships and information transfer mechanisms among various regions. To address this issue, we proposed a framework to predict the cognitive function status in the patients with end-stage renal disease (ESRD) at a functional subnetwork scale (CFSFSS). The nodes from different network indicators were combined to form the functional subnetworks. The area under the curve (AUC) of the topological attribute parameters of functional subnetworks were extracted as features, which were selected by the minimal Redundancy Maximum Relevance (mRMR). The parameter combination with improved fitness was searched by the enhanced whale optimization algorithm (E-WOA), so as to optimize the parameters of support vector regression (SVR) and solve the global optimization problem of the predictive model. Experimental results indicated that CFSFSS achieved superior predictive performance compared to other methods, by which the mean absolute error (MAE), mean absolute percentage error (MAPE), and root mean square error (RMSE) were up to 0.5951, 0.0281 and 0.9994, respectively. The functional subnetwork effectively identified the active brain regions associated with the cognitive function status, which offered more precise features. It not only helps to more accurately predict the cognitive function status, but also provides more references for clinical decision-making and intervention of cognitive impairment in ESRD patients.

In the software defined network (SDN)/network function virtualization (NFV)-enabled networks, service function chains (SFCs) should typically be allocated to deploy these services, which not only entails meeting the service’s Quality of Service (QoS) requirements, but also considering the infrastructure’s limitations. Although this issue has received much attention in the literature, the dynamics, intricacy, complexity and unpredictability of the issue provide several difficulties for researchers and engineers. The traditional methods (e.g., exact, heuristic, meta-heuristic, and game, etc.) are subjected to the complexity of multi-domain cloud network scenarios with dynamic network states, high-speed computational requirements, and enormous service requests. Recent studies have shown that reinforcement learning (RL) is a promising way to deal with the limitations of the traditional methods. On-policy and off-policy are two key categories in the field of RL models, and they both have promising advantages in deal with dynamic resource allocation problems. This paper contains two innovative points at two levels. Firstly, in order to deal with SFC embedding problem in dynamic multi-domain networks, a mixed Markov model combining Markov decision process (MDP) and hidden Markov model (HMM) is constructed, and the corresponding RL model-solving algorithms are proposed. Secondly, in order to distinguish the appropriate model in a given network scenario, the on-policy RL based multiple domain SFC embedding algorithm is compared with the off-policy one. The obtained simulation results show that the proposed RL algorithms can outperform the current baselines in terms of delay, load balancing and response time. Furthermore, we also point out that the off-policy based algorithm is more suitable for small-scale dynamic network scenarios, while the on-policy based algorithm is more suitable for medium to large-scale network scenarios with high convergence requirements.

Keypoint matching plays a vital role in the realm of synthetic aperture radar (SAR) image processing, serving as a crucial component within this domain. Another key fact to remember keypoint matching is a crucial step in change detection and image stitching. In the context of SAR images, a scale-invariant feature transformation (SIFT)-based approach, known as SAR–SIFT, presents a notable advantage by mitigating the impact of speckle noise; however, it cannot yield accurate edge information, and the resulting keypoints are nonuniformly distributed. We propose an edge enhancement and homogeneous spatial key point improved SAR–SIFT framework based on an unbiased difference-ratio (UDR) edge detector (called EEKHI–SAR–SIFT) to solve the above problems. The algorithm relies on the characteristics of edge unbiased localization and constant false alarm rate of UDR edge extraction to reduce the extracted wrong corner information as well as enhance the extraction exactness of keypoints. In addition, adaptive nonmaximum suppression (ANMS) method is applied to homogenize the dense keypoints with a large initial number that are gained by means of the EEKHI–SAR–SIFT algorithm and reduce their local clustering. Finally, a descriptor construction strategy that retains multiscale information is adopted to improve the descriptor uniqueness. Tests using multiple sets of SAR image data from different satellites (Gaofen-3, RADARSAT, and Sentinel-1A) demonstrate that the efficacy of the proposed EEKHI–SAR–SIFT algorithm reduces the root mean square error is about 1–2 pixel lower than the final result of the original SAR–SIFT algorithm.

Abstract Background The association between non-alcoholic fatty liver disease (NAFLD) and osteoarthritis (OA) has not been well elucidated. The aim of the present study was to investigate the association between NAFLD and OA in the US adults. Methods A cross-sectional study was performed on participants in the 2017–2018 National Health and Nutrition Examination Survey (NHANES) cycle. NAFLD was defined by the vibration-controlled transient elastography. The diagnosis of OA was based on self-reported data. Weighted multiple logistic regression models and stratified analyses were performed to explore the relationship and verify the stability of the conclusions. Sensitivity analysis using multiple imputation for missing data and propensity score matching (PSM) were performed. Results In total, 2622 participants [Male: 1260 (47.8%)] were included in this study with a mean age of 48.1 years old (95% CI, 46.6–49.6 years old), containing 317 (12.8%) OA patients and 1140 NAFLD patients (41.5%). A logistic regression indicated a significant association between NAFLD and OA without adjustment [odds ratio (OR) = 2.05; 95% CI, 1.52–2.78]. The association remained stable after adjustment for covariates (OR = 1.72; 95% CI, 1.26–2.34). Sensitivity analysis of missing data with multiple interpolation and PSM found similar results. A significant and consistent association of NAFLD with OA was still observed in each subgroup stratified by age and metabolic syndrome (MetS). Stratified by sex, obesity, and sensitivity c-reactive protein (hs-CRP) category, a statistically significant association was only shown in females, those without obesity, and those without hyper hs-CRP. The results illustrated that the relationship between NAFLD and OA was stable in all subgroups and had no interaction. Conclusions NAFLD was positively correlated with OA. Given the current pandemic of NAFLD and OA, clinicians should screen for NAFLD in arthritis patients and intervene early.

Abstract Background Abnormal activation of FAK is associated with tumor development and metastasis. Through interactions with other intracellular signalling molecules, FAK influences cytoskeletal remodelling, modulation of adhesion signalling, and activation of transcription factors, promoting migration and invasion of tumor cells. However, the exact mechanism that regulates these processes remains unresolved. Herein, our findings indicate that the S-palmitoylation of FAK is crucial for both its membrane localization and activation. Methods The palmitoylation of FAK in U251 and T98G cells was assessed by an acyl-PEG exchange (APE) assay and a metabolic incorporation assay. Cellular palmitoylation was inhibited using 2-bromopalmitate, and the palmitoylation status and cellular localization of FAK were determined. A metabolic incorporation assay was used to identify the potential palmitoyl acyltransferase and the palmitoylation site of FAK. Cell Counting Kit-8 (CCK8) assays, colony formation assays, and Transwell assays were conducted to assess the impact of ZDHHC5 in GBM. Additionally, intracranial GBM xenografts were utilized to investigate the effects of genetically silencing ZDHHC5 on tumor growth. Results Inhibiting FAK palmitoylation leads to its redistribution from the membrane to the cytoplasm and a decrease in its phosphorylation. Moreover, ZDHHC5, a protein-acyl-transferase (PAT), catalyzes this key modification of FAK at C456. Knockdown of ZDHHC5 abrogates the S-palmitoylation and membrane distribution of FAK and impairs cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Taken together, our research reveals the crucial role of ZDHHC5 as a PAT responsible for FAK S-palmitoylation, membrane localization, and activation. Conclusions These results imply that targeting the ZDHHC5/FAK axis has the potential to be a promising strategy for therapeutic interventions for glioblastoma (GBM). Video Abstract

ABSTRACTColorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (ApcMin/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.

IntroductionWaardenburg syndrome (WS) is a genetic disorder characterized by hearing loss, hypopigmentation, and distinct facial features. Despite > 60% molecular diagnosis rate for WS patients, pathogenic variants within coding regions are predominant, with few non-coding copy number variations (CNVs) reported.MethodsIn this study, we performed whole genome sequencing (WGS) on 59 undiagnosed WS patients and analyzed the CNVs within the promoter and enhancer regions of the SOX10 gene.ResultsWe identified five novel pathogenic deletions ranging from 448 bp to 70 kb upstream of SOX10. Two deletions were in the enhancer region, while three were in the promoter and 5'UTR region. These CNVs manifested as WS type II in eight patients from five unrelated families, demonstrating phenotypic heterogeneity. Furthermore, analysis of CNV1 within the enhancer region suggested a potential mechanism involving Alu-mediated non-allelic homologous recombination (NAHR).ConclusionOur findings extend the mutation spectrum of the SOX10 gene and elucidate the pathogenic role of CNVs in cis-regulatory elements, particularly variations in enhancer and promoter regions, thereby enhancing clinical gene detection and interpretation of non-coding regions.

Abstract Cancer is a disease with molecular heterogeneity that is closely related to gene mutations and epigenetic changes. The principal histological subtype of lung cancer is non‐small cell lung cancer (NSCLC). Long noncoding RNA (lncRNA) is a kind of RNA that is without protein coding function, playing a critical role in the progression of cancer. In this research, the regulatory mechanisms of lncRNA phosphorylase kinase regulatory subunit alpha 1 antisense RNA 1 (PHKA1‐AS1) in the progression of NSCLC were explored. The increased level of N6‐methyladenosine (m6A) modification in NSCLC caused the high expression of PHKA1‐AS1. Subsequently, high‐expressed PHKA1‐AS1 significantly facilitated the proliferation and metastasis of NSCLC cells, and these effects could be reversed upon the inhibition of PHKA1‐AS1 expression, both in vivo and in vitro. Additionally, the target protein of PHKA1‐AS1 was actinin alpha 4 (ACTN4), which is known as an oncogene. Herein, PHKA1‐AS1 could enhance the protein stability of ACTN4 by inhibiting its ubiquitination degradation process, thus exerting the function of ACTN4 in promoting the progress of NSCLC. In conclusion, this research provided a theoretical basis for further exploring the potential mechanism of NSCLC metastasis and searching novel biomarkers related to the pathogenesis and progression of NSCLC.

Summary: Background: A variety of symptoms, particularly cognitive, psychiatric and neurological symptoms, may persist for a long time among individuals recovering from COVID-19. However, the underlying mechanism of these brain abnormalities remains unclear. This study aimed to investigate the long-term neuroimaging effects of COVID-19 infection on brain functional activities using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Fifty-two survivors 27 months after infection (mild-moderate group: 25 participants, severe-critical: 27 participants), from our previous community participants, along with 35 healthy controls, were recruited to undergo fMRI scans and comprehensive cognitive function measurements. Participants were evaluated by subjective assessment of Cognitive Failures Questionnaire-14 (CFQ-14) and Fatigue Scale-14 (FS-14), and objective assessment of Montreal Cognitive Assessment (MoCA), N-back, and Simple Reaction Time (SRT). Each had rs-fMRI at 3T. Measures such as the amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated. Findings: Compared with healthy controls, survivors of mild-moderate acute symptoms group and severe-critical group had a significantly higher score of cognitive complains involving cognitive failure and mental fatigue. However, there was no difference of cognitive complaints between two groups of COVID-19 survivors. The performance of three groups was similar on the score of MoCA, N-back and SRT. The rs-fMRI results showed that COVID-19 survivors exhibited significantly increased ALFF values in the left putamen (PUT.L), right inferior temporal gyrus (ITG.R) and right pallidum (PAL.R), while decreased ALFF values were observed in the right superior parietal gyrus (SPG.R) and left superior temporal gyrus (STG.L). Additionally, decreased ReHo values in the right precentral gyrus (PreCG.R), left postcentral gyrus (PoCG.L), left calcarine fissure and surrounding cortex (CAL.L) and left superior temporal gyrus (STG.L). Furthermore, significant negative correlations between the ReHo values in the STG.L, and CFQ-14 and mental fatigue were found. Interpretation: This long-term study suggests that individuals recovering from COVID-19 continue to experience cognitive complaints, psychiatric and neurological symptoms, and brain functional alteration. The rs-fMRI results indicated that the changes in brain function in regions such as the putamen, temporal lobe, and superior parietal gyrus may contribute to cognitive complaints in individuals with long COVID even after 2-year infection. Funding: The National Programs for Brain Science and Brain-like Intelligence Technology of China, the National Natural Science Foundation of China, Natural Science Foundation of Beijing Municipality of China, and the National Key Research and Development Program of China.

In seismic nuclear monitoring, attenuation models are important prerequisites for reliably estimating the explosive yield in an uncalibrated region without the occurrence of standard events. The seismic moment obtained by fitting source spectra is related to the source energy. This approach is appropriate for estimating yield, as the attenuation effects on the propagation path can be accurately considered. In this study, we collected 2022 vertical component waveforms in and around the Korean Peninsula from May 2010 to May 2022 to construct a high-resolution broadband Lg-wave attenuation model and inverted the Lg-wave source excitation spectra of the nuclear explosion simultaneously with attenuation correction. We obtained the scalar seismic moments by fitting the theoretical source spectra based on the Brune (J. Geophys. Res., 1970, 75, 4997–5009) model. Under the given emplacement conditions and burial depths, the seismic moments can be used to estimate yields of the North Korean nuclear tests, which are 4.6, 8.5, 19.9, 20.9, 24.7, and 337.4 kt for six nuclear explosions that occurred between 2006 and 2017. Our results are consistent with those obtained from previous teleseismic observations.

In light of escalating global climate change concerns and the pressing need to address industries with high carbon emissions and pollution, enhancing the preparation of phenol-formaldehyde epoxy resins has emerged as a critical research focus. This study seeks to fabricate waterborne phenol-formaldehyde epoxy resins with superior performance by investigating pivotal factors influencing their properties and refining preparation methods. Utilizing tetrabutylammonium bromide as a phase transfer catalyst, the phenol-formaldehyde epoxy resins are synthesized via a two-step alkalization process. Subsequent etherification reactions involve modifying the phenol-formaldehyde epoxy resins using cationic modifier diethanolamine (DEA) and anionic modifier sodium p-amino benzenesulfonate, resulting in waterborne phenol-formaldehyde epoxy resins. Subsequently, in situ synthesis is employed to produce nanoscale silica (SiO2) modified waterborne phenol-formaldehyde epoxy resins. The findings reveal that when the ratio of n1 to n2 falls within the range of 1/3.25 to 1/3, the emulsion displays a moderate particle size and maintains stable storage. Furthermore, an increase in DEA dosage leads to a particle size of less than 324 nm when the ratio of n1 to n2 exceeds 1/3, indicating stability. Moreover, optimal stability and prolonged storage lifespan are achieved when the nano SiO2 content is approximately 1.5%. This study contributes by synthesizing high-quality waterborne phenol-formaldehyde epoxy resin emulsions through optimized methods. The research findings offer a theoretical foundation for this domain and support the practical application of low-carbon and environmentally friendly concepts in the coatings industry.

The joining of Inconel 625 and GRCop42 using additive manufacturing is required for thermal management of high operating temperature components such as rocket combustion chambers. Though prior efforts have been made to use laser directed energy deposition to join these materials, the impact of laser power and deposition sequence on microstructure of these joints is not well understood. In this study, Inconel 625 onto GRCop42 and GRCop42 onto Inconel 625 joints are fabricated by powder directed-energy-deposition at various laser powers and subsequently subjected to characterization in terms of present defects, grain morphology, and phases. Results show lack-of-fusion free Inconel 625 onto GRCop42 joints can be fabricated by increasing the laser power in the first layer. Substrate remelting in GRCop42 onto Inconel 625 joints is found to result in a melt pool composition which induces liquid-state immiscibility, resulting in a Cu-deprived liquid solidifying to form crack prone islands. Increasing laser power decreases the embrittlement of these islands due to the precipitation of a lower volume fraction of intermetallic phases.

The Carboniferous to Permian tectono-sedimentary evolution of the southern Junggar area brings new insights into understanding the subduction-collision processes in the northern Tianshan region. Integrating geophysics, geochemistry, and geochronology approaches, this study investigates the Carboniferous–Permian strata in the southern Junggar Basin. The results have revealed three distinct tectono-stratigraphic evolutionary stages, each marked by a distinctive volcano-sedimentary sequence. The Early Carboniferous strata suggest intense volcanic activities in the southern Junggar area. During the Late Carboniferous, the southern Junggar Basin was controlled by normal faulting in an extensional setting, receiving sedimentary inputs from the Junggar terrane. The Lower Permian, unconformably overlying the Upper Carboniferous, was shaped by an extensional regime and is comprised by volcano-clastic sequences that received detritus from the Yili-Central Tianshan block. These findings indicate that a Late Carboniferous forearc basin developed in the southern Junggar area, and it evolved into a post-collisional rift in the Early Permian. This period marked a dynamic shift from bidirectional subduction (rollback) to the detachment of the North Tianshan oceanic slab. We propose that the collision between the Yili-Central Tianshan block and the Junggar terrane, along with the closure of the North Tianshan Ocean, likely occurred in the Late Carboniferous (ca.306–303 Ma).

Abstract The diurnal variation and distribution of lunar surficial hydration (OH/H2O) is of great significance for understanding the solar wind implantation and water cycle on the Moon. Lunar south pole is an ideal place to study the diurnal variation of surficial hydration due to the large number of repeat observations of the same region, which is very limited in mid‐ or low‐latitudes. Here we showed clear 0.5‐hr interval diurnal variation of surficial hydration at lunar south pole. The variation of hydration band depth with local time is exactly the opposite to the variation of temperature, indicating that lunar surficial hydration changes sufficiently with temperature. This relationship indicates that both the diurnal variation and hydration content are latitude dependent. Our observations support the hypothesis that the diurnal variation of hydration on the Moon is due to the formation of metastable hydroxyl.

Grandparenting is becoming increasingly prevalent worldwide, especially in Chinese society. However, the impact of grandparenting on older adults’ health remains unclear. This study examined whether and how grandparenting is associated with depressive symptoms in Chinese older adults and the role of intergenerational support (i.e., financial, emotional, and instrumental support) in this relationship. Using data from the China Longitudinal Aging Social Survey (CLASS) 2018 wave, the researchers employed multivariate linear regression models to investigate variations in depressive symptoms and their associations with grandparenting; the role of intergenerational support was also explored. The results indicated that older adults who engage in grandparenting, particularly in non-intensive care, experience a reduction in depressive symptoms, even after accounting for sociodemographic and health-related factors. Overall, intergenerational support plays a mediating role in the relationship between grandparenting and associated mental health outcomes. Bidirectional emotional and financial support and receiving instrumental support were associated with lower depressive symptoms among Chinese grandparents. In general, the findings of this study suggest that grandparenting, along with intergenerational support, provides certain protective health benefits for Chinese grandparents. With rapid changes in Chinese society, further prospective longitudinal studies are needed to examine family contexts in the relationship between grandchild caregiving and associated health outcomes.

Abstract Background The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case–control cohorts is lacking. Methods To address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets. Results In subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients. Conclusions Our study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.

Abstract Understanding how dietary polysaccharides affect mucin O-glycosylation and gut microbiota could provide various nutrition-based treatments. Here, the O-glycan profile of the colonic mucosa and gut microbiome were investigated in C57BL/6J mice fed six structurally diverse dietary polysaccharides and a mixture of six fibers. Dietary polysaccharides increased total O-glycans, mainly by stimulating neutral glycans. Highly branched arabinogalactan promoted terminally fucosylated core 1 O-glycans; whereas linear polysaccharides, including pectin, konjac glucomannan, inulin, and the fiber mixture, favored terminally di-fucosylated O-glycans. The last three polysaccharides also lowered the level of sulfated O-glycans and sialylated mono-fucosylated O-glycans. Varied monosaccharide composition in mixed polysaccharides had a synergistic beneficial effect, boosting fucosylated neutral glycans, decreasing acidic glycans, and stimulating microbial richness and diversity. Dietary polysaccharides containing arabinose and sulfate groups enhanced the relative abundances of Akkermansia and Muribaculaceae, respectively. The present comparison reveals the relationship between dietary polysaccharide structure, mucin O-glycan composition, and intestinal microorganisms.

There is currently great interest in developing an environment-friendly, low-cost, and scalable approach for producing stimuli-responsive fluorescent hydrogels (FHs) with excellent mechanical property, rewritable fluorescence, and dual anti-counterfeiting capabilities. Herein, by applying natural, environment-friendly, and sustainable curcumin as a responsive agent, tough pH-responsive FHs (pH-FHs) are fabricated via a facile preparation strategy. These materials have outstanding mechanical performances: ultimate stress of 180 kPa, an ultimate strain of ∼2500%, and good anti-fatigue performances against compression. These pH-FHs are able to sense ammonia and formaldehyde gas, resulting in both a color change and fluorescence for dual anti-counterfeiting functionality. This sensing information is stored individually by the pH-FHs and could be externally removed using formaldehyde gas to achieve a rewritable system. Our study provides valuable insights that are expected to facilitate the development of smart FHs for information encryption and anti-counterfeiting applications.

Abstract Background Salmonella Enteritidis is a zoonotic pathogen and poses a substantial risk to human health, as well as significant financial losses to the livestock and poultry industries. It is currently urgent to identify alternatives to antibiotic treatment. Results In this study, we explored the influence of Puerarin on the immunological response, intestinal flora, serum metabolome, and growth performance of chicks infected with Salmonella Enteritidis. Chicks were weighed at specific time points and the average daily gain (ADG) was calculated. Serum, intestinal, and cecal content samples were collected on days 10 and 17. The results showed that 100 mg/kg of Puerarin significantly suppressed inflammation and enhanced immune function. Metabolomic analysis showed significant differences in serum metabolites after Puerarin treatment and suggested that Puerarin may regulate abnormal amino acid and lipid metabolism after Salmonella Enteritidis infection through the autophagic and ABC transporter pathways. In addition, Puerarin suppressed Salmonella Enteritidis-induced intestinal flora dysbiosis through modulation of the microbial community structures (increased Lactobacillus, Faecalibacterium, and Subdoligranulum), as demonstrated by 16S rRNA analysis. Conclusions In conclusion, Puerarin can improve growth performance in chicks, suppress the inflammatory response in vivo, enhance immunity, and regulate lipid and amino acid metabolism and the intestinal flora.

In the bearing-based formation control of autonomous surface vehicles, the scaling maneuver capability is greatly limited when faced with actuator faults and uncertainties. Under these circumstances, to better realize the formation scaling maneuver, a concise adaptive fault-tolerant formation scaling control scheme is proposed for autonomous vehicles with bearing measurements. By means of dynamic surface control, parameter integration and the adaptive technique, the tedious derivative calculation of virtual control signals is avoided and the prescribed formation scaling maneuver is achieved without knowing specific information about the faults and models. It is shown that both yaw angle tracking errors and bearing errors are able, ultimately, to be made uniformly bounded using this scheme. Meanwhile, only one control parameter and one adaptive parameter need to be updated during the formation scaling process. Stability analysis and comparative results are provided to verify the validity of the developed scheme.

Convenient and consistent phase convention is important in the construction of the hadronic Lagrangian. However, the importance of phase convention has been overlooked for a long time, and the sources of different conventions are never explicitly addressed. This obscure situation can cause mistakes and misinterpretations in hadron physics. In this paper, we systematically analyze and compare the flavor SU3 phase conventions from the perspective of the quark model. All sources that could lead to different conventions are pointed out and carefully studied. With the tool of the quark model, we also clarify some misconceptions and demonstrate a consistent way to incorporate different conventions.

IntroductionMycobacterium tuberculosis (Mtb), the main cause of tuberculosis (TB), has brought a great burden to the world's public health. With the widespread use of Mtb drug-resistant strains, the pressure on anti-TB treatment is increasing. Anti-TB drugs with novel structures and targets are urgently needed. Previous studies have revealed a series of CYPs with important roles in the survival and metabolism of Mtb. However, there is little research on the structure and function of CYP138.MethodsIn our study, to discover the function and targetability of CYP138, a cyp138-knockout strain was built, and the function of CYP138 was speculated by the comparison between cyp138-knockout and wild-type strains through growth curves, growth status under different carbon sources, infection curves, SEM, MIC tests, quantitative proteomics, and lipidomics.Results and discussionThe knockout of cyp138 was proven to affect the Mtb's macrophage infection, antibiotics susceptibility, and the levels of fatty acid metabolism, membrane-related proteins, and lipids such as triacylglycerol. We proposed that CYP138 plays an important role in the synthesis and decomposition of lipids related to the cell membrane structure as a new potential anti-tuberculosis drug target.

ABSTRACT Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo. The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of M. avium and M. abscessus were 0.05–0.94 μg/mL, 0.88–7.22 μg/mL (M. abscessus subsp. abscessus), and 0.22–8.67 μg/mL (M. abscessus subsp. massiliense), respectively, which were slightly higher than those of BDQ. For M. avium, M. abscessus, and M. chelonae, WX-081 can reduce the intracellular bacterial load by 0.13–1.18, 0.18–1.50, and 0.17–1.03 log10 colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both in vivo and in vitro. WX-081 is a promising clinical candidate and should be studied further in clinical trials.IMPORTANCEDue to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000–2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.