Activity-dependent post-translational regulation of palmitoylating and depalmitoylating enzymes in the hippocampus.

Activity-induced changes in protein palmitoylation can regulate the plasticity of synaptic connections, critically impacting learning and memory. Palmitoylation is a reversible post-translational modification regulated by both palmitoyl-acyl transferases that mediate palmitoylation and palmitoyl thioesterases that depalmitoylate proteins. However, it is not clear how fluctuations in synaptic activity can mediate the dynamic palmitoylation of neuronal proteins. Using primary hippocampal cultures, we demonstrate that synaptic activity does not impact the transcription of palmitoylating and depalmitoylating enzymes, changes in thioesterase activity, or post-translational modification of the depalmitoylating enzymes of the ABHD17 family and APT2 (also known as LYPLA2). In contrast, synaptic activity does mediate post-translational modification of the palmitoylating enzymes ZDHHC2, ZDHHC5 and ZDHHC9 (but not ZDHHC8) to influence protein-protein interactions, enzyme stability and enzyme function. Post-translational modifications of the ZDHHC enzymes were also observed in the hippocampus following fear conditioning. Taken together, our findings demonstrate that signaling events activated by synaptic activity largely impact activity of the ZDHHC family of palmitoyl-acyl transferases with less influence on the activity of palmitoyl thioesterases.

Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

Respiratory pathogen dynamics in community fever cases: Jiangsu Province, China (2023-2024).

BACKGROUND: Respiratory infectious diseases have the highest incidence among infectious diseases worldwide. Currently, global monitoring of respiratory pathogens primarily focuses on influenza and coronaviruses. This study included influenza and other common respiratory pathogens to establish a local respiratory pathogen spectrum. We investigated and analyzed the co-infection patterns of these pathogens and explored the impact of lifting non-pharmaceutical interventions (NPIs) on the transmission of influenza and other respiratory pathogens. Additionally, we used a predictive model for infectious diseases, utilizing the commonly used An autoregressive comprehensive moving average model (ARIMA), which can effectively forecast disease incidence. METHODS: From June 2023 to February 2024, we collected influenza-like illness (ILI) cases weekly from the community in Xuanwu District, Nanjing, and obtained 2046 samples. We established a spectrum of respiratory pathogens in Nanjing and analysed the age distribution and clinical symptom distribution of various pathogens. We compared age, gender, symptom counts, and viral loads between individuals with co-infections and those with single infections. An autoregressive comprehensive moving average model (ARIMA) was constructed to predict the incidence of respiratory infectious diseases. RESULTS: Among 2046 samples, the total detection rate of respiratory pathogen nucleic acids was 53.37% (1092/2046), with influenza A virus 479 cases (23.41%), influenza B virus 224 cases (10.95%), and HCoV 95 cases (4.64%) being predominant. Some pathogens were statistically significant in age and number of symptoms. The positive rate of mixed infections was 6.11% (125/2046). There was no significant difference in age or number of symptoms between co-infection and simple infection. After multiple iterative analyses, an ARIMA model (0,1,4), (0,0,0) was established as the optimal model, with an R2 value of 0.930, indicating good predictive performance. CONCLUSIONS: The spectrum of respiratory pathogens in Nanjing, Jiangsu Province, was complex in the past. The primary age groups of different viruses were different, causing various symptoms, and the co-infection of viruses did not correlate with the age and gender of patients. The ARIMA model estimated future incidence, which plateaued in subsequent months.

Cognitive Health Benefits of Everyday Physical Activity in a Diverse Sample of Middle-Aged Adults.

BACKGROUND: Physical activity has been associated with a wide range of health benefits including long-term benefits for cognitive and brain health. Whether episodes of everyday physical activity are associated with immediate cognitive benefits remains unknown. PURPOSE: The purpose of the current study was to examine whether episodes of physical activity, occurring over the course of participants' daily lives, are associated with short-term improvements in cognitive health. METHODS: Participants completed a 9-day ecological momentary assessment protocol involving 5 daily assessments of self-reported physical activity and ambulatory cognitive assessments of processing speed and visuospatial working memory. Data were analyzed in a multilevel modeling framework to explore changes in performance on each task associated with physical activity during the period leading up to the assessment as well as individual differences in average frequency of physical activity. RESULTS: Results of MLMs indicated that engaging in physical activity during the period (~3.5 hr) leading up to an assessment was associated with improvements in processing speed equivalent to 4 years of cognitive aging. Such improvements were observed for both light and moderate-to-vigorous physical activity levels. No association was observed for visuospatial working memory accuracy; however, response time during the working memory task reliably mirrored the association observed for processing speed. The short-term benefits were observed, particularly, for individuals with an overall higher frequency of reported physical activity. CONCLUSIONS: Our findings suggest that engaging in everyday physical activity of any intensity level may have short-term, acute benefits for cognitive health and point to new potential targets for intervention. CLINICAL TRIAL INFORMATION: NCT03240406.

Exercise may help improve brain health and prevent brain disease (e.g., Alzheimer's disease). But, what are the possible brain health benefits of "everyday" types of physical activities like playing with our kids or walking the dog? The challenge is designing a study that can see these benefits in action. Recent advances in smartphones allow us to interact with research participants continuously as they go about their daily lives. We asked our participants to check in with us 6 times per day (every ~3.5 hrs) for 7 days and report whether they had been physically active in the past few hours. Every time they checked in, we also asked them to play a few "brain games" (brief cognitive assessments) to measure their cognitive functioning throughout each day. When participants reported being physically active sometime in the previous 3.5 hrs, they showed improvements in mental speed equivalent to being 4 years younger. This benefit was observed regardless of whether the activities they reported were higher intensity (e.g., running/jogging) or lower intensity (e.g., walking, chores). These findings suggest that everyday physical activity may promote cognitive health in midlife and that the benefits may be enjoyed immediately.

Schisandrin A: A sustainable antiviral and immunomodulatory agent against spring viraemia of carp virus in aquaculture.

Spring viraemia of carp virus (SVCV) is a major threat to the aquaculture industry, causing severe economic losses and significantly impacting fish health. Despite this, no approved antiviral treatments are currently available for use in aquaculture, underscoring the urgent need for effective interventions. This study evaluated the antiviral and immunomodulatory potential of Schisandrin A (SA), a bioactive compound derived from the traditional Chinese medicinal herb Schisandra chinensis, against SVCV. Through a combination of in vitro and in vivo experiments, SA was found to significantly inhibit SVCV replication, lower the viral titer, and improve survival rates in infected juvenile carp. Mechanistically, SA enhanced the host's innate immune response, as demonstrated by the upregulation of key antiviral genes including interferon-alpha1 (ifna1), interferon-gamma (ifnγ), interferon-stimulated gene 15 (isg15), and myxovirus resistance 1 (mx1). Additionally, SA exhibited potent antioxidative properties, preserving mitochondrial integrity and reducing oxidative stress in SVCV-infected cells. These findings showed the dual role of SA in both directly suppressing viral replication and modulating the immune response, offering a multifaceted approach to managing SVCV infection. Given its low toxicity and biodegradability, SA emerges as a promising, sustainable antiviral agent for aquaculture. This study highlights the potential of SA to enhance biosecurity and promote sustainability in the industry, paving the way for the development of eco-friendly antivirals that could improve the management of viral diseases, ensuring healthier fish populations and greater economic stability.

A coumarin derivative C7 exhibits antiviral activity against WSSV by reducing phosphatidylcholine content in shrimp.

The white spot syndrome virus (WSSV) causes white spot disease (WSD), a severe condition in crustacean aquaculture, leading to significant economic losses. Our previous study demonstrated that C7 is an effective therapeutic agent against WSSV infection in aquaculture. It specifically blocked viral horizontal transmission and reduced shrimp mortality in a dose- and time-dependent manner. Here, we report the potential antiviral mechanism of C7 in shrimp. C7 regulated abnormal glycerophospholipid metabolism caused by WSSV and inhibited phosphatidylcholine (PC) synthesis by more than twofold, potentially enhancing shrimp resistance to viral infection. As the primary phospholipid in the cell membrane, PC is one of the main reactants in lipid peroxidation. Our results indicated that C7 significantly reduced the levels of lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) induced by WSSV, whereas PC had the opposite effect. Accumulation of lipid peroxidation products inhibits stimulator of interferon genes (STING) signaling. Further evidence showed that C7 promoted STING transport from the endoplasmic reticulum to the Golgi apparatus, significantly activating the expression of the shrimp interferon analogue Vago4 gene. In contrast, PC suppressed Vago4 expression. Our results demonstrated that C7 inhibited PC synthesis, reduced the degree of lipid peroxidation, promoted STING translocation, activated Vago4 expression, and ultimately exerted antiviral effects. Therefore, C7 exhibits immunoregulatory activity as a preventative agent for enhancing the innate immunity of shrimp, making it potentially useful for future immunomodulatory approaches.

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder.

BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

Non-Destructive Monitoring of Foliar Fungicide Efficacy with Hyperspectral Sensing in Grapevine.

Frequent fungicide applications are required to manage grapevine powdery mildew (Erysiphe necator). However, this practice is costly and has led to widespread fungicide resistance. A method of monitoring in-field fungicide efficacy could help growers maximize spray-interval length, thereby reducing costs and the rate of fungicide resistance emergence. The goal of this study was to evaluate if hyperspectral sensing in the visible to shortwave infrared range (400 to 2,400 nm) can quantify foliar fungicide efficacy on grape leaves. Commercial formulations of metrafenone, Bacillus mycoides isolate J (BmJ), and sulfur were applied on Chardonnay grapevines in vineyard or greenhouse settings. Foliar reflectance was measured with handheld hyperspectral spectroradiometers at multiple days post-application. Fungicide efficacy was estimated as a proxy for fungicide residue and disease control measured with the Blackbird microscopy imaging robot. Treatments could be differentiated from the untreated control with an accuracy of 73.06% for metrafenone, 67.76% for BmJ, and 94.10% for sulfur. The change in spectral reflectance was moderately correlated with the cube root of the area under the disease progress curve for metrafenone- and sulfur-treated samples (R2 = 0.38 and 0.36, respectively) and with sulfur residue (R2 = 0.42). BmJ treatment impacted foliar physiology by enhancing the leaf mass/area and reducing the nitrogen and total phenolic content as estimated from spectral reflectance. The results suggest that hyperspectral sensing can be used to monitor in-situ fungicide efficacy, and the prediction accuracy depends on the fungicide and the time point measured. The ability to monitor in-situ fungicide efficacy could facilitate more strategic fungicide applications and promote sustainable grapevine protection. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

A fast and smooth one-electron approach for investigating charge transfer states and D1-D0 crossings for systems with odd numbers of electrons.

We propose an efficient version of ensemble Hartree-Fock/density functional theory to calculate a set of two charge-transfer states for systems with odd-numbers of electrons. The approach does require definitions of donor/acceptor fragments; however, the approach is not very sensitive to such definitions-even in the limit of very strong electronic coupling. The key ansatz is that, by mandating that the vector space spanned by the active orbitals projects equally onto the donor and acceptor fragments, such a constraint eliminates all intra-molecular local excitations and makes it far easier to generate potential energy surfaces that are smooth over a wide region of configuration space. The method is fast, working with only two electron configurations, and should be useful for ab initio non-adiabatic dynamics in the near future.

A simple one-electron expression for electron rotational factors.

Within the context of fewest-switch surface hopping (FSSH) dynamics, one often wishes to remove the angular component of the derivative coupling between states J and K. In a previous set of papers, Shu et al. [J. Phys. Chem. Lett. 11, 1135-1140 (2020)] posited one approach for such a removal based on direct projection, while we isolated a second approach by constructing and differentiating a rotationally invariant basis. Unfortunately, neither approach was able to demonstrate a one-electron operatorÔ whose matrix element JÔK was the angular component of the derivative coupling. Here, we show that a one-electron operator can, in fact, be constructed efficiently in a semi-local fashion. The present results yield physical insight into designing new surface hopping algorithms and are of immediate use for FSSH calculations.

Practical phase-space electronic Hamiltonians for ab initio dynamics.

Modern electronic structure theory is built around the Born-Oppenheimer approximation and the construction of an electronic Hamiltonian Hel(X) that depends on the nuclear position X (and not the nuclear momentum P). In this article, using the well-known theory of electron translation (Γ') and rotational (Γ″) factors to couple electronic transitions to nuclear motion, we construct a practical phase-space electronic Hamiltonian that depends on both nuclear position and momentum, HPS(X,P). While classical Born-Oppenheimer dynamics that run along the eigensurfaces of the operator Hel(X) can recover many nuclear properties correctly, we present some evidence that motion along the eigensurfaces of HPS(X,P) can better capture both nuclear and electronic properties (including the elusive electronic momentum studied by Nafie). Moreover, only the latter (as opposed to the former) conserves the total linear and angular momentum in general.

Microplastic-induced NAFLD: Hepatoprotective effects of nanosized selenium.

Polystyrene microplastics (MPs) are persistent environmental pollutants commonly encountered in daily human life. Numerous studies have demonstrated their ability to induce liver damage, including oxidative stress, inflammation, and lipid accumulation. However, limited information exists regarding preventive measures against this issue. In our study, we investigated the potential preventive role of selenium nanoparticles (YC-3-SeNPs) derived from Yak-derived Bacillus cereus, a novel nanobiomaterial known for its antioxidant properties and lipid metabolism regulation. Using transcriptomic and metabolomic analyses, we identified key genes and metabolites associated with oxidative stress and lipid metabolism imbalance induced by MPs. Upregulated genes (Scd1, Fasn, Irs2, and Lpin) and elevated levels of arachidonic and palmitic acid accumulation were observed in MP-exposed mice, but not in those exposed to SeNPs. Further experiments confirmed that SeNPs significantly attenuated liver lipid accumulation and degeneration caused by MPs. Histological results and pathway screening validated our findings, revealing that MPs suppressed the Pparα pathway and Nrf2 pathway, whereas SeNPs activated both pathways. These findings suggest that MPs may contribute to the development of nonalcoholic fatty liver disease (NAFLD), while SeNPs hold promise as a future nanobio-product for its prevention.

Clinical Outcome of Monochorionic Diamniotic Twins with Intrauterine Growth Restriction.

OBJECTIVE: This study investigated the clinical outcome of monochorionic diamniotic (MCDA) twins with selective intrauterine growth restriction (sIUGR). STUDY DESIGN: International Peace Maternal and Child Health Hospital of Shanghai ultrasound database was investigated to identify all MCDA delivered from January 2013 to December 2017. After identifying 43 pairs of MCDA twins with sIUGR and 282 pairs of normal MCDA twins, we compared clinical outcomes between the two groups. RESULTS: Compared with normal twins, sIUGR fetuses had significantly shorter gestational age at delivery, smaller average birth weight of both twins, more significant intertwin difference in birth weight, lower Apgar scores, and higher intrauterine fetal demise (IUFD) rate, and smaller placental weight. The rate of abnormal umbilical cord insertions and abnormal blood flow in the ductus venosus (DV) and middle cerebral artery (MCA) is significantly higher in the sIUGR group. In addition, the subtype analysis of sIUGR groups indicated the poorest outcomes in type II with no significant difference between type I and III. CONCLUSION: MCDA twins with sIUGR generally exhibited limited clinical outcomes than normal MCDA twins. These limitations are mainly associated with abnormal umbilical cord insertions and blood flow in the DV and MCA. Clinical outcomes differed among the three types of sIUGR, with type II having the worst prognosis and the highest IUFD rate. KEY POINTS: · sIUGR generally exhibited limited clinical outcomes than normal MCDA twins.. · These limitations are mainly associated with blood flow of the DV and MCA.. · sIUGR with type II has the worst prognosis and the highest IUFD rate..

The thymus regulates skeletal muscle regeneration by directly promoting satellite cell expansion.

The thymus is the central immune organ, but it is known to progressively degenerate with age. As thymus degeneration is paralleled by the wasting of aging skeletal muscle, we speculated that the thymus may play a role in muscle wasting. Here, using thymectomized mice, we show that the thymus is necessary for skeletal muscle regeneration, a process tightly associated with muscle aging. Compared to control mice, the thymectomized mice displayed comparable growth of muscle mass, but decreased muscle regeneration in response to injury, as evidenced by small and sparse regenerative myofibers along with inhibited expression of regeneration-associated genes myh3, myod, and myogenin. Using paired box 7 (Pax7)-immunofluorescence staining and 5-Bromo-2'-deoxyuridine-incorporation assay, we determined that the decreased regeneration capacity was caused by a limited satellite cell pool. Interestingly, the conditioned culture medium of isolated thymocytes had a potent capacity to directly stimulate satellite cell expansion in vitro. These expanded cells were enriched in subpopulations of quiescent satellite cells (Pax7highMyoDlowEdUpos) and activated satellite cells (Pax7highMyoDhighEdUpos), which were efficiently incorporated into the regenerative myofibers. We thus propose that the thymus plays an essential role in muscle regeneration by directly promoting satellite cell expansion and may function profoundly in the muscle aging process.

Dynamically adjustable SVEIR(MH) model of multiwave epidemics: Estimating the effects of public health measures against COVID-19.

The COVID-19 pandemic was characterized by multiple subsequent, overlapping outbreaks, as well as extremely rapid changes in viral genomes. The information about local epidemics spread and the epidemic control measures was shared on a daily basis (number of cases and deaths) via centralized repositories. The vaccines were developed within the first year of the pandemic. New modes of monitoring and sharing of epidemic data were implemented using Internet resources. We modified the basic SEIR compartmental model to include public health measures, multiwave scenarios, and the variation of viral infectivity and transmissibility reflected by the basic reproduction number R0 of emerging viral variants. SVEIR(MH) model considers the capacity of the medical system, lockdowns, vaccination, and changes in viral reproduction rate on the epidemic spread. The developed model uses daily infection reports for assessing the epidemic dynamics, and daily changes of mobility data from mobile phone networks to assess the lockdown effectiveness. This model was deployed to six European regions Baden-Württemberg (Germany), Belgium, Czechia, Lombardy (Italy), Sweden, and Switzerland for the first 2 years of the pandemic. The correlation coefficients between observed and reported infection data showed good concordance for both years of the pandemic (ρ = 0.84-0.94 for the raw data and ρ = 0.91-0.98 for smoothed 7-day averages). The results show stability across the regions and the different epidemic waves. Optimal control of epidemic waves can be achieved by dynamically adjusting epidemic control measures in real-time. SVEIR(MH) model can simulate different scenarios and inform adjustments to the public health policies to achieve the target outcomes. Because this model is highly representative of actual epidemic situations, it can be used to assess both the public health and socioeconomic effects of the public health measures within the first 7 days of the outbreak.

Profiling of d-alanine production by the microbial isolates of rat gut microbiota.

d-alanine (d-Ala) and several other d-amino acids (d-AAs) act as hormones and neuromodulators in nervous and endocrine systems. Unlike the endogenously synthesized d-serine in animals, d-Ala may be from exogenous sources, e.g., diet and intestinal microorganisms. However, it is unclear if the capability to produce d-Ala and other d-AAs varies among different microbial strains in the gut. We isolated individual microorganisms of rat gut microbiota and profiled their d-AA production in vitro, focusing on d-Ala. Serial dilutions of intestinal contents from adult male rats were plated on agar to obtain clonal cultures. Using MALDI-TOF MS for rapid strain typing, we identified 38 unique isolates, grouped into 11 species based on 16S rRNA gene sequences. We then used two-tier screening to profile bacterial d-AA production, combining a d-amino acid oxidase-based enzymatic assay for rapid assessment of non-acidic d-AA amount and chiral LC-MS/MS to quantify individual d-AAs, revealing 19 out of the 38 isolated strains as d-AA producers. LC-MS/MS analysis of the eight top d-AA producers showed high levels of d-Ala in all strains tested, with substantial inter- and intra-species variations. Though results from the enzymatic assay and LC-MS/MS analysis aligned well, LC-MS/MS further revealed the existence of d-glutamate and d-aspartate, which are poor substrates for this enzymatic assay. We observed large inter- and intra-species variation of d-AA production profiles from rat gut microbiome species, demonstrating the importance of chemical profiling of gut microbiota in addition to sequencing, furthering the idea that microbial metabolites modulate host physiology.

Molecular epidemiology analysis of symptomatic and asymptomatic norovirus infections in Chinese infants.

BACKGROUND: Norovirus is a leading cause of acute gastroenteritis among children. Previous studies based on symptomatic infections indicated that mutations, rather than recombination drove the evolution of the norovirus ORF2. These characteristics were found in hospital-based symptomatic infections, whereas, asymptomatic infections are frequent and contribute significantly to transmission. METHODS: We conducted the first norovirus molecular epidemiology analysis covering both symptomatic and asymptomatic infections derived from a birth cohort study in the northern China. RESULTS: During the study, 14 symptomatic and 20 asymptomatic norovirus infections were detected in 32 infants. Out of the 14 strains that caused symptomatic infections, 12 strains were identified as GII.3[P12], and others were GII.4[P31]. Conversely, 17 asymptomatic infections were caused by GII.4[P31], two by GII.2[P16], and one by GII.4[P16]. Regardless of symptomatic and asymptomatic infections, the mutations were detected frequently in the ORF2 region, and almost all recombination were identified in the RdRp-ORF2 region. The majority of the mutations were located around the predefined epitope regions of P2 subdomain indicating a potential for immune evasion. CONCLUSION: The role of symptomatic as well as asymptomatic infections in the evolution of norovirus needs to be evaluated continuously.

Application of rhein as an immunostimulant controls spring viremia of carp virus infection.

In recent years, the exploration of natural compounds possessing both immunostimulatory and antiviral activities has attracted growing attention in aquaculture research. Consequently, the pursuit of identifying natural products exhibiting anti-SVCV potential as immunostimulants holds significant promise, offering a pathway to mitigate the economic ramifications inflicted by SVCV outbreaks in aquaculture settings. Among them, rhein emerges as a particularly compelling contender. Boasting a widespread distribution, well-established extraction methods, and multiple biological activities, it has exhibited the capacity to enhance the antiviral activity of host cells in vitro by blocking the viral internalization process, with a peak inhibition rate of 44.0%. Based on this intervention, rhein inhibited apoptosis and mitochondrial damage triggered by SVCV infection, ultimately producing a significant antiviral effect. Moving beyond the laboratory setting, rhein's efficacy translates effectively into in vivo scenarios. It has demonstrated substantial antiviral potency by increasing the expression of antiviral-related genes, most notably, retinoic acid-inducible gene I (RIG-I), interferon-φ (IFN-φ) and IFN-stimulated gene product 15 (ISG15). In concert with this genetic modulation, rhein efficiently reduces the viral load, precipitating a consequential enhancement in the survival rate of SVCV-infected fish, elevating it to an encouraging 16%. In conclusion, the outcomes of our investigation offer a compelling testament to rhein's potential as a valuable immunomodulator in the battle against SVCV infections in aquaculture, and the remarkable attributes exhibited by rhein underscore its viability for future commercial deployment.

Timing of cardiac resynchronization therapy implantation.

AIMS: The optimum timing of cardiac resynchronization therapy (CRT) implantation is unknown. We explored long-term outcomes after CRT in relation to the time interval from a first heart failure hospitalization (HFH) to device implantation. METHODS AND RESULTS: A database covering the population of England (56.3 million in 2019) was used to quantify clinical outcomes after CRT implantation in relation to first HFHs. From 2010 to 2019, 64 968 patients [age: 71.4 ± 11.7 years; 48 606 (74.8%) male] underwent CRT implantation, 57% in the absence of a previous HFH, 12.9% during the first HFH, and 30.1% after ≥1 HFH. Over 4.54 (2.80-6.71) years [median (interquartile range); 272 989 person-years], the time in years from the first HFH to CRT implantation was associated with a higher risk of total mortality [hazard ratio (HR); 95% confidence intervals (95% CI)] (1.15; 95% CI 1.14-1.16, HFH (HR: 1.26; 95% CI 1.24-1.28), and the combined endpoint of total mortality or HFH (HR: 1.19; 95% CI 1.27-1.20) than CRT in patients with no previous HFHs, after co-variate adjustment. Total mortality (HR: 1.67), HFH (HR: 2.63), and total mortality or HFH (HR: 1.92) (all P < 0.001) were highest in patients undergoing CRT ≥2 years after the first HFH. CONCLUSION: In this study of a healthcare system covering an entire nation, delays from a first HFH to CRT implantation were associated with progressively worse long-term clinical outcomes. The best clinical outcomes were observed in patients with no previous HFH and in those undergoing CRT implantation during the first HFH. CONDENSED ABSTRACT: The optimum timing of CRT implantation is unknown. In this study of 64 968 consecutive patients, delays from a first heart failure hospitalization (HFH) to CRT implantation were associated with progressively worse long-term clinical outcomes. Each year from a first HFH to CRT implantation was associated with a 21% higher risk of total mortality and a 34% higher risk of HFH. The best outcomes after CRT were observed in patients with no previous HFHs and in those undergoing implantation during their first HFH.

Improved prognosis after cardiac resynchronization therapy over a decade.

AIMS: The past decade has seen an increased delivery of cardiac resynchronization therapy (CRT) for patients with heart failure (HF). We explored whether clinical outcomes after CRT have changed from the perspective of an entire public healthcare system. METHODS AND RESULTS: A national database covering the population of England (56.3 million in 2019) was used to explore clinical outcomes after CRT from 2010 to 2019. A total of 64 698 consecutive patients (age 71.4 ± 11.7 years; 74.8% male) underwent CRT-defibrillation [n = 32 313 (49.7%)] or CRT-pacing [n = 32 655 (50.3%)] implantation. From 2010-2011 to 2018-2019, there was a 76% increase in CRT implantations. During the same period, the proportion of patients with hypertension (59.6-73.4%), diabetes (26.5-30.8%), and chronic kidney disease (8.62-22.5%) increased, as did the Charlson comorbidity index (CCI ≥ 3 from 20.0% to 25.1%) (all P < 0.001). Total mortality decreased at 30 days (1.43-1.09%) and 1 year (9.51-8.13%) after implantation (both P < 0.001). At 2 years, total mortality [hazard ratio (HR): 0.72; 95% confidence interval (CI) 0.69-0.76] and total mortality or HF hospitalization (HR: 0.59; 95% CI 0.57-0.62) decreased from 2010-2011 to 2018-2019, after correction for age, race, sex, device type (CRT-defibrillation or pacing), comorbidities (hypertension, diabetes, chronic kidney disease, and myocardial infarction), or the CCI (HR: 0.81; 95% CI 0.77-0.85). CONCLUSIONS: From the perspective of an entire public health system, survival has improved and HF hospitalizations have decreased after CRT implantation over the past decade. This prognostic improvement has occurred despite an increasing comorbidity burden.