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Summary: Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years. Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries’ data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models. Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40–1.58) and 1.40 (1.38–1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17–1.49) in 1995–1999 and 1.95 (1.53–2.49) in 2015–2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer. Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China.

Pepper (Capsicum annuum L) is one of the most important vegetables grown worldwide. Nevertheless, the key structural and regulatory genes involved in anthocyanin accumulation in pepper have not been well understood or fine mapped yet. In this study, F1, F2, BC1P1, and BC1P2 pepper populations were analyzed and these populations were derived from a cross between line 14-Z4, which has yellow anthers and green stems, and line 14-Z5, which has purple anthers and stems. The results showed that the yellow anthers and green stems were determined by a single recessive locus called to as ayw. While, using preliminary and fine mapping techniques, ayw locus was located between markers aywSNP120 and aywSNP124, with physical distance of 0.2 Mb. The CA11g18550 gene was identified as promising candidate for the ayw locus, as it co-segregated with the yellow anthers and green stems phenotypes. CA11g18550 encodes a homolog of the F3’5’H (flavonoid 3’,5’-hydroxylase) anthocyanin synthesis structure gene. The missense mutation of CA11g18550 possibly resulted in a loss-of-function. The expression analysis showed that CA11g18550 was significantly expressed in the stems, leaves, anthers and petals in 14-Z5, and it’s silencing caused the stems changing from purple to green. This study provides a theoretical basis for using yellow anthers and green stems in pepper breeding and helps to advance the understanding of anthocyanin synthesis.

Background: Diabetic retinopathy (DR) remains one of the most common complications of diabetes despite great efforts to uncover its underlying mechanisms. The pathogenesis of DR is characterized by the deterioration of the neurovascular unit (NVU), showing damage of vascular cells, activation of glial cells and dysfunction of neurons. Activation of the hexosamine biosynthesis pathway (HBP) and increased protein O-GlcNAcylation have been evident in the initiation of DR in patients and animal models. Scope of review: The impairment of the NVU, in particular, damage of vascular pericytes and endothelial cells arises in hyperglycemia-independent conditions as well. Surprisingly, despite the lack of hyperglycemia, the breakdown of the NVU is similar to the pathology in DR, showing activated HBP, altered O-GlcNAc and subsequent cellular and molecular dysregulation. Major conclusions: This review summarizes recent research evidence highlighting the significance of the HBP in the breakdown of the NVU in hyperglycemia-dependent and -independent manners, and thus identifies joint avenues leading to vascular damage as seen in DR and thus identifying novel potential targets in such retinal diseases.

Background: Virtual reality (VR) programs based on motion capture camera are the most convenient and cost-effective approaches for remote rehabilitation. Assessment of physical function is critical for providing optimal VR rehabilitation training; however, direct muscle strength measurement using camera-based kinematic data is impracticable. Therefore, it is necessary to develop a method to indirectly estimate the muscle strength of users from the value obtained using a motion capture camera.Objects: The purpose of this study was to determine whether the pedaling speed converted using the VR engine from the captured foot position data in the VR environment can be used as an indirect way to evaluate knee muscle strength, and to investigate the validity and reli-ability of a camera-based VR program.Methods: Thirty healthy adults were included in this study. Each subject performed a 15-sec-ond maximum pedaling test in the VR and built-in speedometer modes. In the VR speedom-eter mode, a motion capture camera was used to detect the position of the ankle joints and automatically calculate the pedaling speed. An isokinetic dynamometer was used to assess the isometric and isokinetic peak torques of knee flexion and extension.Results: The pedaling speeds in VR and built-in speedometer modes revealed a significant-ly high positive correlation (r = 0.922). In addition, the intra-rater reliability of the pedal-ing speed in the VR speedometer mode was good (ICC [intraclass correlation coefficient] = 0.685). The results of the Pearson correlation analysis revealed a significant moderate positive correlation between the pedaling speed of the VR speedometer and the peak torque of knee isokinetic flexion (r = 0.639) and extension (r = 0.598).Conclusion: This study suggests the potential benefits of measuring the maximum pedal-ing speed using 3D depth camera in a VR environment as an indirect assessment of muscle strength. However, technological improvements must be followed to obtain more accurate estimation of muscle strength from the VR cycling test.

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease. Methods In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home. RNA from the fingerstick blood was tested using DxTerity’s 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method. Results Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease. From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to patients with mild to moderate disease conditions. These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases. These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA). Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives). Conclusions Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity. These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits.

Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.

Manipulating the redox chemistry of transition metal dichalcogenides still faces challenges. Here the authors report that tensile-strained MoSe2 can pass on the strain to its sodiated product Mo, and thus regulate the Gibbs free energy in the charging process to enable the reversible sodium storage.

Accurate drug delivery to the lesion has been deliberated for several decades, but one important phenomenon is usually neglected that the immune system can prevent smooth transportation of nanomedicine. Although injection would reduce first-pass effect, macrophages in the blood can still recognize and phagocytose nanomedicine. Here we show that a lubricated nanocontainer, which is prepared based on polyelectrolytes and mesoporous silica nanoparticles, can accurately target muscarinic bioreceptor while escaping from the identification of macrophages. Through in vitro and in vivo studies, this nanocontainer, combining both immune escape and bioreceptor targeting, has greatly improved the drug bioavailability. Additionally, this nanocontainer shows good biocompatibility, and the targeted heart tissues and other important metabolic organs, such as liver and kidney, keep physiological structures and functions without the detection of side effects. Furthermore, the mechanism of immune escape for the developed nanocontainer has been investigated by lubrication test and molecular simulation. We anticipate that our study will establish a new perspective on the achievement of immune escape-based targeted drug delivery, which can provide a fundamental approach for the design of related biomaterials.

Chicken infectious anemia (CIA) is caused by chicken anemia virus (CAV). Recently, severe anemia has emerged in layer chickens (8 to 10-week-old) on poultry farms in China. However, the etiological characteristics and pathogenic potential of CAV in chickens at 6 weeks or older are not well understood. In this study, we isolated a CAV strain, termed SD15, from two-month-old chicken with severe anemia and analyzed the genetic evolution relationship. We found that strain SD15 had the highest homology (98.9%) with CAV18 strain. Comparison with 33 reference strains revealed 16 amino acid mutations in strain SD15, two of which were previously unknown (F210S in VP1 and L25S in Vp3). Compared with low pathogenic strains (Cux-1 and C14), highly pathogenic strains (SDLY08 and SD15) had three base mutations in their noncoding region. To further understand its pathogenicity, 10-week-old specific-pathogen-free (SPF) chickens were challenged with the novel strain and SDLY08. No obvious clinical symptoms were observed in the SDLY08 group. However, SD15-infected chickens showed significant growth retardation and immunosuppression. The main manifestations of immunosuppression were the significantly reduced thymus and bursa indices and AIV-H9 vaccine-induced antibody levels (P < 0.05). The lowest number of red blood cells in the SD15 group was just 60% of that in the control group. Taken together, the novel strain SD15 not only showed higher pathogenicity but also exhibited the potential ability to break the age resistance of older chickens to CAV. Our study enhanced the understanding of the epidemiological characteristics of chickens infected with severe anemia and can facilitate the development of improved control strategies of CIA in China.

ABSTRACT: Epidemiologic investigations in recent years have shown that the detection rate of avian hepatitis E virus (HEV) in chicken flocks is increasing in China. Nevertheless, effective prevention and control measures are still lacking. In this study, specific pathogen-free (SPF) chicken serum against HEV was prepared using recombinant HEV open reading frames (ORF2 and ORF3) proteins as immunogens. An SPF chicken infection model was established by intravenous inoculation of chick embryos. Swab samples were collected at 7, 14, 21, and 28 d of age and used to detect avian HEV load, along with other indicators, by fluorescence quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) assay. The therapeutic effects on blocking vertical HEV transmission were observed, by using the methods of antibody application alone, mixed, or combined application of each of the 2 antibodies with type I interferon. The results showed that type I interferon alone or in combination with antiserum reduced the positive rate of HEV from 100 to 62.5% and 25%, respectively. However, the avian HEV-positivity rate was reduced to 75, 50, and 37.5% after type I interferon was used alone or in combination with antisera against ORF2 and ORF3, respectively. The inhibitory effect of type I interferon alone or in combination with an antiserum, on HEV replication was more significant in cells than in vivo. In this study, the inhibitory effect of type I interferon alone or in combination with an antiserum on avian HEV replication was observed in vitro and in vivo, providing the necessary technical reserve for disease prevention and control.

BackgroundIn the past few decades, heat waves and seasonal variation linked with global warming are causing frequent fluctuations of water temperature in aquatic environments, resulting in further challenges for marine organisms. As a poikilothermic marine animal and a temperate species, sea cucumber A. japonicus is also very sensitive to temperature variation and shows a limited ability to adapt to environmental temperature changes. However, the molecular mechanisms by which A. japonicus perceives signals from such a diverse environment including the trigger of aestivation still remain unclear. TRP (transient receptor potential) superfamily, as the great potential “sentinel” of the organism in response to the changes of the external environment signals, perceived little attention and will be the future great candidates for sensory function research in echinoderm.MethodsBLAST program was applied to identify the AjTRPs based on A. japonicus transcriptome database. Gene structure analysis of AjTRPs and phylogenetic analysis of TRPs were performed. The expression profiles of AjTRPs in different tissues and in response to different heat stress treatments (chronic/ acute) were measured using qRT-PCR.ResultsA total of 54 TRPs were identified in A. japonicus. Gene structure analysis showed that the exon numbers and the domains of AjTRPs varied greatly. Phylogenetic analysis indicated that AjTPRs were mainly grouped into six subfamilies: TRPA, TRPM, TRPC, TRPV, TRPML, and TRPP. Copy numbers of each TRP member in marine invertebrates including A. japonicus were more than those in vertebrates, however some TRP channel members were lost in invertebrates. Expression profile detection suggested that the representative 15 AjTRP genes belonging to 6 subfamilies were expressed in all tissues examined.ConclusionOur findings indicate that the plastic evolutionary history of TRP channel genes and suggest that TRPM2-1, TRPM2-2, TRPM3, and TRPC3-1 are potential thermo-TRP proteins involved in thermal regulation in A. japonicus. This work facilitates the knowledge of TRP-mediated sensory systems in echinoderms, provides new insights into the mechanisms of aestivation and global warming adaptation in marine invertebrates.

Cell therapy holds great promise in addressing a wide range of malignant diseases, such as cancers and infectious diseases. The convergence of chemistry, engineering, and material sciences further create tremendous opportunities to upgrade their therapeutic potential by integrating them with different functional motifs, which can strengthen the inherent features of cells and further render them with new functionalities. A rational selection of the cell decoration methods is of great importance to ensure desired cell modification while maximumly preserving the properties and biofunctions of cells. Bio‐orthogonal chemistry allows covalent modification of cells at favorable reaction rates under mild biological conditions without the perturbation of the biofunctions of the engineered cells or disturbance of the biosystem. Among various types of bio‐orthogonal reactions, cycloaddition reactions are widely adopted for cell engineering. This review presents a summary of the latest progress in the development of bio‐orthogonal chemistry‐based strategies for cell engineering with a focus on cycloaddition reactions, highlights their applications in disease diagnosis and therapy, and discusses the prospects of this cell engineering technique.

Hepatitis E virus (HEV) is relevant to public health worldwide, and it affects a variety of animals. Big liver and spleen disease (BLS) and hepatitis-splenomegaly syndrome (HSS) associated with avian HEV (aHEV) were first reported in 1988 and in 1991, respectively. Here, cell culture–adapted aHEV genotype 3 strain, YT-aHEV (YT strain), a typical genotype isolated in China, was used for basic and applied research. We evaluated liver injury during the early stages of infection caused by the YT strain in vivo. Both in vivo and in vitro experimental data demonstrated that viral infection induces innate immunity, with mRNA expression levels of two key inflammatory factors, interleukin-1β (IL-1β) and IL-18, significantly upregulated. The YT strain infection was associated with the activation of Toll-like receptors (TLRs), nuclear factor kappa B (NF-κB), caspase-1, and NOD-like receptors (NLRs) in the liver and primary hepatocellular carcinoma epithelial cells (LMH). Moreover, inhibiting c-Jun N-terminal kinase, extracellular signal–regulated kinase (ERK1 or 2), P38, NF-κB, or caspase-1 activity has different effects on NLRs, and there is a mutual regulatory relationship between these signaling pathways. The results show that SB 203580, U0126, and VX-765 inhibited IL-1β and IL-18 induced by the YT strain, whereas Pyrrolidinedithiocarbamate (PDTC) had no significant effect on the activity of IL-1β and IL-18. Pretreatment of cells with SP600125 had an inhibitory effect on IL-18 but not on IL-1β. The analysis of inhibition results suggests that there is a connection between Mitogen-activated protein kinase (MAPK), NF-κB, and the NLRs signaling pathways. This study explains the relationship between signaling pathway activation (TLRs, NF-κB, MAPK, and NLR–caspase-1) and viral-associated inflammation caused by YT strain infection, which will help to dynamic interaction between aHEV and host innate immunity.

Rabbit Viral Hemorrhagic Disease (RHD) is a highly contagious and fatal infection, resulting in considerable economic losses to the rabbit industry. Consequently, it is essential to develop a fast and accurate diagnostic method for RHDV GI.1. In this study, a rapid simple reverse transcriptase recombinase polymerase amplification (RTRPA) for RHDV GI.1 was successfully developed using specific primers to RHDV GI.1 VP60 gene. Results indicated that the entire amplification process could be achieved in an isothermal condition at 40°C for 30 minutes, with good specificity and no reaction to other common rabbit disease pathogens, and a high sensitivity of upto 0.1LD50 of RHDV GI.1. Then, RT-RPA method was used to detect 1144 clinical samples, and the positive rates were 0.95%, 1.29% and 2.50% in Zaozhuang, Linyi, and Liaocheng in Shandong Province, respectively (the Fisher's exact test, P = 0.413), suggesting that there is no significant difference in RHDV GI.1 infection among the different regions. In conclusion, this study established a RT-RPA assay which is suitable for quick detection and monitoring of RHDV GI.1, thus making it a viable option for epidemiological surveillance.

Background: Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan’su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan’su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer. Methodology: The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in vivo. Results: With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1. Conclusion: BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.

Abstract Background Sex determination mechanisms are complicated and diverse across taxonomic categories. Sea cucumber Apostichopus japonicus is a benthic echinoderm, which is the closest group of invertebrates to chordate, and important economic and ecologically aquaculture species in China. A. japonicus is dioecious, and no phenotypic differences between males and females can be detected before sexual maturation. Identification of sex determination locus will broaden knowledge about sex-determination mechanism in echinoderms, which allows for the identification of sex-linked markers and increases the efficiency of sea cucumber breeding industry. Results Here, we integrated assembly of a novel chromosome-level genome and resequencing of female and male populations to investigate the sex determination mechanisms of A. japonicus. We built a chromosome-level genome assembly AJH1.0 using Hi-C technology. The assembly AJH1.0 consists of 23 chromosomes ranging from 22.4 to 60.4 Mb. To identify the sex-determination locus of A. japonicus, we conducted genome-wide association study (GWAS) and analyses of distribution characteristics of sex-specific SNPs and fixation index FST. The GWAS analysis showed that multiple sex-associated loci were located on several chromosomes, including chromosome 4 (24.8%), followed by chromosome 9 (10.7%), chromosome 17 (10.4%), and chromosome 18 (14.1%). Furthermore, analyzing the homozygous and heterozygous genotypes of plenty of sex-specific SNPs in females and males confirmed that A. japonicus might have a XX/XY sex determination system. As a physical region of 10 Mb on chromosome 4 included the highest number of sex-specific SNPs and higher FST values, this region was considered as the candidate sex determination region (SDR) in A. japonicus. Conclusions In the present study, we integrated genome-wide association study and analyses of sex-specific variations to investigate sex determination mechanisms. This will bring novel insights into gene regulation during primitive gonadogenesis and differentiation and identification of master sex determination gene in sea cucumber. In the sea cucumber industry, investigation of molecular mechanisms of sex determination will be helpful for artificial fertilization and precise breeding.

Increased density of tumor associated macrophages has been correlated with tumor recurrence following surgery. Here the authors design an alginate-based hydrogel encapsulating anti-PD-1-conjugated platelets and nanoparticles loaded with the macrophage-depleting CSF-1R inhibitor pexidartinib, showing inhibition of post-surgery tumor recurrence in preclinical models.

Large-scale, two-sided matching platforms must find market outcomes that align with user preferences while simultaneously learning these preferences from data. Classical notions of stability (Gale and Shapley, 1962; Shapley and Shubik, 1971) are, unfortunately, of limited value in the learning setting, given that preferences are inherently uncertain and destabilizing while they are being learned. To bridge this gap, we develop a framework and algorithms for learning stable market outcomes under uncertainty. Our primary setting is matching with transferable utilities, where the platform both matches agents and sets monetary transfers between them. We design an incentive-aware learning objective that captures the distance of a market outcome from equilibrium. Using this objective, we analyze the complexity of learning as a function of preference structure, casting learning as a stochastic multi-armed bandit problem. Algorithmically, we show that “optimism in the face of uncertainty,” the principle underlying many bandit algorithms, applies to a primal-dual formulation of matching with transfers and leads to near-optimal regret bounds. Our work takes a first step toward elucidating when and how stable matchings arise in large, data-driven marketplaces. [ABSTRACT FROM AUTHOR]