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Abstract Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

ObjectivesEvidence on the relationship between self-rated health status and incident type 2 diabetes (T2DM) in China is scarce. This study aims to examine the prospective association of self-rated health status with the subsequent risk of T2DM among middle-aged and older Chinese subjects.MethodsData were obtained from the China Health and Retirement Longitudinal Study of 9844 Chinese individuals aged 45 years or older. Cox proportional hazards models were used to yield hazard ratios (HRs) relating self-rated health status to the 7-year incidence of T2DM, adjusting for conventional risk factors.ResultsCompared to those with very good or good self-rated health, individuals with poor health had a significantly higher risk of developing T2DM in the multivariable-adjusted model [HR = 1.36 (1.07, 1.73)]. Subgroup analysis by sex showed stronger associations in women [HR = 1.53 (1.11, 2.12)]. Interaction analyses indicated that factors such as age, sex, obesity, smoking status, drinking status, history of hypertension and history of dyslipidemia did not modify the association (all P-interaction >0.05).ConclusionPoor self-rated health status is associated with a higher risk of developing T2DM in middle-aged and older Chinese people.

In mammals, 17-beta hydroxysteroid dehydrogenase 2 (Hsd17b2) enzyme specifically catalyzes the oxidation of the C17 hydroxyl group and efficiently regulates the activities of estrogens and androgens to prevent diseases induced by hormone disorders. However, the functions of the hsd17b2 gene involved in animal sex differentiation are still largely unclear. The ricefield eel (Monopterus albus), a protogynous hermaphroditic fish with a small genome size (2n = 24), is usually used as an ideal model to study the mechanism of sex differentiation in vertebrates. Therefore, in this study, hsd17b2 gene cDNA was cloned and its mRNA expression profiles were determined in the ricefield eel. The cloned cDNA fragment of hsd17b2 was 1230 bp, including an open reading frame of 1107 bp, encoding 368 amino acid residues with conserved catalytic subunits. Moreover, real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis showed that hsd17b2 mRNA expressed strongly in the ovaries at early developmental stages, weakly in liver and intestine, and barely in testis and other tissues. In particular, hsd17b2 mRNA expression was found to peak in ovaries of young fish and ovotestis at the early stage, and eventually declined in gonads from the late ovotestis to testis. Likewise, chemical in situ hybridization results indicated that the hsd17b2 mRNA signals were primarily detected in the cytoplasm of oogonia and oocytes at stage I–II, subsequently concentrated in the granulosa cells around the oocytes at stage Ⅲ–Ⅳ, but undetectable in mature oocytes and male germ cells. Intriguingly, in ricefield eel ovaries, hsd17b2 mRNA expression could be significantly reduced by 17β-estradiol (E2) or tamoxifen (17β-estradiol inhibitor, E2I) induction at a low concentration (10 ng/mL) and increased by E2I induction at a high concentration (100 ng/mL). On the other hand, both the melatonin (MT) and flutamide (androgen inhibitor, AI) induction could significantly decrease hsd17b2 mRNA expression in the ovary of ricefield eel. This study provides a clue for demonstrating the mechanism of sexual differentiation in fish. The findings of our study imply that the hsd17b2 gene could be a key regulator in sexual differentiation and modulate sex reversal in the ricefield eel and other hermaphroditic fishes.

Abstract Magnetic skyrmions with a well-defined spin texture have shown unprecedented potential for various spintronic applications owning to their topologically non-trivial and quasiparticle properties. To put skyrmions into practical technology, efficient manipulation, especially the inhibition of skyrmion Hall effect (SkHE) has been intensively pursued. In spite of the recent progress made on reducing SkHE in several substituted systems, such as ferrimagnets and synthetic antiferromagnets, the organized creation and current driven motion of skyrmions with negligible SkHE in ferromagnets remain challenging. Here, by embedding the [Co/Pd] multilayer into a surface acoustic wave (SAW) delay line where the longitudinal leaky SAW is excited to provide both the strain and thermal effect, we experimentally realized the ordered generation of magnetic skyrmions. The resultant current-induced skyrmions movement with negligible SkHE was observed, which can be attributed to the energy redistribution of the system during the excitation of SAW. Our findings open up an unprecedentedly new perspective for manipulating topological solitons, which could possibly trigger the future discoveries in skyrmionics and spin acousto-electronics.

Abstract Aim To explore the relationship between filial obligation and caregiver depression across cultures. Design Systematic review and meta‐analysis. Methods Twelve databases were reviewed for dissertations and peer‐reviewed articles on filial obligation and caregiver depression among adult children, published before January 2020. In total, 476 titles and abstracts were retrieved. Final analysis included six studies; of these, four were included in the meta‐analysis. Results Fixed‐effects model indicated that a stronger perception of filial obligation was associated with increased depressive symptoms among caregivers across cultures (β = 0.14, 95% CI [0.04, 0.24], p 0.05, N = 880). Therefore, caregivers' perceptions of filial obligation should be clinically assessed and normalised to reduce their depressive symptoms.

Abstract Chimeric antigen receptor (CAR) T cells have been successfully used in adoptive cell therapy for malignancies. However, some obstacles, including side effects such as graft‐versus‐host disease and cytokine release syndrome, therapy resistance, limited sources, as well as high cost, limited the application of CAR T cells. Recently, CAR natural killer (NK) cells have been pursued as the effector cells for adoptive immunotherapy for their attractive merits of strong intrinsic antitumor activity and relatively mild side effects. Additionally, CAR NK cells can be available from various sources and do not require strict human leukocyte antigen matching, which suggests them as promising “off‐the‐shelf” products for clinical application. Although the use of CAR NK cells is restrained by the limited proliferation and impaired efficiency within the immunosuppressive tumor microenvironment, further investigation in optimizing CAR structure and combination therapies will overcome these challenges. This review will summarize the advancement of CAR NK cells, CAR NK cell manufacture, the clinical outcomes of CAR NK therapy, the challenges in the field, and prospective solutions. Besides, we will discuss the emerging application of other immune cells for CAR engineering. Collectively, this comprehensive review will provide a valuable and informative summary of current progress and evaluate challenges and future opportunities of CAR NK cells in tumor treatment.

The rapid evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the emergence of new variants with different genetic profiles, with important implications for public health. The continued emergence of new variants with unique genetic features and potential changes in biological properties poses significant challenges to public health strategies, vaccine development, and therapeutic interventions. Omicron variants have attracted particular attention due to their rapid spread and numerous mutations in key viral proteins. This review aims to provide an updated and comprehensive assessment of the epidemiological characteristics, immune escape potential, and therapeutic advances of the SARS-CoV-2 Omicron XBB.1.5 variant, as well as other variants.

By the end of 2022, different variants of Omicron had rapidly spread worldwide, causing a significant impact on the Coronavirus disease 2019 (COVID-19) pandemic situation. Compared with previous variants of severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), these new variants of Omicron exhibited a noticeable degree of mutation. The currently developed platforms to design COVID-19 vaccines include inactivated vaccines, mRNA vaccines, DNA vaccines, recombinant protein vaccines, virus-like particle vaccines, and viral vector vaccines. Many of these platforms have obtained approval from the US Food and Drug Administration (FDA) or the WHO. However, the Omicron variants have spread in countries where vaccination has taken place; therefore, the number of cases has rapidly increased, causing concerns about the effectiveness of these vaccines. This article first discusses the epidemiological trends of the Omicron variant and reviews the latest research progress on available vaccines. Additionally, we discuss progress in the development progress and practical significance of universal vaccines. Next, we analyze the neutralizing antibody effectiveness of approved vaccines against different variants of Omicron, heterologous vaccination, and the effectiveness of multivalent vaccines in preclinical trials. We hope that this review will provide a theoretical basis for the design, development, production, and vaccination strategies of novel coronavirus vaccines, thus helping to end the SARS-CoV-2 pandemic.

Background: Inadequate sleep behaviors may confer a higher risk of premature death, however, evidence in patients with chronic noncommunicable disease (NCD) is scarce. To investigate the relationship between sleep duration and mortality from all-cause and heart diseases in NCD patients from a prospective cohort. Methods: Totally, 14,171 participants with at least one NCD, including 8275 with hypertension, 7547 with high cholesterol, 4065 with diabetes, and 5815 with chronic renal failure were enrolled from the National Health and Nutrition Examination Survey during 2005–2014. Cox proportional hazard models were performed to estimate the hazard ratio (HR) for sleep duration and mortality after adjusting for potential confounding factors. Results: After a median follow-up of 9 years, 2514 all-cause deaths were identified. Compared with sleeping 7–8 h/day, sleeping over 8 h/day was significantly associated with a higher risk of all-cause mortality, where the multivariable-HRs were 1.29 (1.11, 1.50) for hypertension, 1.23 (1.01, 1.51) for high cholesterol, 1.44 (1.13, 1.82) for diabetes, and 1.36 (1.10, 1.68) for chronic renal failure. Similar patterns were observed for heart disease mortality. A nonlinear association was detected between sleep duration and mortality in patients with NCD. Age modified the association in patients with hypertension (P-interaction: 0.036). Trouble sleeping modified the association in patients with diabetes (P-interaction: 0.042). Conclusions: Long sleep duration was associated with higher risks of all-cause and heart disease mortality in patients with chronic NCD. Our findings highlight that improving sleep behaviors may decrease the risk of premature deaths and help to NCD tertiary prevention.

Zygote arrest-1 (Zar1) and Wilms’ tumor 1 (Wt1) play an important role in oogenesis, with the latter also involved in testicular development and gender differentiation. Here, Lczar1 and Lcwt1b were identified in Asian seabass (Lates calcarifer), a hermaphrodite fish, as the valuable model for studying sex differentiation. The cloned cDNA fragments of Lczar1 were 1192 bp, encoding 336 amino acids, and contained a zinc-binding domain, while those of Lcwt1b cDNA were 1521 bp, encoding a peptide of 423 amino acids with a Zn finger domain belonging to Wt1b family. RT-qPCR analysis showed that Lczar1 mRNA was exclusively expressed in the ovary, while Lcwt1b mRNA was majorly expressed in the gonads in a higher amount in the testis than in the ovary. In situ hybridization results showed that Lczar1 mRNA was mainly concentrated in oogonia and oocytes at early stages in the ovary, but were undetectable in the testis. Lcwt1b mRNA was localized not only in gonadal somatic cells (the testis and ovary), but also in female and male germ cells in the early developmental stages, such as those of previtellogenic oocytes, spermatogonia, spermatocytes and spermatids. These results indicated that Lczar1 and Lcwt1b possibly play roles in gonadal development. Therefore, the findings of this study will provide a basis for clarifying the mechanism of Lczar1 and Lcwt1b in regulating germ cell development and the sex reversal of Asian seabass and even other hermaphroditic species.

Objective To evaluate the efficacy and safety of human coagulation factor Ⅷ developed by Shenzhen Weiguang Biological products Co, Ltd in the treatment of patients with hemophilia A. Methods A prospective, multi-center, open, single-group clinical study was conducted. A total of 65 subjects with hemophilia A were enrolled, and human coagulation factor Ⅷ(FⅧ) was injected according to the patients’ bleeding severity. The improvement score of bleeding symptoms and signs after the first infusion of the first bleeding event and the transfusion efficiency of FⅧ activity at 10 min and 1 hour after infusion were taken as the main efficacy indexes. The improvement scores of bleeding symptoms and signs after the first infusion and the increase of FⅧ activity at 10 min and 1 hour after infusion were the secondary efficacy indexes. Results The 65 subjects were enrolled in safety analysis set (SS) and full analysis set (FAS), and 58 of them were enrolled in protocol analysis set (PPS). Ten minutes and one hour after the first infusion, the level of factor Ⅷ activity in the subjects increased significantly, and the FⅧ activity increased by 100% or more in more than 79% of the subjects. The average infusion efficiency of FⅧ activity in all subjects was more than 100%. In 70% of the subjects, the pain was relieved rapidly and /or the bleeding symptoms were significantly improved 8 hours after each bleeding infusion, and the improvement rate of bleeding symptoms and signs reached 100% 72 hours after infusion. Conclusion After infusion of human coagulation factor Ⅷ, the activity level of factor Ⅷ in patients with hemophilia A significantly increased. The infusion efficiency can reach a optimal level, and the bleeding symptoms can be significantly improved.

Ferromagnet/spacer/ferromagnet sandwiches have been studied extensively, and used in a variety of spintronic devices. Here, Zhou et al. create an all anti-ferromagnetic sandwich of Fe2O3/Cr2O3/Fe2O3, and demonstrate strong orthogonal coupling between the top and bottom Fe2O3 layers.

A solid-state mixing method was adopted to prepare a new Pr0.8Sr0.2Fe0.7Ni0.3O3−δ-Pr1.2Sr0.8Fe0.4Ni0.6O4+δ (PSFN113-214) composite cathode oxide for the solid oxide fuel cells (SOFCs). Herein, heterointerface engineering was investigated for the performance enhancement. It was found that the oxygen vacancy content could be increased by mixing the PSFN214 with PSFN113, which gave rise to the formation of a heterostructure, and resulted in the promotion of oxygen ion transport as well as the specific surface area. The optimum mixing ratio 5:5 resulted in the highest oxygen vacancy content and the largest specific surface area, indicating the strongest interface effect. Polarization resistance of PSFN113-214 (5:5) was 0.029 Ω cm2 at 800°C, which was merely 24% of PSFN113 and 39% of PSFN214. The corresponding maximum power density was 0.699 W cm−2, which was nearly 1.44 times of PSFN113 and 1.24 times of PSFN214. Furthermore, the voltage attenuation rate after 100 h was merely 0.0352% h−1. Therefore, the new PSFN113-214 composite could be a prospective cathode oxide for SOFCs.

Synthetic antiferromagnets (SAF), formed out of alternating layers of a ferromagnet with neutral spacer combine technologically appealing properties of both antiferromagnets and ferromagnets. Here, Chen et al demonstrate controlled switching of an SAF, without the need for an applied magnetic field.

Soil water content (SWC) is a critical indicator for engineering construction, crop production, and the hydrologic cycle. The rapid and accurate assessment of SWC is of great importance. At present, digital images are becoming increasingly popular in environmental monitoring and soil property analysis owing to the advantages of non-destructiveness, cheapness, and high-efficiency. However, the capture of high-quality digital image and effective color information acquisition is challenging. For this reason, a photographic platform with an integrated experimental structure configuration was designed to yield high-quality soil images. The detrimental parameters of the platform including type and intensity of the light source and the camera shooting angle were determined after systematic exploration. A new method based on Gaussian fitting gray histogram for extracting RGB image feature parameters was proposed and validated. The correlation between 21 characteristic parameters of five color spaces (RGB, HLS, CIEXYZ, CIELAB, and CIELUV) and SWC was investigated. The model for the relationship between characteristic parameters and SWC was constructed by using least squares regression (LSR), stepwise regression (STR), and partial least squares regression (PLSR). Findings showed that the camera platform equipped with 45° illumination D65 light source, 90° shooting angle, 1900~2500 lx surface illumination, and operating at ambient temperature difference of 5 °C could produce highly reproducible and stable soil color information. The effects of image scale had a great influence on color feature extraction. The entire area of soil image, i.e., 3,000,000 pixels, was chosen in conjunction with a new method for obtaining color features, which is beneficial to eliminate the interference of uneven lightness and micro-topography of soil samples. For the five color spaces and related 21 characteristic parameters, RGB and CIEXYZ spaces and characteristic parameter of lightness both exhibited the strongest correlation with SWC. The PLSR model based on soil specimen images ID had an excellent predictive accuracy and the best stability (R2 = 0.999, RMSE = 0.236). This study showed the potential of the application of color information of digital images to predict SWC in agriculture and geotechnical engineering.

Amorphous pseudocapacitive nanomaterials are highly desired in energy storage applications for their disordered crystal structures, fast electrochemical dynamics, and outstanding cyclic stability, yet hardly achievable using the state-of-the-art synthetic strategies. Herein, for the first time, high capacitive fiber electrodes embedded with nanosized amorphous molybdenum trioxide (A-MoO3-x) featuring an average particle diameter of ~20 nm and rich oxygen vacancies are obtained via a top-down method using α-MoO3 bulk belts as the precursors. The Jahn-Teller distortion in MoO6 octahedra due to the doubly degenerate ground state of Mo5+, which can be continuously strengthened by oxygen vacancies, triggers the phase transformation of α-MoO3 bulk belts (up to 30 μm long and 500 nm wide). The optimized fibrous electrode exhibits among the highest volumetric performance with a specific capacitance (CV) of 921.5 F cm-3 under 0.3 A cm-3, endowing the fiber-based weaveable supercapacitor superior CV and EV (energy density) of 107.0 F cm-3 and 9.5 mWh cm-3, respectively, together with excellent cyclic stability, mechanical robustness, and rate capability. This work demonstrates a promising strategy for synthesizing nanosized amorphous materials in a scalable, cost-effective, and controllable manner.

PurposeThis study aimed to evaluate the mechanism by which miR-29c expression in fibroblasts regulates renal interstitial fibrosis.MethodsWe stimulated NRK-49F cells with TGF-β1 to mimic the effects of fibrosis in vitro, while unilateral ureteral obstruction (UUO) was performed to obstruct the mid-ureter in mice. MiR-29c mimic or miR-29c inhibitor was used to mediate genes expressions in vitro. The recombinant adeno associated virus (rAAV) vectors carrying a FSP1 promoter that encodes miR-29c precursor or miR-29c inhibitor was used to mediate genes expressions in vivo, and a flank incision was made to expose the left kidney of each animal.ResultsIn the present study, TGF-β1 was demonstrated to regulate miR-29c expression through Wnt/β-catenin signaling. In contrast, miR-29c appears to inhibit the Wnt/β-catenin pathway by suppressing TPM1 expression. As suggested by this feedback mechanism, miR-29c may be a key fibrosis-related microRNA expressed by fibroblasts in TGF-β1/Wnt/β-catenin-driven renal fibrosis, and manipulation of miR-29c action may accordingly offer a potential therapeutic pathway for renal fibrosis treatment.ConclusionMiR-29c expression was downregulated in UUO mouse kidneys as well as TGF-β1-treated NRK-49F cells, which thus inhibits myofibroblast formation via targeting of TPM1. Additionally, the production of extracellular matrix (ECM) in renal fibroblasts appears to be controlled by the reciprocal regulation of miR-29c action and the Wnt/β-catenin pathway.

This study aimed to isolate, prepare and identify the main flavonoids from a standardized Smilax glabra flavonoids extract (SGF) using preparative HPLC, MS, 1H NMR and 13C NMR, determine the contents of these flavonoids using UPLC, then compare their pharmacological activities in vitro. We obtained six flavonoids from SGF: astilbin (18.10%), neoastilbin (11.04%), isoastilbin (5.03%), neoisoastilbin (4.09%), engeletin (2.58%) and (−)-epicatechin (1.77%). The antioxidant activity of six flavonoids were evaluated by determining the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2′-Azinobis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS+) radical scavenging activity and ferric reducing antioxidant power (FRAP). In addition, the anti-inflammatory activity of six flavonoids were evaluated by determining the production of cytokines (IL-1β, IL-6), nitric oxide (NO) using enzyme linked immunosorbent assay and the NF-κB p65 expression using Western blotting in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The results showed that (−)-epicatechin, astilbin, neoastilbin, isoastilbin and neoisoastilbin had strong antioxidant activities, not only in DPPH and ABTS+ radicals scavenging capacities, but in FRAP system. Furthermore, all the six flavonoids could significantly inhibit the secretion of IL-1β, IL-6, NO (p < 0.01) and the protein expression of NF-κB p-p65 (p < 0.01) in LPS-stimulated RAW264.7 cells. This study preliminarily verified the antioxidant and anti-inflammatory activities of six flavonoids in S. glabra.