Effect of vitamin C supplementation on outcomes in patients with COVID-19: a systematic review and meta-analysis.

Background: Since the emergence of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), millions of lives have been lost, posing formidable challenges to healthcare systems worldwide. Our study aims to conduct a meta-analysis to evaluate the efficacy of vitamin C supplementation in reducing in-hospital mortality rates and shortening the length of ICU or hospital stays among patients diagnosed with COVID-19. Methods: A comprehensive systematic review and meta-analysis was conducted, sourcing data from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Our analysis focused on randomized clinical trials comparing the efficacy of vitamin C supplementation with standard care in adult COVID-19 patients. Results: Through meticulous examination of 11 clinical trials, our meta-analysis found that vitamin C supplementation did not reduce in-hospital mortality rates in COVID-19 patients compared to those receiving standard care (Risk Ratio [RR] = 0.85; 95% Confidence Interval [CI]: 0.62-1.17; p = 0.31). Similarly, the analysis indicated no significant difference in the length of ICU stays between both cohorts. Additionally, the occurrence of other adverse events was found to be similar across both groups treated with vitamin C supplementation and standard care (all p > 0.05). Conclusion: Vitamin C supplementation did not reduce in-hospital mortality or ICU stay durations in patients with COVID-19. The interpretation of these findings is limited by the small number of available studies and participants, which affects the strength of the conclusions. Clinical trial registration: Identifier CRD42024497474.

Leukocyte immunoglobulin-like receptor B4: A keystone in immune modulation and therapeutic target in cancer and beyond.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) significantly impacts immune regulation and the pathogenesis and progression of various cancers. This review discusses LILRB4's structural attributes, expression patterns in immune cells, and molecular mechanisms in modulating immune responses. We describe the influence of LILRB4 on T cells, dendritic cells, NK cells, and macrophages, and its dual role in stimulating and suppressing immune activities. The review discusses the current research on LILRB4's involvement in acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, hepatocellular carcinoma, and extramedullary multiple myeloma. The review also describes LILRB4's role in autoimmune disorders, infectious diseases, and other conditions. We evaluate the recent advancements in targeting LILRB4 using monoclonal antibodies and peptide inhibitors and their therapeutic potential in cancer treatment. Together, these studies underscore the need for further research on LILRB4's interactions in the tumor microenvironment and highlight its importance as a therapeutic target in oncology and for future clinical innovations.

Enhanced surface antimicrobial, biocompatible and mechanical properties of 3D printed titanium alloys by electrophoretic deposition of chitosan/ZnO.

In this study, to address the susceptibility of 3D-printed titanium implants to bacterial infection, we propose to form a chitosan/ZnO composite coating by electrophoretic deposition to enhance its antimicrobial, biocompatible, and mechanical properties. The surface morphology of the composite coating is relatively flat, showing good hydrophilicity and coating adhesion, and the corrosion current density is significantly lower than that of the untreated titanium alloy. According to the results of the study, the composite coatings containing more than 0.1 g of ZnO (Z2, Z3, Z4 groups) showed excellent antibacterial effects against Staphylococcus aureus and Escherichia coli, with antibacterial rates of more than 95 %, and the medium-concentration ZnO coatings (Z2 group) showed good cellular activity, with cell viability rates of more than 80 %. In contrast, the high-concentration ZnO coatings (Z3, Z4 groups) showed a certain degree of cytotoxicity. The inherent film-forming property of the composite coating enabled the cells to adhere well to the coating surface. It was found through SBF body fluid immersion that Zn²âº can increase the rate of hydroxyapatite precipitation and enhance bioactivity. These results emphasize the importance of precise control of the ZnO content in the improved antimicrobial and biocompatible chitosan-ZnO composite coatings to ensure excellent antimicrobial properties and necessary biocompatibility.

Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair.

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for targeting undruggable proteins, and the molecular warheads targeting E3 ligases play a crucial role. Recently, we explored an alkenyl oxindole warhead targeting the E3 ligase DCAF11 and sought to validate its potential. In this study, we synthesized a range of BRD4 PROTACs (8a-8o, 14a-14f, 22a-22m) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified L134 (22a) as a potent BRD4 degrader, achieving BRD4 degradation (Dmax > 98%, DC50 = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by L134 was mediated through the ubiquitin-proteasome system in a DCAF11-dependent manner. Therefore, this study provides a rapid screening method for effective PROTACs and highlights the PROTAC L134 based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.

Bacterial specialists playing crucial roles in maintaining system stability and governing microbial diversity in bioremediation of oil-polluted sediments under typical deep-sea condition.

Ecologically, interactions and contributions of microbiota generalists and specialists remain largely unexplored in remediation of deep-sea oil pollution. Herein, ecological and evolutionary characteristics of the two taxa were comprehensively investigated in restoration of oil-polluted sediment at deep-sea microcosm. Niche-specialized taxa exhibited rapid speciation rate, more complex network structure and highly interspecific mutualism. In contrast, generalists possessed higher richness but with poor local performance, as evidenced by higher extinction rate, lower stability, and more interspecific antagonism. Generalists were the primary oil degraders, while specialists acted as auxiliaries promoting degradation via production of biofilm and biosurfactant. Evolutionarily, the continuous transition from specialists to generalists insured the exclusion of generalist at a relatively constant level for ecological trade-offs. Collectively, the findings emphasize the importance of specialists in facilitating oil degradation by elucidating their vital roles in maintaining system stability and regulating microbial diversity during process, and offer valuable guidance for designing remediation plans.

Projections of Socioeconomic Costs for Individuals with Dementia in China 2020-2050: Modeling Study.

Background: Previous estimates on future socioeconomic costs of dementia in China are inconsistent, and the main drivers of these costs are unclear. Objective: This study projected future socioeconomic costs (healthcare, formal social care, and informal care costs) and value of quality adjusted life years (QALYs) lost to dementia in China and assessed drivers of socioeconomic costs. Methods: Based on our prior projection on dementia cases to 2050 by a Markov model, we forecasted future socioeconomic costs and the value of QALYs from a societal perspective, utilizing the China Health and Retirement Longitudinal Study and the Chinese Longitudinal Healthy Longevity Survey. In our main analysis, dementia incidence increased by 2.9% annually, while sensitivity analyses considered a flat or 1.0% annual decrease in the temporal trend of dementia incidence. Furthermore, we decomposed socioeconomic costs changes (2018 US$) into population growth, population aging, dementia prevalence and average socioeconomic costs per case. Results: The annual socioeconomic costs and value of QALYs lost to dementia will reach $1,233 billion and $702 billion by 2050. If dementia incidence stays constant or decreases by 1.0% annually, the costs and QALYs would respectively decrease by 34% or 43% in 2050. Informal care is currently, and projected to remain, the largest share of socioeconomic costs. Population aging and rising dementia prevalence will mainly drive the growth in socioeconomic costs through 2050. Conclusions: Dementia casts an increasingly large economic burden on Chinese society, mainly driven by fast aging population and growing dementia prevalence.

Dimension compensation of printed master molds by a desktop LCD 3D printer for high-precision microfluidic applications.

Recent advances in low-cost liquid crystal display (LCD) 3D printing have popularized its use in creating microfluidic master molds and complete devices. However, the quality and precision of these fabrications often fall short of the rigorous standards required for advanced microfluidic applications. This study introduces a novel approach to enhance the dimensional accuracy of microchannels produced using a desktop LCD 3D printer. We propose a method for dimension compensation, optimize the printing parameters, and provide a straightforward post-treatment technique to ensure high-quality curing of polydimethylsiloxane (PDMS) in master molds made from photosensitive resin. Our investigation assesses the precision of 3D printing across three different scales of square cross-section microchannels by measuring their widths and heights, leading to the determination of optimal printing parameters that minimize dimensional errors. The dimensional errors are further reduced by introducing a series of dimension compensation factors, which correct the nominal dimensions of the microchannels by using the compensation factors in 3D printing. The dimensional accuracy is significantly improved after compensation even in fabricating complex microchannels of triangular cross-sections. Finally, a spiral channel of trapezoidal-like cross-section with tilted edges is fabricated for microfluidic application, and highly efficient particle separation is realized in the channel. The proposed method provides new insights for utilizing desktop LCD 3D printers to achieve high-accuracy microstructures necessary for advanced microfluidic applications.

Spiral microchannels with concave cross-section for enhanced cancer cell inertial separation.

Inertial microfluidic technologies have proven effective for particle focusing and separation in many microchannels, typically the channels with the rectangular and trapezoidal shapes. To advance particle focusing in complex channels, we propose a spiral channel combining rectangular and concave cross-sections for high-resolution particle and cell focusing and separation. Numerical simulations were conducted to illustrate the effects of channel geometry on secondary flow distribution and particle focusing positions. The simulation shows the concave cross-section generates two asymmetrical Dean vortices skewing towards the inner and outer channel walls, resulting to stronger flow velocity magnitudes near the walls than the channel center. Consequently, larger particles focus near the inner wall, while smaller particles are trapped closer to the outer wall under the influence of the stronger velocity magnitude near the walls. A microfluidic chip with the proposed channel geometry, along with a traditional rectangular channel, was fabricated by 3D printing and PDMS casting. Fluorescent microbeads were used to investigate inertial focusing and separation behaviors in the microfluidic chips. Experimental results show that the concave channel facilitates particle focusing or trapping much closer to the walls than the traditional rectangular channel, achieving better separation resolution. Finally, the proposed channel was applied to separate lung cancer A549 cells from human blood, achieving a cancer cell recovery rate of ~ 84.78% (enrichment ratio over 820-fold) and a blood cell rejection rate of ~ 99.88%. This innovative channel design in inertial microfluidics offers new insights for enhanced particle focusing and holds significant promise for cell manipulation with improved separation resolution.

Intermolecular sulfur atom transfer cascade enabled late-stage introduction of sulfilimines into peptides.

Sulfilimines, a privileged class of -S(iv)[double bond, length as m-dash]N- functional groups found in nature, have been exploited as valuable building blocks in organic synthesis and as pharmacophores in drug discovery, and have aroused significant interest in the chemical community. Nevertheless, strategies for late-stage introduction of sulfilimines into peptides and proteins have still met with limited success. Herein, we have developed a method of introducing biological sulfilimine fragments into peptides by an intermolecular sulfur atom transfer cascade reaction, utilizing hydroxylamine condensed with the acid moieties of peptides and varied diaryl disulfides. It provides a convenient, efficient, metal-free and widely applicable method for late-stage modification and functionalization of peptides at their acid sites both in the homogeneous phase and on-resins in SPPS. Moreover, the modified peptides with sulfilimines have been demonstrated as cleavable linkers for peptide conjugates under reducible conditions, providing unique opportunities in peptide therapeutics development and drug discovery.

UFMylation is involved in serum inflammatory cytokines generation and splenic T cell activation induced by lipopolysaccharide.

UFMylation, a novel ubiquitin-like protein modification system, has been recently found to be activated in inflammation. However, the effects of UFMylation activation on inflammation in vivo remains unclear. In the present study, we generated a UFMylation activated mice using transgenic (TG) techniques. Lipopolysaccharide (LPS) was used to induce systemic inflammation in both TG and non-transgenic (NTG) mice. Serum cytokines were detected using a Mouse Cytokine Array, and the proportions of splenic NK, B and T cells were determined by using flow cytometry. We found that TG mice showed increased serum G-CSF, TNF RII and decreased serum TCA-3, CD30L, bFGF, IL-15 and MIG compared with NTG mice at baseline. Furthermore, serum cytokines in TG mice exhibited different responses to LPS compared to NTG mice. LPS up-regulated serum TNF RII, G-CSF, MCP-5, RANTES, KC, BLC, MIG and down-regulated IL-1b, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-15, IL-17, IFN-γ, TCA-3, Eotaxin-2, LIX, MCP-1, TNFα, GM-CSF in NTG mice, whereas LPS up-regulated G-CSF, MCP-5, RANTES, KC, BLC, MIG, ICAM-1, PF4, Eotaxin, CD30L, MIP-1a, TNFRI and down-regulated IL-1b, IL-3, LIX, MCP-1, TNFα, GM-CSF in TG mice. Data from flow cytometry indicated that LPS significantly reduced the percentages of NK and NKT cells in NTG mice, whereas UFMylation activation inhibited LPS-induced NKT cell decrease. The proportions of B cells, total CD4+ and total CD8+ T cells were comparable between TG and NTG mice in response to LPS treatment, whereas the percentages of CD4+CD69+ and CD8+CD69+T cells were lower in TG mice. These findings suggest that UFMylation may alter LPS-induced serum cytokine profile and participate in splenic T cell activation in vivo.

Interactions between Inhibitors and 5-Lipoxygenase: Insights from Gaussian Accelerated Molecular Dynamics and Markov State Models.

Inflammation is a protective stress response triggered by external stimuli, with 5-lipoxygenase (5LOX) playing a pivotal role as a potent mediator of the leukotriene (Lts) inflammatory pathway. Nordihydroguaiaretic acid (NDGA) functions as a natural orthosteric inhibitor of 5LOX, while 3-acetyl-11-keto-ß-boswellic acid (AKBA) acts as a natural allosteric inhibitor targeting 5LOX. However, the precise mechanisms of inhibition have remained unclear. In this study, Gaussian accelerated molecular dynamics (GaMD) simulation was employed to elucidate the inhibitory mechanisms of NDGA and AKBA on 5LOX. It was found that the orthosteric inhibitor NDGA was tightly bound in the protein's active pocket, occupying the active site and inhibiting the catalytic activity of the 5LOX enzyme through competitive inhibition. The binding of the allosteric inhibitor AKBA induced significant changes at the distal active site, leading to a conformational shift of residues 168-173 from a loop to an α-helix and significant negative correlated motions between residues 285-290 and 375-400, reducing the distance between these segments. In the simulation, the volume of the active cavity in the stable conformation of the protein was reduced, hindering the substrate's entry into the active cavity and, thereby, inhibiting protein activity through allosteric effects. Ultimately, Markov state models (MSM) were used to identify and classify the metastable states of proteins, revealing the transition times between different conformational states. In summary, this study provides theoretical insights into the inhibition mechanisms of 5LOX by AKBA and NDGA, offering new perspectives for the development of novel inhibitors specifically targeting 5LOX, with potential implications for anti-inflammatory drug development.

A bibliometric analysis of radiation-induced brain injury: a research of the literature from 1998 to 2023.

BACKGROUND: Radiation-induced brain injury (RIBI) is a debilitating sequela after cranial radiotherapy. Research on the topic of RIBI has gradually entered the public eye, with more innovations and applications of evidence-based research and biological mechanism research in the field of that. This was the first bibliometric analysis on RIBI, assessing brain injury related to radiation articles that were published during 1998-2023, to provide an emerging theoretical basis for the future development of RIBI. METHODS: Literature were obtained from the Web of Science Core Collection (WOSCC) from its inception to December 31, 2023. The column of publications, author details, affiliated institutions and countries, publication year, and keywords were also recorded. RESULTS: A total of 2543 journal articles were selected. The annual publications on RIBI fluctuated within a certain range. Journal of Neuro-oncology was the most published journal and Radiation Oncology was the most impactful one. LIMOLI CL was the most prolific author with 37 articles and shared the highest h-index with BARNETT GH. The top one country and institutions were the USA and the University of California System, respectively. Clusters analysis of co-keywords demonstrated that the temporal research trends in this field primarily focused on imaging examination and therapy for RIBI. CONCLUSION: This study collects, visualizes, and analyzes the literature within the field of RIBI over the last 25 years to map the development process, research frontiers and hotspots, and cutting-edge directions in clinical practice and mechanisms related to RIBI.

Switching engineered Vitreoscilla hemoglobin into carbene transferase for enantioselective SH insertion.

An attractive strategy for efficiently forming CS bonds is through the use of diazo compounds SH insertion. However, achieving good enantioselective control in this reaction within a biocatalytic system has proven to be challenging. This study aimed to enhance the activity and enantioselectivity of to enable asymmetric SH insertion. The researchers conducted site-saturation mutagenesis (SSM) on 5 amino acid residues located around the iron carbenoid intermediate within a distance of 5 Å, followed by iterative saturation mutagenesis (ISM) of beneficial mutants. Through this process, the beneficial variant VHbSH(P54R/V98W) was identified through screening with 4-(methylmercapto) phenol as the substrate. This variant exhibited up to 4-fold higher catalytic efficiency and 6-fold higher enantioselectivity compared to the wild-type VHb. Computational studies were also conducted to elucidate the detailed mechanism of this asymmetric SH insertion, explaining how active-site residues accelerate this transformation and provide stereocontrol.

Hypothesis tests in ordinal predictive models with optimal accuracy.

In real-world applications involving multi-class ordinal discrimination, a common approach is to aggregate multiple predictive variables into a linear combination, aiming to develop a classifier with high prediction accuracy. Assessment of such multi-class classifiers often utilizes the hypervolume under ROC manifolds (HUM). When dealing with a substantial pool of potential predictors and achieving optimal HUM, it becomes imperative to conduct appropriate statistical inference. However, prevalent methodologies in existing literature are computationally expensive. We propose to use the jackknife empirical likelihood method to address this issue. The Wilks' theorem under moderate conditions is established and the power analysis under the Pitman alternative is provided. We also introduce a novel network-based rapid computation algorithm specifically designed for computing a general multi-sample $U$-statistic in our test procedure. To compare our approach against existing approaches, we conduct extensive simulations. Results demonstrate the superior performance of our method in terms of test size, power, and implementation time. Furthermore, we apply our method to analyze a real medical dataset and obtain some new findings.

The synergistic effect of the atherogenic index of plasma and hyperuricemia on the prediction of coronary chronic total occlusion lesion: an observational cross-sectional study.

Background: The atherogenic index of plasma (AIP) and hyperuricemia (HUA) have been shown to be closely associated with morbidity and mortality of coronary artery disease. However, studies targeting predictive value of AIP and HUA for chronic total occlusion (CTO) lesions are still lacking. Methods: In total, 5,238 patients meeting the eligibility criteria were recruited in this analysis. CTO was defined as the condition of lesions without forward blood flow and with over three months of occlusion time. AIP was calculated as log10 [triglycerides (mmol/L)/high-density lipoprotein cholesterol (mmol/L)]. HUA was defined based on sex-specific criteria: serum uric acid 420 and 360 µmol/L for males and females, respectively. Results: CTO lesions were presented in 907 (17.3%) patients. Compared with patients showing lower AIP levels and non-HUA, the CTO lesion risks increased by 5.225 and 2.765 times in patients with higher AIP levels and HUA. Patients with AIP >0.15 and HUA exhibited the greatest CTO incidence (odds ratio 11.491; 95% confidence interval 9.019-14.641, P < 0.001). In addition, AIP combined with HUA had significantly increased effects (a 38.5% increase in CTO risk) relative to the sum of respective effects. Conclusion: Patients having higher AIP levels and HUA exhibited the highest CTO incidence, in comparison with patients who have the increased single index. AIP combined with HUA displayed significant synergistic effect on the prediction of CTO lesion.

Exploring genetic associations in systemic lupus erythematosus through Mendelian randomization: implications for novel biomarkers and therapeutic targets.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a significant health burden. There is an essential need for novel biomarkers and therapeutic targets to improve diagnosis and management. Mendelian randomization (MR) was applied to explore causal links between SLE and various biomarkers like immune cells, metabolites, and inflammatory cytokines using multiple databases. Initially, biomarkers significantly associated with SLE were identified. Bidirectional MR helped clarify these relationships, and a two-step mediation MR examined their effects on SLE risk. Intersection analysis was used to identify biomarkers with consistent effects across datasets. Four biomarkers were identified as having significant associations with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI levels [odds ratio (OR), 1.379; 95% confidence interval (CI), 1.180 to 1.613; FDR, 0.046], IL-17A levels (OR, 2.197; 95% CI, 1.412 to 3.418; FDR, 0.044), N-acetyl-aspartyl-glutamate (NAAG) levels (OR, 0.882; 95% CI, 0.831 to 0.936; FDR, 0.030), and ribitol levels (OR, 0.743; 95% CI, 0.644 to 0.857; FDR, 0.012). Bidirectional MR showed an inverse effect of NAAG on IL-17A levels (OR, 0.978; 95% CI, 0.962 to 0.994; p = 0.006). Mediation analysis indicated that NAAG influenced SLE risk both directly (beta = - 0.108) and indirectly through IL-17A (beta = - 0.018), highlighting the potential mediating role of IL-17A. After expanding the significance criteria to p < 0.05, intersection analysis across multiple datasets revealed 29 biomarkers with consistent beta directions, including 19 potential risk factors (beta > 0) and 10 protective factors (beta < 0) for SLE. This research has revealed significant genetic associations with SLE and demonstrated that IL-17A mediates the relationship between NAAG levels and SLE risk, highlighting potential new targets for personalized therapeutic interventions. Key Points • This study employs MR to identify significant genetic associations between various biomarkers and SLE, providing novel insights into potential biomarkers and therapeutic targets. • Four key biomarkers were identified as significantly associated with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI, IL-17A, N-acetyl-aspartyl-glutamate (NAAG), and ribitol. • The findings suggest that NAAG levels have a protective effect against SLE, partly mediated through IL-17A, indicating a complex interplay between these biomarkers in the pathogenesis of SLE. • Intersectional analysis across multiple datasets revealed 29 biomarkers with consistent effects on SLE risk, highlighting new directions for future research and potential personalized therapeutic strategies.

Projection for dementia burden in China to 2050: a macro-simulation study by scenarios of dementia incidence trends.

Background: It is unclear how temporal trends in dementia incidence, alongside fast-changing demography, will influence China's future dementia burden. We developed a Markov model that combines population trends in dementia, mortality, and dementia-related comorbidities, to forecast and decompose the burden of dementia in China to 2050. Methods: Population-based Chinese ageing cohorts provided input data for a 10-health-state Markov macrosimulation model, IMPACT-China Ageing Model (CAM), to predict sex- and age-specific dementia prevalence among people aged 50+ by year to 2050. We assumed three potential future scenarios representing the range of likely dementia incidence trends: upward (+2.9%), flat (0%) or downward (-1.0%). Sensitivity analyses were conducted to examine uncertainty associated with trends in mortality rates and CVD incidence. The projected dementia burden was decomposed into population growth, population ageing, and changing dementia prevalence corresponding to the three incidence trend scenarios. Findings: Under the upward trend scenario, the estimated number of people living with dementia is projected to rise to 66.3 million (95% uncertainty interval (UI) 64.7-68.0 million), accounting for 10.4% of the Chinese population aged 50+ by 2050. This large burden will be lower, 43.9 (95% UI 42.9-45.0) million and 37.5 (95% UI 36.5-38.4) million, if dementia incidence remains constant or decreases. Robustness of the projection is confirmed by sensitivity analyses. Decomposition of the change in projected dementia cases indicates dominate effects of increasing dementia prevalence and population ageing, and a relatively minor contribution from negative population growth. Interpretation: Our findings highlight an impending surge in dementia cases in China in the forthcoming decades if the upward trend in dementia incidence continues. Public health interventions geared towards dementia prevention could play a pivotal role in alleviating this burgeoning disease issue. Funding: National Science Foundation of China/UK Economic and Social Research Council.

Multi-omics reveals bufadienolide Q-markers of Bufonis Venenum based on antitumor activity and cardiovascular toxicity in zebrafish.

BACKGROUND: Bufonis Venenum (BV) is a traditional animal-based Chinese medicine with therapeutic effects against cancer. However, its clinical use is significantly restricted due to associated cardiovascular risks. BV's value in China's market is typically assessed based on "content priority," focusing on indicator components. However, these components of BV possess both antitumor activity and toxicity, and the correlation between the antitumor activity and toxicity of BV has not yet been elucidated. PURPOSE: This study employs an integrated multi-omics approach to identify bufadienolide Q-markers and explore the correlation between BV's antitumor activity and toxicity. The aim is to establish a more comprehensive method for BV's quality. METHODS: Normal zebrafish and HepG2 xenograft zebrafish were chosen as activity and toxicity evaluation models. Ultra-high performance liquid chromatography (UHPLC) coupled with a linear ion trap orbitrap (LTQ-Orbitrap) mass spectrometry was used to quantify eight batches of BV and key "toxic and effective" components were screened out. Transcriptomic and metabolomic analyses were performed to elucidate the regulatory mechanisms underlying the antitumor activity and cardiovascular toxicity of the key components in BV. RESULTS: Eight key "toxic and effective" compounds were identified: resibufogenin, cinobufagin, arenobufagin, bufotalin, bufalin, gamabufotalin, desacetylcinobufagin, and telocinobufagin. The findings showed that bufalin and cinobufagin interfered with calcium homeostasis through CaV and CaSR, induced cardiotoxicity, and upregulated CASP9 to activate myocardial cell apoptosis. However, desacetylcinobufagin exhibited greater potential in terms of anti-tumor effects. Combining the results of untargeted and targeted metabolomics revealed that desacetylcinobufagin could have a callback effect on differential lipids and correct abnormal energy and amino acid metabolism caused by cancer, similar to cinobufagin and bufalin. Microscale thermophoresis (MST) ligand binding measurements also showed that the binding of desacetylcinobufagin to GPX4 has a more potent ability to induce ferroptosis in tumor cells compared to cinobufagin. CONCLUSION: An innovative evaluation method based on the zebrafish was developed to investigate the relationship between the toxicity and efficacy of BV. This study identified toxicity and activity Q-markers and explored the mechanism between the two effects of BV. The research data could offer valuable insights into the efficacy of BV. Additionally, desacetylcinobufagin, an active ingredient with low toxicity, was found to enhance the quality of BV.

Evidence for the production of asexual resting cysts in a free-living species of Symbiodiniaceae (Dinophyceae).

Coral reef ecosystems are the most productive and biodiverse marine ecosystems, with their productivity levels highly dependent on the symbiotic dinoflagellates belonging to the family Symbiodiniaceae. As a unique life history strategy, resting cyst production is of great significance in the ecology of many dinoflagellate species, those HABs-causing species in particular, however, there has been no confirmative evidence for the resting cyst production in any species of the family Symbiodiniaceae. Based on morphological and life history observations of cultures in the laboratory and morpho-molecular detections of cysts from the marine sediments via fluorescence in situ hybridization (FISH), cyst photography, and subsequent singe-cyst PCR sequencing, here we provide evidences for the asexual production of resting cysts by Effrenium voratum, the free-living, red tide-forming, and the type species of the genus Effrenium in Symbiodiniaceae. The evidences from the marine sediments were obtained through a sequential detections: Firstly, E. voratum amplicon sequence variants (ASVs) were detected in the cyst assemblages that were concentrated with the sodium polytungstate (SPT) method from the sediments collected from different regions of China Seas by high-throughput next generation sequencing (NGS); Secondly, the presence of E. voratum in the sediments was detected by PCR using the species-specific primers for the DNA directly extracted from sediment; Thirdly, E. voratum cysts were confirmed by a combined approach of FISH using the species-specific probes, light microscopic (LM) photography of the FISH-positive cysts, and a subsequent single-cyst PCR sequencing for the FISH-positive and photographed cysts. The evidences from the laboratory-reared clonal cultures of E. voratum include that: 1) numerous cysts formed in the two clonal cultures and exhibited a spherical shape, a smooth surface, absence of ornaments, and a large red accumulation body; 2) cysts could maintain morphologically intact for a storage of two weeks to six months at 4 °C in darkness and of which 76-92 % successfully germinated through an internal development processes within a time period of 3-21 days after being transferred back to the normal culturing conditions; 3) two or four germlings were released from each cyst through the cryptopylic archeopyle in all cysts with continuous observations of germination processes; and 4) while neither sexual mating of gametes nor planozygote (cells with two longitudinal flagella) were observed, the haploidy of cysts was proven with flow cytometric measurements and direct LM measurements of fluorescence from cells stained with either propidium iodide (PI) or DAPI, which together suggest that the cysts were formed asexually. All evidences led to a conclusion that E. voratum is capable of producing asexual resting cysts, although its sexuality cannot be completely excluded, which guarantees a more intensive investigation. This work fills a gap in the knowledge about the life cycle, particularly the potential of resting cyst formation, of the species in Symbiodiniaceae, a group of dinoflagellates having unique life forms and vital significance in the ecology of coral reefs, and may provide novel insights into understanding the recovery mechanisms of coral reefs destructed by the global climate change and suggest various forms of resting cysts in the cyst assemblages of dinoflagellates observed in the field sediments, including HABs-causing species.

Association of C-reactive protein/albumin ratio with mortality in patients with Traumatic Brain Injury: A systematic review and meta-analysis.

Objective: This study examines the C-reactive protein (CRP)/albumin ratio (CAR) as an inflammation-based prognostic score for predicting mortality in patients with Traumatic Brain Injury (TBI). Methods: We systematically searched the electronic databases PubMed, Embase, and Cochrane up to February 2024. Our inclusion criteria encompassed studies investigating CAR-predicted mortality in patients with TBI. We calculated the Odds Ratio (OR) and associated 95 % confidence intervals (95 % CI) using a random-effects model. Quality assessment of the included studies was appraised using a Newcastle-Ottawa scale. Results: A total of five studies comprising 1040 patients were included in this meta-analysis. The pooled results indicated that CAR was associated with mortality in patients with TBI (OR = 1.88, 95 % CI: 1.05-3.36, P < 0.0001). The findings of subgroup analysis indicated that the relationship between CAR and mortality in patients with TBI did not vary with the severity of the condition. Conclusions: CAR emerges as a valuable prognostic tool for mortality in patients with TBI, underscoring its potential role in early risk stratification and management strategies.