Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Nondestructive flash cathode recycling.

Effective recycling of end-of-life Li-ion batteries (LIBs) is essential due to continuous accumulation of battery waste and gradual depletion of battery metal resources. The present closed-loop solutions include destructive conversion to metal compounds, by destroying the entire three-dimensional morphology of the cathode through continuous thermal treatment or harsh wet extraction methods, and direct regeneration by lithium replenishment. Here, we report a solvent- and water-free flash Joule heating (FJH) method combined with magnetic separation to restore fresh cathodes from waste cathodes, followed by solid-state relithiation. The entire process is called flash recycling. This FJH method exhibits the merits of milliseconds of duration and high battery metal recovery yields of ~98%. After FJH, the cathodes reveal intact core structures with hierarchical features, implying the feasibility of their reconstituting into new cathodes. Relithiated cathodes are further used in LIBs, and show good electrochemical performance, comparable to new commercial counterparts. Life-cycle-analysis highlights that flash recycling has higher environmental and economic benefits over traditional destructive recycling processes.

Genome-Wide Association Studies of Growth Trait Heterosis in Crossbred Meat Rabbits.

The application of heterosis can not only effectively improve the disease resistance and meat quality of livestock, but also significantly enhance the reproduction and growth of livestock and poultry. We conducted genome-wide association studies using data from F2 crossbred meat rabbits to screen out candidate genes with significant dominant effects associated with economic trait variation. High-throughput sequencing technology was used to obtain SNPs covering the whole genome to evaluate the homozygosity of the population genome, and analyze the number, length, frequency, and distribution of ROHs in the population. Candidate genes related to economic traits of meat rabbits were searched based on high-frequency ROH regions. After quality control filtering of genotype data, 380 F2 crossbred rabbits were identified with 78,579 SNPs and 42,018 ROHs on the autosomes. The fitting of the Logistic growth curve model showed that 49-day-old rabbits were a growth inflection point. Then, through genome-wide association studies, 10 SNP loci and seven growth trait candidate genes were found to be significantly related to body weight in meat rabbits at 84 days of age. In addition, we revealed the functional roles and locations of 20 candidate genes in the high-frequency ROH region associated with economic traits in meat rabbits. This study identified potential genes associated with growth and development in the high-frequency ROH region of meat rabbits. In this study, the identified candidate genes can be used as molecular markers for assisted selection in meat rabbits. At the same time, the inbreeding situation based on ROH assessment can provide reference for breeding and breeding preservation of meat rabbits.

Saliva, Plasma, and Multifluid Metabolomic Signatures of Periodontal Disease, Type 2 Diabetes Progression, and Markers of Glycemia and Dyslipidemia Among Puerto Rican Adults With Overweight and Obesity.

BACKGROUND: Evidence from cohort studies indicates a bidirectional relationship between periodontal disease and type 2 diabetes (T2D), but the underlying mechanisms remain unknown. In this study, we aimed to (1) identify saliva, plasma, and multifluid metabolomic signatures associated with periodontal disease and (2) determine if these signatures predict T2D progression and cardiometabolic biomarkers at year 3. METHODS AND RESULTS: We included participants from the SOALS (San Juan Overweight Adult Longitudinal Study) (n=911). Metabolites from saliva (k=635) and plasma (k=1051) were quantified using liquid chromatography-mass spectrometry. We applied elastic net regression with 10-fold cross-validation to identify baseline metabolomic signatures of periodontal disease. Multivariable Cox proportional hazards regression and linear regression were used to evaluate the association with T2D progression and biomarker concentrations. Metabolomic profiles included highly weighted metabolites related to lysine and pyrimidine metabolism. Periodontal disease or its 3 metabolomic signatures were not associated with T2D progression in 3 years. Prospectively, 1-SD increments in the multifluid and saliva metabolomic signatures were associated with higher low-density lipoprotein (multifluid: 12.9±5.70, P=0.02; saliva: 13.3±5.11, P=0.009). A 1-SD increment in the plasma metabolomic signature was also associated with Homeostatic Model Assessment for Insulin Resistance (2.67±1.14, P=0.02) and triglyceride (0.52±0.18, P=0.002). CONCLUSIONS: Although metabolomic signatures of periodontal disease could not predict T2D progression, they were associated with low-density lipoprotein, triglyceride, and Homeostatic Model Assessment for Insulin Resistance levels at year 3.

Peripheral immunity is associated with cognitive impairment after acute minor ischemic stroke and transient ischemic attack.

Immunoinflammation is associated with the development of post-stroke cognitive impairment (PSCI), however, peripheral immunity has not been fully explored. We aimed to investigate the association between PSCI and peripheral immune indicators, including neutrophil, lymphocyte, and mononuclear percentages and counts; the systemic immune inflammation index; platelet-to-lymphocyte ratio; neutrophil-to-lymphocyte ratio (NLR); and lymphocyte-to-monocyte ratio. A total of 224 patients with acute minor ischemic stroke or transient ischemic attack with 6-12 months of follow-up were included. PSCI was defined as a Montreal Cognitive Assessment score < 22 during the follow-up period. We performed logistic regression, subgroup analyses based on age and sex, and further established predictive models. We found that increased innate immunity indicators (neutrophils, neutrophil percentage) increased the risk of PSCI, whereas increased adaptive immunity indicator (lymphocytes) were protective against PSCI, especially in patients aged 50-65 years. Neutrophil percentage and NLR improved the predictive efficacy of the models that included demographic, clinical, and imaging information, with the area under the curve increased from 0.765 to 0.804 and 0.803 (P = 0.042 and 0.049, respectively). We conducted a comprehensive analysis of peripheral immunity in PSCI, providing a novel perspective on the early detection, etiology, and treatment of PSCI.

Identification and validation of immune-related gene signature models for predicting prognosis and immunotherapy response in hepatocellular carcinoma.

Background: This study seeks to enhance the accuracy and efficiency of clinical diagnosis and therapeutic decision-making in hepatocellular carcinoma (HCC), as well as to optimize the assessment of immunotherapy response. Methods: A training set comprising 305 HCC cases was obtained from The Cancer Genome Atlas (TCGA) database. Initially, a screening process was undertaken to identify prognostically significant immune-related genes (IRGs), followed by the application of logistic regression and least absolute shrinkage and selection operator (LASSO) regression methods for gene modeling. Subsequently, the final model was constructed using support vector machines-recursive feature elimination (SVM-RFE). Following model evaluation, quantitative polymerase chain reaction (qPCR) was employed to examine the gene expression profiles in tissue samples obtained from our cohort of 54 patients with HCC and an independent cohort of 231 patients, and the prognostic relevance of the model was substantiated. Thereafter, the association of the model with the immune responses was examined, and its predictive value regarding the efficacy of immunotherapy was corroborated through studies involving three cohorts undergoing immunotherapy. Finally, the study uncovered the potential mechanism by which the model contributed to prognosticating HCC outcomes and assessing immunotherapy effectiveness. Results: SVM-RFE modeling was applied to develop an OS prognostic model based on six IRGs (CMTM7, HDAC1, HRAS, PSMD1, RAET1E, and TXLNA). The performance of the model was assessed by AUC values on the ROC curves, resulting in values of 0.83, 0.73, and 0.75 for the predictions at 1, 3, and 5 years, respectively. A marked difference in OS outcomes was noted when comparing the high-risk group (HRG) with the low-risk group (LRG), as demonstrated in both the initial training set (P <0.0001) and the subsequent validation cohort (P <0.0001). Additionally, the SVMRS in the HRG demonstrated a notable positive correlation with key immune checkpoint genes (CTLA-4, PD-1, and PD-L1). The results obtained from the examination of three cohorts undergoing immunotherapy affirmed the potential capability of this model in predicting immunotherapy effectiveness. Conclusions: The HCC predictive model developed in this study, comprising six genes, demonstrates a robust capability to predict the OS of patients with HCC and immunotherapy effectiveness in tumor management.

Higher-order exceptional points in parity-time symmetry and the optical gyroscope.

The practical application of integrated gyroscopes in engineering has not yet been fully realized due to the linear correlation between the Sagnac effect and dimensions. In recent demonstrations, gyroscopes operating near exceptional points (EPs) under parity-time (PT) symmetry have shown significant potential in enhancing their response to rotational rates. However, constructing higher-order EPs with refined physical properties poses a considerable challenge. Additionally, current methods for constructing higher-order EPs with robustness primarily rely on passive cavities, with almost no reports on constructing robust EPs using PT-symmetric systems that encompass both gain and loss. Here, we propose a robust design for a scalable fabrication of higher-order EP gyroscopes with PT-symmetric structure. We investigate the influence of perturbations on the frequency splitting of the higher-order EP gyroscope and demonstrate that it is possible to achieve a resonance splitting eight orders of magnitude higher than that obtained through the classical Sagnac effect. In comparison to the previously proposed PT-symmetric gyroscope, our solution allows a tunable frequency splitting by adjusting the phase shift, making it more measurable at the output power spectrum.

Comprehensive assessment of ocular parameters for identifying diagnostic indicators of diabetic peripheral neuropathy.

PURPOSE: To explore variations in systemic and ocular parameters among patients with diabetes, both with and without diabetic peripheral neuropathy (DPN) and to identify sensitive indicators for DPN diagnosis. METHODS: Ninty-five patients with type 2 diabetes mellitus (T2DM) were involved in this cross-sectional study, including 49 without DPN and 46 with DPN. Ocular parameters were obtained using optical coherence tomography angiography (OCTA) and corneal confocal microscopy (CCM). RESULT: Patients with DPN presented with significantly higher HbA1c (p < 0.05) and glycated albumin (GA, p < 0.01) levels, increased prevalence of diabetic retinopathy (DR, p < 0.05), and lower serum albumin (ALB, p < 0.01) and red blood cell (RBC, p < 0.05) levels. Ocular assessments revealed reduced corneal nerve fiber length (CNFL, p < 0.001) and enlarged foveal avascular zone (FAZ) area (p < 0.05) in DPN group. Logistic regression analysis indicated a significant association of presence of DR, RBC, GA, ALB, CNFL and DPN (p < 0.05, respectively). In the binary logistic regression for DPN risk, all three models including the presence of DR and CNFL exhibited the area under the curve (AUC) exceeding 0.8. CONCLUSION: The study establishes a strong correlation between ocular parameters and DPN, highlighting CCM's role in early diagnosis. Combining systemic and ocular indicators improves DPN risk assessment and early management.

Morchella Effectively Removes Microcystins Produced by Microcystis aeruginosa.

Microcystins (MCs) produced by Microcystis aeruginosa are harmful to animal and human health, and there is currently no effective method for their removal. Therefore, the development of biological approaches that inhibit cyanobacteria and remove MCs is needed. We identified strain MB1, confirmed as Morchella, using morphological and mole-cular evolution methods. To assess the impact of strain MB1 on M. aeruginosa, we conducted an experiment in which we inoculated M. aeruginosa with Morchella strain MB1. After their co-cultivation for 4| |d, the inoculation with 0.9696| |g MB1 completely inhibited and removed M. aeruginosa while concurrently removing up to 95% of the MC content. Moreover, within 3| |d of their co-cultivation, MB1 removed more than 50% of nitrogen and phosphorus from the M. aeruginosa solution. Therefore, the development of effective biological techniques for MC removal is paramount in safeguarding both the environment and human well-being. We herein successfully isolated MB1 from its natural habitat. This strain effectively inhibited and removed M. aeruginosa and also reduced the content of nitrogen and phosphorus in the M. aeruginosa solution. Most importantly, it exhibited a robust capability to eliminate MCs. The present results offer a new method and technical reference for mitigating harmful algal blooms.

Synergistic Interaction of Ionic Liquid Grafted Poly(vinylidene Fluoride) and Carbon Nanotubes to Construct Water Treatment Membranes with Multiple Separation Properties.

In this study, the dual strategy of 1-butyl-3-vinylimidazolium bromide ionic liquid (IL) grafting and carbon nanotubes (CNTs) nanocomposition was applied to modify poly(vinylidene fluoride) (PVDF)-based membranes. The highly hydrophilic/oleophobic and fouling-resistant PVDF-g-IL/CNTs membranes with excellent separation efficiency were obtained by the nonsolvent-induced phase separation method with ethanol-water mixed solution as the coagulation bath. The grafted IL not only generated hydrophilic groups on PVDF chains but also acted together with the CNTs to induce the formation of hydrophilic ß-crystalline phase of PVDF, which significantly improved the hydrophilicity and pore structure of the modified PVDF membranes. As a result, the pure water flux of the optimal membrane increased up to 294.2 L m-2 h-1, which was 5.2 times greater than that of the pure PVDF membrane. Simultaneously, the electrostatic interaction of the positive IL and the integration of CNTs enhanced adsorption sites of the membranes, producing exceptional retention and adsorption of dye wastewater and oil-water emulsion. This study presents a straightforward and efficient approach for fabricating PVDF separation membranes, which have potential applications in the purification of various polluted wastewater.

Impact of Preseason Climate Factors on Vegetation Photosynthetic Phenology in Mid-High Latitudes of the Northern Hemisphere.

During the period preceding the vegetation growing season (GS), temperature emerges as the pivotal factor determining phenology in northern terrestrial ecosystems. Despite extensive research on the impact of daily mean temperature (Tmean) during the preseason period, the influence of diurnal temperature range (DTR) on vegetation photosynthetic phenology (i.e., the impact of the plant photosynthetic cycle on seasonal time scale) has largely been neglected. Using a long-term vegetation photosynthetic phenology dataset and historical climate data, we examine vegetation photosynthetic phenology dynamics and responses to climate change across the mid-high latitudes of the Northern Hemisphere from 2001 to 2020. Our data reveal an advancing trend in the start of the GS (SOS) by -0.15 days per year (days yr-1), affecting 72.1% of the studied area. This is particularly pronounced in western Canada, Alaska, eastern Asia, and latitudes north of 60°N. Conversely, the end of the GS (EOS) displays a delaying trend of 0.17 days yr-1, impacting 62.4% of the studied area, especially northern North America and northern Eurasia. The collective influence of an earlier SOS and a delayed EOS has resulted in the notably prolonged length of the GS (LOS) by 0.32 days yr-1 in the last two decades, affecting 70.9% of the studied area, with Eurasia and western North America being particularly noteworthy. Partial correlation coefficients of the SOS with preseason Tmean, DTR, and accumulated precipitation exhibited negative values in 98.4%, 93.0%, and 39.2% of the study area, respectively. However, there were distinct regional variations in the influence of climate factors on the EOS. The partial correlation coefficients of the EOS with preseason Tmean, DTR, and precipitation were positive in 58.6%, 50.1%, and 36.3% of the region, respectively. Our findings unveil the intricate mechanisms influencing vegetation photosynthetic phenology, holding crucial significance in understanding the dynamics of carbon sequestration within terrestrial ecosystems amidst climate change.

Genomic and biological control of Sclerotinia sclerotiorum using an extracellular extract from Bacillus velezensis 20507.

Introduction: Sclerotinia sclerotiorum is a known pathogen that harms crops and vegetables. Unfortunately, there is a lack of effective biological control measures for this pathogen. Bacillus velezensis 20507 has a strong antagonistic effect on S. Sclerotiorum; however, the biological basis of its antifungal effect is not fully understood. Methods: In this study, the broad-spectrum antagonistic microorganisms of B. velezensis 20507 were investigated, and the active antifungal ingredients in this strain were isolated, purified, identified and thermal stability experiments were carried out to explore its antifungal mechanism. Results: The B. velezensis 20507 genome comprised one circular chromosome with a length of 4,043,341 bp, including 3,879 genes, 185 tandem repeats, 87 tRNAs, and 27 rRNAs. Comparative genomic analysis revealed that our sequenced strain had the closest genetic relationship with Bacillus velezensis (GenBank ID: NC 009725.2); however, there were significant differences in the positions of genes within the two genomes. It is predicted that B. velezensis 20507 encode 12 secondary metabolites, including difficidin, macrolactin H, fengycin, surfactin, bacillibactin, bacillothiazole A-N, butirosin a/b, and bacillaene. Results showed that B. velezensis 20507 produced various antagonistic effects on six plant pathogen strains: Exserohilum turcicum, Pyricularia oryzae, Fusarium graminearum, Sclerotinia sclerotiorum, Fusarium oxysporum, and Fusarium verticillioides. Acid precipitation followed by 80% methanol leaching is an effective method for isolating the antifungal component ME80 in B. velezensis 20507, which can damage the membranes of S. sclerotiorum hyphae and has good heat resistance. Using high-performance liquid chromatography, and Mass Spectrometry analysis, it is believed that fengycin C72H110N12O20 is the main active antifungal substance. Discussion: This study provides new resources for the biological control of S. Sclerotiorum in soybeans and a theoretical basis for further clarification of the mechanism of action of B. velezensis 20507.

Identification, degradation characteristics, and application of a newly isolated pyridine-degrading Paracidovorax sp. BN6-4.

The Paracidovorax sp. BN6-4 capable of degrading high concentrations of pyridine was isolated from the coking sludge. The removal rate of BN6-4 to 1,000 mg/L pyridine during 48 h was 97.49 ±1.59%. The primary intermediate metabolites of pyridine degradation by strain BN6-4 were identified by gas chromatography-mass spectrometry (GC-MS), including N-Ethylurea, acetamidoacetaldehyde, and N-Hydroxymethylacetamide, etc. Subsequently, two different biodegradation pathways of pyridine were proposed. First, the hydroxylation of pyridine to form the intermediates pyridin-2(1H)-one and 5,6-dihydropyridine-2,5-diol, the former undergoing oxidative ring opening and the latter oxidative ring opening via N-C2 and C2-C3 ring opening to ammonia and carbon dioxide. Furthermore, the organic matter was greatly degraded by the bioremediation of real coking wastewater using BN6-4. This study enriched the microbial resource for pyridine degradation and provided new insights about the biodegradation pathway of pyridine, which is of great significance for the pyridine pollution control and coking wastewater treatment.

Distinguishing nitroimidazoles from nitrofurans via luminescence sensing.

Similarity of nitroimidazole and nitrofuran antibiotics in molecular structure and photophysical properties makes them difficult to distinguish via luminescence sensing technology. Herein, this is solved by a dye-encapsulated lanthanide metal-organic framework luminescent sensor.

Split household and smoking behaviour of rural migrants in China.

OBJECTIVES: This study aimed to address the direct impact of split households on smoking behaviour. Three types of spilt households (sole migration, couple migration, and family migration) were incorporated to explore the concise effect of different split household forms. This study also examined factors that contributed to the narrowing gap in smoking prevalence between 2008 and 2018. STUDY DESIGN: Retrospective observational study. METHODS: Data were obtained from the Rural Urban Migration (RUMiC-2009) and China Household Income Project (CHIP2018). Analyses were conducted using chi-squared tests/analysis of variance tests and multiple logit regression. The order probit model with sample selection was conducted to correct for selection bias. Fairlie decomposition was used to quantify the contribution of individual variables to the observed differences in smoking prevalence. RESULTS: Smoking prevalence for all migrants decreased by 5.79% between 2008 and 2018. The results in 2008 reveal the positive and significant contribution of couple migration (coefficient = -0.4608; 95% CI = [-0.6453, -0.2762]) and family migration (coefficient = -0.3705; 95% CI = [-0.5959, -0.1452]) on the reduction of smoking; the finding for family migration remained robust in 2018. Measurable factors partially explain the decline in smoking disparity. The migration of families, working in the construction and manufacturing industries, and educational attainment were the largest contributing factors to the declining gap in smoking prevalence. CONCLUSIONS: The increase in family migration and education, and decrease in the number of workers in the construction and manufacturing industries, contributed to a decrease in smoking prevalence. Public policies should target sole migrants, couple migrants, individuals with lower education levels, and those working in the construction and manufacturing industries.

Prevalence of hypertension and related risk factors in older Chinese population: a meta-analysis.

Objective: Hypertension is the most challenging public health problem worldwide and seriously affects human health. To date, there are no epidemiological studies on the prevalence of and risk factors for hypertension among older people in mainland China. Methods: We conducted a meta-analysis of the prevalence and risk factors of hypertension among the older population in mainland China. We searched Chinese and English databases for Chinese and English literature on hypertension epidemiology published between 2000 and 2022, and hypertension data among the older population were extracted from the included literature. A meta-analysis was performed using a random-effects model (I2 > 50%) with 95% confidence intervals for the forest plots. Data were processed using RevMan 5.3. Forty-nine publications (with data from 84,429 samples) met the evaluation criteria and were included in this study. Results: We found that the total prevalence of hypertension was 47%. The total prevalence rate of the older population in China from 2000 to 2010 was 50%, and the prevalence rate from 2011 to 2021 was 45%, with no significant differences. The total prevalence in Central China was the highest (59%). There was no significant correlation between the prevalence rate of the older population, sex, and urban or rural areas. Conclusion: Hypertension is common among the older population in China, and its control rate is low. Therefore, effective prevention and treatment measures, as well as education, should be formulated to improve the diagnosis and treatment of hypertension in the older population.

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin.

The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.

A unique subseafloor microbiosphere in the Mariana Trench driven by episodic sedimentation.

Hadal trenches are characterized by enhanced and infrequent high-rate episodic sedimentation events that likely introduce not only labile organic carbon and key nutrients but also new microbes that significantly alter the subseafloor microbiosphere. Currently, the role of high-rate episodic sedimentation in controlling the composition of the hadal subseafloor microbiosphere is unknown. Here, analyses of carbon isotope composition in a ~ 750 cm long sediment core from the Challenger Deep revealed noncontinuous deposition, with anomalous 14C ages likely caused by seismically driven mass transport and the funneling effect of trench geomorphology. Microbial community composition and diverse enzyme activities in the upper ~ 27 cm differed from those at lower depths, probably due to sudden sediment deposition and differences in redox condition and organic matter availability. At lower depths, microbial population numbers, and composition remained relatively constant, except at some discrete depths with altered enzyme activity and microbial phyla abundance, possibly due to additional sudden sedimentation events of different magnitude. Evidence is provided of a unique role for high-rate episodic sedimentation events in controlling the subsurface microbiosphere in Earth's deepest ocean floor and highlight the need to perform thorough analysis over a large depth range to characterize hadal benthic populations. Such depositional processes are likely crucial in shaping deep-water geochemical environments and thereby the deep subseafloor biosphere. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00212-y.

VvATG6 contributes to copper stress tolerance by enhancing the antioxidant ability in transgenic grape calli.

Autophagy, a conserved degradation and reuse process, plays a crucial role in plant cellular homeostasis during abiotic stress. Although numerous autophagy-related genes (ATGs) that regulate abiotic stress have been identified, few functional studies have shown how they confer tolerance to copper (Cu) stress. Here, we cloned a novel Vitis vinifera ATG6 gene (VvATG6) which was induced by 0.5 and 10 mM Cu stress based on transcriptomic data, and transgenic Arabidopsis thaliana, tobacco (Nicotiana tabacum), and grape calli were successfully obtained through Agrobacterium-mediated genetic transformation. The overexpression of VvATG6 enhanced the tolerance of transgenic lines to Cu. After Cu treatment, the lines that overexpressed VvATG6 grew better and increased their production of biomass compared with the wild-type. These changes were accompanied by higher activities of antioxidant enzymes and a lower accumulation of deleterious malondialdehyde and hydrogen peroxide in the transgenic plants. The activities of superoxide dismutase, peroxidase, and catalase were enhanced owing to the elevation of corresponding antioxidant gene expression in the VvATG6 overexpression plants under Cu stress, thereby promoting the clearance of reactive oxygen species (ROS). Simultaneously, there was a decrease in the levels of expression of RbohB and RbohC that are involved in ROS synthesis in transgenic plants under Cu stress. Thus, the accelerated removal of ROS and the inhibition of its synthesis led to a balanced ROS homeostasis environment, which alleviated the damage from Cu. This could benefit from the upregulation of other ATGs that are necessary for the production of autophagosomes under Cu stress. To our knowledge, this study is the first to demonstrate the protective role of VvATG6 in the Cu tolerance of plants. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01415-y.

Evolving copy number gains promote tumor expansion and bolster mutational diversification.

The timing and fitness effect of somatic copy number alterations (SCNA) in cancer evolution remains poorly understood. Here we present a framework to determine the timing of a clonal SCNA that encompasses multiple gains. This involves calculating the proportion of time from its last gain to the onset of population expansion (lead time) as well as the proportion of time prior to its first gain (initiation time). Our method capitalizes on the observation that a genomic segment, while in a specific copy number (CN) state, accumulates point mutations proportionally to its CN. Analyzing 184 whole genome sequenced samples from 75 patients across five tumor types, we commonly observe late gains following early initiating events, occurring just before the clonal expansion relevant to the sampling. These include gains acquired after genome doubling in more than 60% of cases. Notably, mathematical modeling suggests that late clonal gains may contain final-expansion drivers. Lastly, SCNAs bolster mutational diversification between subpopulations, exacerbating the circle of proliferation and increasing heterogeneity.