Advances in the Duck Hepatitis A virus and lessons learned from those in recent years.

Duckviral hepatitis (DVH) is a highly lethal and highly transmissible viral infectious disease of ducklings caused by the Duck Hepatitis A virus (DHAV), which is characterized by clinical neurological symptoms and liver enlargement with spot-like hemorrhages. In recent years, the change in diagnosis, prevention, and control of the disease has brought great challenges due to the mutation and recombination of epidemic strains, outbreaks and epidemics of genotype 3 (DHAV-3), and the rising trend of mixed infections. Here, we review DHAV on aspects of molecular biological characteristics, epidemiology, pathologic changes, pathogenesis, diagnosis, prevention, and control of the DVH to provide a scientific basis for basic and applied research in the future.

Isolation and pathogenicity of a fowl adenovirus 8b (FAdV-8b) strain in Cherry Valley ducks.

AbstractInclusion body hepatitis (IBH) is an economically important viral disease primarily affecting the poultry industry. In this study, we isolated a strain of FAdV-8b (strain SDYT) from naturally infected ducks and the hexon and fiber gene sequences were analysed by polymerase chain reaction (PCR) amplification. In order to study the pathogenicity of FAdV-8b on Cherry Valley ducks, we inoculated 10- and 20-day-old ducks with 0.3 ml of FAdV-4 virus (TCID50 of 105.5/0.1 ml) either orally or intramuscularly. Clinical signs, gross lesions and histopathological changes, cytokines, viral load and antibody levels were noticed and recorded within 15 days after infection.Pathomorphological investigations revealed that ducks in the experimental group exhibited hepatitis symptoms. Histopathology showed multiple-organ damage, including serious liver and kidney lesions. Furthermore, elevated levels of inflammatory cytokines and antibodies was noticed, due to the infection and innate immune response. At later stage of infection immunosuppression occurred, resulting in decreased levels of cytokines. Determination of viral load indicated that the virus was present in several organs, with the highest viral DNA load found in the liver, followed by the kidney. Compared to birds infected orally, the intramuscular group exhibited the highest viral load. In summary, this study increases our understanding of the pathogenicity of FAdV-8b in ducks and establishes a model that will inform antiviral drug testing and vaccine evaluation for IBH, thereby preventing and reducing the spread of IBH in the poultry industry.

Associations of dietary inflammatory index with low estimated glomerular filtration rate, albuminuria and chronic kidney disease in U.S adults: Results from the NHANES 2011-2018.

BACKGROUND AND AIMS: Chronic Kidney Disease (CKD) is characterized by a high inflammation status with ever-increasing prevalence, and defined as low estimated glomerular filtration rate (eGFR) or albuminuria. Both low eGFR and albuminuria can have independent effects on the body. The dietary inflammatory index (DII) is a validated tool used to assess the inflammatory potential of the diet. We aim to explore not only the association between DII and CKD, but also the associations of DII with low eGFR and albuminuria, respectively. In addition, their associations in different subgroups remain to be explored. METHODS AND RESULTS: 18,070 participants from the 2011-2018 NHANES with complete data of dietary intake and laboratory data were involved in our study. The data of 24-hour dietary recall interview was used to calculate DII, CKD could be reflected by laboratory data of creatinine and albumin. Then weighted multivariate logistic regression models and subgroup analyses were performed. The prevalence of low eGFR, albuminuria and CKD were 6.8%, 9.8% and 14.5%, respectively. A positive association between DII and low eGFR was observed (OR=1.12, 95%CI: 1.05-1.21), Q2, Q3 and Q4 are positively associated with a significant 39%, 65% and 71% increased risk of low eGFR compared with Q1 (P for trend<0.05). DII was also associated with CKD (OR=1.06, 95%CI: 1.01-1.11). CONCLUSION: Significant positive associations of DII with CKD and low eGFR were observed. But we didn't find such association between DII and albuminuria.

Synergistic chemo-photodynamic therapy by "big & small combo nanoparticles" sequential release system.

Chemo-photodynamic combination has been manifested great potential for synergistic cancer therapy. Moreover, the synergistic efficacy could be significantly enhanced by well-designed sequential release manner of photosensitizers (PSs). Here we propose a "big & small combo nanoparticles (NPbig&small)" system for double loading PSs methylene blue (MB) and single absorbing chemotherapeutics drug Gemcitabine hydrochloride (GM·HCl). The "grown-in" MB from NPbig&small show two-peak sequential release profile, significantly improve the absorbed chemotherapeutic efficacy of GM·HCl. The corresponding two-peak sequential release profile can be illustrated by related mathematics function. The sequential release property was clearly observed through morphological evolution of NPs both in water and cells by TEM. Furthermore, NPbig&small demonstrate well EPR effect and improved synergistic efficacy from in vitro and in vivo results. Thus, NPbig&small chemo-photodynamic system and the programmable sequential release mechanism provide a promising platform that ensures an enhanced synergistic chemo-photodynamic effect in cancer treatment.

Vaccines for African swine fever: an update.

African swine fever (ASF) is a fatal infectious disease of swine caused by the African swine fever virus (ASFV). Currently, the disease is listed as a legally notifiable disease that must be reported to the World Organization for Animal Health (WOAH). The economic losses to the global pig industry have been insurmountable since the outbreak of ASF. Control and eradication of ASF are very critical during the current pandemic. Vaccination is the optimal strategy to prevent and control the ASF epidemic, but since inactivated ASFV vaccines have poor immune protection and there aren't enough cell lines for efficient in vitro ASFV replication, an ASF vaccine with high immunoprotective potential still remains to be explored. Knowledge of the course of disease evolution, the way of virus transmission, and the breakthrough point of vaccine design will facilitate the development of an ASF vaccine. In this review, the paper aims to highlight the recent advances and breakthroughs in the epidemic and transmission of ASF, virus mutation, and the development of vaccines in recent years, focusing on future directions and trends.

Exposure to Cadmium, Lead, Mercury, and Arsenic and Uric Acid Levels: Results from NHANES 2007-2016.

Mechanisms underlying abnormal uric acid (UA) levels from exposure to toxic metals/metalloids have not been not fully elucidated, especially in the context of mixtures. The aim was to identify major toxic metals/metalloids that affected UA levels with a mixture exposure concept in the association model. From 2007-2016 National Health and Nutrition Examination Survey (NHANES), 4794 adults were involved. Serum UA (SUA) and SUA to serum creatinine ratio (SUA/SCr) were used to estimate the UA levels, and cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As) in the blood and/or urine were evaluated in the study. We assessed the associations between toxic metals and UA levels using linear regression and Bayesian kernel machine regression (BKMR). The median [P25, P75] SUA/SCr and SUA level were 6.22 [5.27, 7.32] and 0.83 [0.72, 0.98], respectively. There was no difference for SUA/SCr by gender (men, 6.25 [5.39, 7.29]; women, 6.17 [5.17, 7.36], P = 0.162), but men had higher SUA than women (men, 0.95 [0.85, 1.05]; women, 0.72 [0.64, 0.82], P < 0.001). Blood Pb (ßmen = 0.651 and ßwomen = 1.014) and urinary Cd (ßmen = 0.252 and ßwomen = 0.613) were positively associated with SUA/SCr, and urinary Pb (ßmen = - 0.462 and ßwomen = - 0.838) was inversely associated with SUA/SCr in multivariate linear regression analysis. However, urinary As (ßmen = 0.351) was positively associated with SUA/SCr only in men. BKMR showed that higher concentrations of exposure to a mixture of toxic metals were positively associated with higher UA levels, where Cd, Pb, and urinary As contributed most to the overall mixture effect in men, while Pb and urinary Cd in women. Our study provided the first evidence that mixtures of metals are associated with the UA levels. Increased concentrations of metals, mainly blood Pb, urinary Cd, and As (only in men) may increase the level of UA.

Orally administered recombinant Lactobacillus expressing African swine fever virus antigens that induced immunity responses.

African swine fever (ASF) is a highly contagious, acute, febrile disease caused by the African swine fever virus (ASFV), with morbidity and mortality rates approaching 100% in domestic and wild swine, resulting in massive economic losses to the pig industry worldwide. This study aimed to express the p30, p54, and p72 proteins encoded by ASFV in vitro using the Lactobacillus lactis (L. lactis) expression system. Here, six new functional recombinant L. lactis were constructed, and the expression of the p30 protein, p54 protein, p72 protein, p30-LTB (heat-labile enterotoxin B, LTB) fusion protein, p54-LTB fusion protein, and the p72-LTB fusion protein was successfully detected by Western blot analysis. Following oral immunization of rabbits with recombinant L. lactis, serum IgG, intestinal mucosal sIgA, cytokines (IL-4 and INF-γ), and splenocyte viability were higher than in the control group via ELISA. Notably, without the LTB adjuvant group, humoral and Th1 cellular immunity were promoted, whereas, with the LTB adjuvant group, local mucosal immunity, humoral immunity, and Th2 cellular immunity were promoted, providing new insights into the design and development of an ASFV subunit vaccine.

MEX3A Impairs DNA Mismatch Repair Signaling and Mediates Acquired Temozolomide Resistance in Glioblastoma.

MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair (MMR) system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in patients with glioblastoma (GBM) who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4-NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA MMR activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient patients with GBM, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM. SIGNIFICANCE: A MEX3A/CCR4-NOT/MSH2 axis plays a crucial role in promoting temozolomide resistance, providing new insights into the function of MEX3A and suggesting MEX3A as a potential therapeutic target in therapy-resistant glioblastoma.

Depression status and insulin resistance in adults with obesity: A cross-sectional study.

OBJECTIVE: Insulin resistance (IR) frequently co-occurs with depression, but inconsistent associations between IR and depression have been reported, and less is known about the association in obesity, a major risk factor for both IR and depression. Thus the association between depression status and IR in a nationally representative sample of the US adults with obesity was evaluated. METHODS: This cross-sectional study involved 3507 adults with obesity from National Health and Nutrition Examination Survey from 2005 to 2016. The homeostasis model assessment of insulin resistance (HOMA-IR) was used, where IR was defined as a HOMA-IR value greater than its 75th percentile. The Patient Health Questionnaire 9 was used to assess the depression status. Multivariate logistic regression model was applied to evaluate the association between depression status and IR. RESULTS: The cut-off value of HOMA-IR in adults with obesity was 5.5, and the prevalence of IR was 26.3% in men, 19.8% in women. The association of depression status with IR depended upon gender (P for depression status by gender interaction = 0.04). Depression status was positively associated with IR in women (P = 0.01), where the ORs (95% CIs) for the risk of IR in the mild, moderate, severe depression status were 1.79 (1.21-2.64), 1.95 (1.10-3.45), and 2.21 (1.04-4.71), respectively (P for trend = 0.002). No association was found in men (P = 0.91). CONCLUSION: Positive association between IR and depression status was identified in women with obesity, where the risk of IR increased with the level of depression status, while no association was found in men with obesity.

Dietary inflammatory index and osteoporosis: the National Health and Nutrition Examination Survey, 2017-2018.

PURPOSE: The dietary inflammatory index (DII) is a scoring system to quantify the inflammatory effects of nutrients and foods. Inflammation may affect bone health. The purpose of this study was to explore the relationships of DII with bone mineral density (BMD) and osteoporosis. METHODS: This study involved 1023 women and 1080 men (age ≥ 50) in the US National Health and Nutrition Survey (NHANES), 2017-2018. Multivariable linear regression models were used to estimate the associations between DII and BMD. Association between DII and osteoporosis was tested with multivariable logistic regression models. RESULTS: In women, DII was negatively associated with total hip and femoral neck BMD after adjusting for covariates (P < 0.05). In men, DII was negatively associated with lumbar spine BMD (P < 0.05). DII was positively associated with osteoporosis in women (P < 0.05). The odds ratios (ORs) (95% CI) for osteoporosis associated with DII quartiles 2, 3 and 4 vs. quartile 1 were 2.95 (1.08, 8.09), 5.63 (2.87, 11.04), and 6.14(2.55, 14.78), respectively. No significant association was observed in men. CONCLUSIONS: Higher DII scores were associated with increase osteoporosis risk in women, while no association was found in men. Greater pro-inflammatory diets might be associated with lower BMD in both women and men.

Multimorbidity study with different levels of depression status.

OBJECTIVE: Depression is one of the leading causes of disability burden and frequently co-occurs with multiple chronic diseases, but limited research has yet evaluated the correlation between multimorbidity and depression status by sex and age. METHODS: 29303 adults from 2005-2016 National Health and Nutrition Examination Survey were involved in the study. The validated Patient Health Questionnaire (PHQ-9) was used to assess depression status. The linear trend of the prevalence of multimorbidity was tested by logistic regressions, which was visualized by the weighted network. Gamma coefficient (γ) was used to evaluate the correlation between multimorbidity and depression status. RESULTS: The prevalence of multimorbidity in participants with no depression, mild depression, moderate depression and severe depression was 52.1%, 63.0%, 68.4% and 76.1%, respectively (p for trend < 0.001). In network analysis, the absolute network density increased with the levels of depression status (from 4.54 to 15.04). Positive correlation was identified between multimorbidity and depression status (γ=0.21, p<0.001), and the correlation was different by sex and age, where it was stronger in women than men (females: γ=0.23, males: γ=0.16), and stronger in the young and the middle-age (young: γ=0.30, middle-age: γ=0.29, old: γ=0.22). LIMITATIONS: This is a cross-sectional study and thus we cannot draw firm conclusions on causal correlations. CONCLUSIONS: Positive correlation between multimorbidity and depression status was identified, where the number of multimorbidity increased with the levels of depression status, especially in females, the young and the middle-age.

The association between fatty acid intake and breast cancer based on the NHANES and Mendelian randomization study.

BACKGROUND: Observational studies have examined the association between fatty acid intake and breast cancer (BC), and the association might vary depending on menopausal status, but the results remain controversial. The objective of this study was to investigate the associations between fatty acid intake and BC. METHODS: The National Health and Nutrition Examination Survey (NHANES) 1999-2016 was used in the study, and stratified analysis by menopausal status was performed. Logistic regression models were used to evaluate the associations between BC and intake of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs), adjusting for covariates. Three two-sample Mendelian randomization (MR) methods-inverse variance weighted (IVW), weighted median, and Mendelian randomization-Egger (MR-Egger) regression-were applied to further verify the associations between intake of fatty acids and BC. RESULTS: Higher intake of MUFAs was associated with lower risk of BC in premenopausal women: ORs (95 %CI): 0.325 (0.110, 0.964). IVW showed that increased intake of MUFAs was associated with a reduced risk of BC: 0.997 (0.995, 1.000), p = 0.024. No associations between BC and SFAs, MUFAs or PUFAs were found in postmenopausal women or in the overall population. CONCLUSIONS: Increasing intake of MUFAs might reduce the risk of BC in premenopausal women. The protective effect of MUFAs on BC was also supported by MR study.

Micro/Nano Technologies for High-Density Retinal Implant.

During the past decades, there have been leaps in the development of micro/nano retinal implant technologies, which is one of the emerging applications in neural interfaces to restore vision. However, higher feedthroughs within a limited space are needed for more complex electronic systems and precise neural modulations. Active implantable medical electronics are required to have good electrical and mechanical properties, such as being small, light, and biocompatible, and with low power consumption and minimal immunological reactions during long-term implantation. For this purpose, high-density implantable packaging and flexible microelectrode arrays (fMEAs) as well as high-performance coating materials for retinal stimulation are crucial to achieve high resolution. In this review, we mainly focus on the considerations of the high-feedthrough encapsulation of implantable biomedical components to prolong working life, and fMEAs for different implant sites to deliver electrical stimulation to targeted retinal neuron cells. In addition, the functional electrode materials to achieve superior stimulation efficiency are also reviewed. The existing challenge and future research directions of micro/nano technologies for retinal implant are briefly discussed at the end of the review.

Chronically Implantable Package Based on Alumina Ceramics and Titanium with High-density Feedthroughs for Medical Implants.

Implantable package to hermetically encapsulate electronics inside human body is critical for active implant devices such as neuroprothesestextbf. To meet the demanding package requirement for smaller size and higher feedthrough density, we propose a high-density (100+ feedthroughs for 10 mm diameter) ceramic/metal composite package with helium leakage rate on the 10-10 Pa m3/s, at the same time possessing the best cytotoxicity level of Grade 0, which enable the chronic implant in human. Pure alumina substrate co-sintered with platinum (Pt) paste filled in micrometer holes have demonstrated extremely good hermetical seal and biocompatibility, then its braze joint with a titanium(Ti) ring was achieved, followed by the laser welding with a Ti cap. Standard helium leakage rate and cytotoxicity experiments have shown each component and joint interface are qualified for 100-year chronic implant, which is significant for various active implant instruments.

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy.

BACKGROUND: Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment. METHODS: PS drug methylene blue (MB) was encapsulated into the center of the NPsmall, NPbig&thin, and NPbig&thick carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NPsmall, NPbig&thin, and NPbig&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NPbig&thin and NPbig&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse Tmax. Also, by adjusting the NPbig&thin and NPbig&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy. RESULTS: In vitro and in vivo results demonstrated that these three pulses Tmax and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment. CONCLUSION: Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.

Shape dependent cytotoxicity of PLGA-PEG nanoparticles on human cells.

We investigated the influence of nanoparticles' shape on the physiological responses of cells, when they were fed with spherical and needle-shaped PLGA-PEG nanoparticles (the volume of the nanoparticles had been chosen as the fixed parameter). We found that both types of NPs entered cells via endocytosis and upon internalization they stayed in membrane bounded vesicles. Needle-shaped, but not the spherical-shaped NPs were found to induce significant cytotoxicity in the cell lines tested. Our study evidenced that the cytotoxicity of needle-shaped NPs was induced through the lysosome disruption. Lysosome damage activated the signaling pathways for cell apoptosis, and eventually caused DNA fragmentation and cell death. The present work showed that physiological response of the cells can be very different when the shape of the fed nanoparticles changed from spherical to needle-like. The finding suggests that the toxicity of nanomaterials also depends on their shape.

Double loaded self-decomposable SiO2 nanoparticles for sustained drug release.

Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms-the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the "grown-in" drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window-a sustained drug delivery system with a great impact on improving the management of chronic diseases.

Rapid endosomal escape of prickly nanodiamonds: implications for gene delivery.

The prickly nanodiamonds easily entered cells via endocytosis followed by unique intracellular translocation characteristics­quick endosomal escape followed by stable residence in cytoplasm. Endosomal membrane rupturing is identified as the major route of nanodiamonds' escaping the vesicle confinement and to the cytoplasm. Little cytotoxicity is observed to associate with the nanodiamonds' cytosolic release. Such features enable its application for gene delivery, which requires both effective cellular uptake and cytosolic release of the gene. Taking green fluorescent protein gene as an example, we demonstrate the successful cytosolic delivery and expression of such a gene using the prickly nanodiamonds as carrier.