BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.

Machine learning-based identification of colorectal advanced adenoma using clinical and laboratory data: a phase I exploratory study in accordance with updated World Endoscopy Organization guidelines for noninvasive colorectal cancer screening tests.

Objective: The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. Methods: We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. Results: The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. Conclusion: The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons.

Adenoma location, size, and morphology are risk factors for FOBT false-negative results in inpatients with advanced colorectal adenoma.

Recently, advanced adenoma (AA) has been recognized as a target for colorectal cancer (CRC) screening. However, the fecal occult blood test (FOBT), the primary non-invasive screening method, shows limited sensitivity in detecting AA. This study investigates the relationship between adenoma characteristics and FOBT false-negative results. In a retrospective cohort study conducted from 2015 to 2022, we examined 342 inpatients with AA who underwent colonoscopy and received qualitative FOBT. FOBT sensitivity was analyzed about various adenoma characteristics, and logistic regression models were employed to investigate the relationship between adenoma features and FOBT false-negative outcomes. FOBT sensitivity in AA inpatients was 52.63%. Significant differences in sensitivity were observed based on adenoma location (left vs. right), morphology (with or without pedunculation), and size (≤ 10 mm vs. > 10 mm). After adjusting for several potential confounders, FOBT showed a reduced false-negative rate in AA with large-sized (OR, 0.49; 95% CI 0.31-0.77), left-sided location (OR, 0.53; 95% CI 0.31-0.89), and pedunculated morphology (OR, 0.73; 95% CI 0.43-1.24). AA with large size, left-sided location, and pedunculated morphology independently contribute to a decreased rate of FOBT false-negative results. However, these adenoma characteristics are not actively modifiable. Therefore, novel non-invasive methods are needed to improve AA detection accuracy.

Improved stereo perception in coronary angiography using the X-ray tube as the viewpoint and validation with 3D printed models.

Coronary angiography (CAG) provides two-dimensional images, but a clinician who is experienced in percutaneous coronary interventions can use information from these images to interpret spatial depth and infer the three-dimensional (3D) locations of vessels. We hypothesized that CAG results were equivalent to the mirror image of a coronary artery perspective projection, and a stereo perception could be easily established when the viewpoint of the angiogram was the X-ray tube instead of the detector. To eliminate the influence of heartbeat and respiration, a 3D-printed a coronary artery model was constructed for analysis. The effects of gantry movements during digital subtraction angiography (DSA) on the image were used to identify factors that affected DSA image transformation. Then, based on these factors, DSA imaging was simulated using UG NX software with three methods: (i) a perspective projection with the detector as the viewpoint; (ii) a parallel projection; and (iii) a mirror image of the perspective projection with the X-ray tube as the viewpoint. Finally, the resulting 3D images were compared with the DSA image. Our mirror image of the coronary artery perspective projection that used the X-ray tube as the viewpoint fused precisely with the CAG results and provided exact simulations of all the effects of DSA gantry movements on the DSA image. CAG results were equivalent to the mirror image of coronary artery perspective projection, and the stereo perception was easily established using the X-ray tube as the viewpoint.

Role of circadian clock in the chronoefficacy and chronotoxicity of clopidogrel.

BACKGROUND AND PURPOSE: The role of circadian locomotor output cycles kaput (CLOCK) in regulating drug chronoefficacy and chronotoxicity remains elusive. Here, we aimed to uncover the impact of CLOCK and dosing time on clopidogrel efficacy and toxicity. EXPERIMENTAL APPROACH: The antiplatelet effect, toxicity and pharmacokinetics experiments were conducted with Clock-/- mice and wild-type mice, after gavage administration of clopidogrel at different circadian time points. The expression levels of drug-metabolizing enzymes were determined by quantitative polymerase chain reaction (qPCR) and western blotting. Transcriptional gene regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. KEY RESULTS: The antiplatelet effect and toxicity of clopidogrel in wild-type mice showed a dosing time-dependent variation. Clock ablation reduced the antiplatelet effect of clopidogrel, but increased clopidogrel-induced hepatotoxicity, with attenuated rhythms of clopidogrel active metabolite (Clop-AM) and clopidogrel, respectively. We found that Clock regulated the diurnal variation of Clop-AM formation by modulating the rhythmic expression of CYP1A2 and CYP3A1, and altered clopidogrel chronopharmacokinetics by regulation of CES1D expression. Mechanistic studies revealed that CLOCK activated Cyp1a2 and Ces1d transcription by directly binding to the enhancer box (E-box) elements in their promoters, and promoted Cyp3a11 transcription through enhancing the transactivation activity of albumin D-site-binding protein (DBP) and thyrotroph embryonic factor (TEF). CONCLUSIONS AND IMPLICATIONS: CLOCK regulates the diurnal rhythmicity in clopidogrel efficacy and toxicity through regulation of CYP1A2, CYP3A11 and CES1D expression. These findings may contribute to optimizing dosing schedules for clopidogrel and may deepen understanding of the circadian clock and chronopharmacology.

Break-induced replication orchestrates resection-dependent template switching.

Break-induced telomere synthesis (BITS) is a RAD51-independent form of break-induced replication that contributes to alternative lengthening of telomeres1,2. This homology-directed repair mechanism utilizes a minimal replisome comprising proliferating cell nuclear antigen (PCNA) and DNA polymerase-δ to execute conservative DNA repair synthesis over many kilobases. How this long-tract homologous recombination repair synthesis responds to complex secondary DNA structures that elicit replication stress remains unclear3-5. Moreover, whether the break-induced replisome orchestrates additional DNA repair events to ensure processivity is also unclear. Here we combine synchronous double-strand break induction with proteomics of isolated chromatin segments (PICh) to capture the telomeric DNA damage response proteome during BITS1,6. This approach revealed a replication stress-dominated response, highlighted by repair synthesis-driven DNA damage tolerance signalling through RAD18-dependent PCNA ubiquitination. Furthermore, the SNM1A nuclease was identified as the major effector of ubiquitinated PCNA-dependent DNA damage tolerance. SNM1A recognizes the ubiquitin-modified break-induced replisome at damaged telomeres, and this directs its nuclease activity to promote resection. These findings show that break-induced replication orchestrates resection-dependent lesion bypass, with SNM1A nuclease activity serving as a critical effector of ubiquitinated PCNA-directed recombination in mammalian cells.

Optimization of the N footprint model and analysis of nitrogen pollution in irrigation areas: A case study of Ningxia Hui Autonomous Region, China.

Water diverted from rivers for irrigation areas often contains large amounts of nitrogen (N), which is frequently overlooked and its role in contributing to N pollution is unknown. To investigate the influence of water diversion on N in different systems within irrigation areas, we developed and optimized the N footprint model, taking into account the N carried by irrigation water diversion and drainage in irrigated areas. This optimized model can serve as a reference for evaluating N pollution in other irrigated areas. By analyzing 29 years (1991-2019) of statistical data from a diverted irrigation area in Ningxia Hui Autonomous Region (Ningxia), China, the study assessed the contribution of water diversion to N in agriculture, animal husbandry, and human domestic activities. The results demonstrated that water diversion and drainage accounted for 10.3% and 13.8% in whole system, of the total N input and output in Ningxia, highlighting the potential N pollution risks associated with these activities. Additionally, the use of fertilizers in the plant subsystem, feed in the animal subsystem, and sanitary sewage in the human subsystem represented the main sources of N pollution in each subsystem. On a temporal scale, the study found that N loss increased year by year before reaching a stable level, indicating that N loss had reached its peak in Ningxia. The correlation analysis suggested that rainfall could regulate N input and output in irrigated areas by showing a negative correlation with water diversion, agricultural water consumption, and N from irrigated areas. Moreover, the study revealed that the amount of N brought by water diverted from rivers for irrigation should be taken into account when calculating the amount of fertilizer N required in the irrigation area.

Establishment of clinical predictive model based on the study of influence factors in patients with colorectal polyps.

Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy and is generally thought to be caused by the transformation of colorectal polyps. It has been shown that early detection and removal of colorectal polyps may reduce the mortality and morbidity of colorectal cancer. Objective: Based on the risk factors associated with colorectal polyps, an individualized clinical prediction model was built to predict and evaluate the possibility of developing colorectal polyp. Methods: A case-control study was conducted. Clinical data were collected from 475 patients who underwent colonoscopy at the Third Hospital of Hebei Medical University from 2020 to 2021. All clinical data were then divided into training sets and validation sets by using R software (7:3). A multivariate logistic analysis was performed to identify the factors associated with colorectal polyps according to the training set, and a predictive nomogram was created by R software based on the multivariate analysis. The results were internally validated by receiver operating characteristic (ROC) curves, calibration curves, and externally validated by validation sets. Results: Multivariate logistic regression analysis showed that age (OR = 1.047, 95% CI = 1.029-1.065), history of cystic polyp (OR = 7.596, 95% CI = 0.976-59.129), and history of colorectal diverticulums (OR = 2.548, 95% CI = 1.209-5.366) were independent risk factors for colorectal polyps. History of constipation (OR = 0.457, 95% CI = 0.268-0.799) and fruit consumption (OR = 0.613, 95% CI 0.350-1.037) were protective factors for colorectal polyps. The nomogram demonstrated good accuracy for predicting colorectal polyps, with both C index and AUC being 0.747 (95% CI = 0.692-0.801). The calibration curves showed good agreement between the predicted risk by the nomogram and real outcomes. Both internal and external validation of the model showed good results. Conclusion: In our study, the nomogram prediction model is reliable and accurate, which can help early clinical screening of patients with high-risk colorectal polyps, improve polyp detection rate, and reduce the incidence of colorectal cancer (CRC).

Comparing critical source areas for the sediment and nutrients of calibrated and uncalibrated models in a plateau watershed in southwest China.

Controlling non-point source pollution is often difficult and costly. Therefore, focusing on areas that contribute the most, so-called critical source areas (CSAs), can have economic and ecological benefits. CSAs are often determined using a modelling approach, yet it has proved difficult to calibrate the models in regions with limited data availability. Since identifying CSAs is based on the relative contributions of sub-basins to the total load, it has been suggested that uncalibrated models could be used to identify CSAs to overcome data scarcity issues. Here, we use the SWAT model to study the extent to which an uncalibrated model can be applied to determine CSAs. We classify and rank sub-basins to identify CSAs for sediment, total nitrogen (TN), and total phosphorus (TP) in the Fengyu River Watershed (China) with and without model calibration. The results show high similarity (81%-93%) between the identified sediment and TP CSA number and locations before and after calibration both on the yearly and seasonal scale. For TN alone, the results show moderate similarity on the yearly scale (73%). This may be because, in our study area, TN is determined more by groundwater flow after calibration than by surface water flow. We conclude that CSA identification with the uncalibrated model for TP is always good because its CSA number and locations changed least, and for sediment, it is generally satisfactory. The use of the uncalibrated model for TN is acceptable, as its CSA locations did not change after calibration; however, the TN CSA number changed by over 60% compared to the figures before calibration on both yearly and seasonal scales. Therefore, we advise using an uncalibrated model to identify CSAs for TN only if water yield composition changes are expected to be limited. This study shows that CSAs can be identified based on relative loading estimates with uncalibrated models in data-deficient regions.

An Update on Gemcitabine-Based Chemosensitization Strategies in Pancreatic Ductal Adenocarcinoma.

Pancreatic cancer is the seventh leading cause of cancer-related deaths, and chemotherapy is one of the most important treatments for pancreatic cancer. Unfortunately, pancreatic cancer cells can block chemotherapy drugs from entering the tumor. This is owing to interactions between the tumor's environment and the cancer cells. Here, we review the latest research on the mechanisms by which pancreatic cancer cells block the chemotherapy drug, gemcitabine. The results of our review can help identify potential therapeutic targets for the blocking of gemcitabine by pancreatic cancer cells and may provide new strategies to help chemotherapy drugs penetrate tumors.

MicroRNA-378a-3p prevents initiation and growth of colorectal cancer by fine tuning polyamine synthesis.

BACKGROUND: Inhibitors of ornithine decarboxylase (ODC) are effective at preventing colorectal cancer (CRC). However, their high toxicity limits their clinical application. This study was aimed to explore the potential of microRNAs (miRNAs) as an inhibitor of ODC. METHODS: miRNA array was used to identify dysregulated miRNAs in CRC tumors of mice and patients. Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) were used to induce CRC in mice. miRNA function in carcinogenesis was determined by soft-agar colony formation, flow cytometry, and wound healing of CRC cells. Mini-circle was used to deliver miRNA into colons. RESULTS: MiRNA profiling identified miR-378a-3p (miR-378a) as the most reduced miRNA in CRC tumors of patients and mice treated with AOM/DSS. Pathway array analysis revealed that miR-378a impaired c-MYC and ODC1 pathways. Further studies identified FOXQ1 (forkhead box Q1) and ODC1 as two direct targets of miR-378a. FOXQ1 activated transcription of c-MYC, a transcription activator of ODC1. In addition to directly targeting ODC1, miR-378a also inhibited expression of ODC1 via the FOXQ1-cMYC axis, thereby inhibiting polyamine synthesis in human CRC cells. Phenotypically, by reducing polyamine synthesis, miR-378a induced apoptosis and inhibited proliferation and migration of CRC cells, while disrupting the association of miR-378a with FOXQ1 and ODC1 offset the effects of miR-378a, suggesting that FOXQ1 and ODC1 were required for miR-378a to inhibit CRC cell growth. MiR-378a treatment robustly prevented growth of HCC by inhibiting polyamine synthesis in AOM/DSS mice. CONCLUSION: MiR-378a prevents CRC by inhibiting polyamine synthesis, suggesting its use as a novel ODC inhibitor against CRC.

Circadian oscillator NPAS2 regulates diurnal expression and activity of CYP1A2 in mouse liver.

We aimed to investigate the potential role of NPAS2 in controlling diurnal expression and activity of hepatic CYP1A2 and to determine the underlying mechanisms. Regulatory effects of NPAS2 on CYP1A2 were determined using Npas2 knockout (Npas2-/-) mice as well as AML-12, Hepa1-6 and HepG2 cells. mRNA and protein levels were detected by reverse transcription-quantitative real-time PCR and western blotting, respectively. In vitro and in vivo CYP1A2 activities were respectively evaluated using the probe substrates phenacetin and theophylline. Transcriptional regulation was investigated using luciferase reporter assays and ChIP-Seq analysis. Loss of Npas2 in mice decreased CYP1A2 expression (at both mRNA and protein levels) and blunted its rhythmicity in the liver. Likewise, Npas2 ablation down-regulated the enzymatic activity of CYP1A2 (probed by metabolism of phenacetin and theophylline) and abrogated its time-dependency. Cell-based assays confirmed that NPAS2 positively regulated CYP1A2 expression. Mechanistic study indicated that NPAS2 trans-activated Cyp1a2 through its specific binding to the -416 bp E-box-like element within the gene promoter. In conclusion, NPAS2 was identified as a key transcriptional regulator of diurnal expression of hepatic CYP1A2 in mice. Our findings have implications for improved understanding of circadian metabolism and chronopharmacokinetics.

ScCBF1 plays a stronger role in cold, salt and drought tolerance than StCBF1 in potato (Solanum tuberosum).

Solanum tuberosum (St) and Solanum commersonii (Sc) are two potato varieties with different freezing tolerance. Among them, St is a freezing-sensitive variety and. Sc is a cold-resistant wild potato. CBF/DREB family members mainly function in response to freezing stress. In order to explore the different roles of St C-Repeat Binding Factor1 (StCBF1) and Sc C-Repeat Binding Factor1 (ScCBF1) in potato plants (Solanum tuberosum) under stress conditions, two kinds of potato lines were obtained with ScCBF1 and StCBF1 overexpressing respectively. Phenotypes analysis showed that both overexpressing ScCBF1 and StCBF1 caused smaller leaves, and reduced tuber yield. While the limited phenotypes of StCBF1 lines were more severe than that of ScCBF lines. After freezing treatment, StCBF1 over expression plants grown better than WT plants and worse than ScCBF1 over expression plants. Specifically, compared with wild-type lines, overexpressing ScCBF1 could up-regulate fatty acid desaturase genes, key enzyme of Calvin cycle genes, and antioxidant enzyme genes. Both ScCBF1 and StCBF1 lines showed higher PSII activity, thus maintaining a higher photosynthetic rate under cold stress. In addition, we also found that overexpression ScCBF1 and StCBF1 could also enhance the drought and salt tolerance in potato. In summary, ScCBF1 plays a stronger role in cold, salt, and drought tolerance than StCBF1 in potato (Solanum tuberosum).

Spatio-temporal variation of net anthropogenic nitrogen inputs (NANI) from 1991 to 2019 and its impacts analysis from parameters in Northwest China.

At present, excessive nutrient inputs caused by human activities have resulted in environmental problems such as agricultural non-point source pollution and water eutrophication. The Net Anthropogenic Nitrogen Inputs (NANI) model can be used to estimate the nitrogen (N) inputs to a region that are related to human activities. To explore the net nitrogen input of human activities in the main grain-producing areas of Northwestern China, the county-level statistical data for the Ningxia province and NANI model parameters were collected, the spatio-temporal distribution characteristics of NANI were analyzed and the uncertainty and sensitivity of the parameters for each component of NANI were quantitatively studied. The results showed that: (1) The average value of NANI in Ningxia from 1991 to 2019 was 7752 kg N km-2 yr-1. Over the study period, the inputs first showed an overall increase, followed by a decrease, and then tended to stabilize. Fertilizer N application was the main contributing factor, accounting for 55.6%. The high value of NANI in Ningxia was mainly concentrated in the Yellow River Diversion Irrigation Area. (2) The 95% confidence interval of NANI obtained by the Monte Carlo approach was compared with the results from common parameters in existing literature. The simulation results varied from -6.4% to 27.4% under the influence of the changing parameters. Net food and animal feed imports were the most uncertain input components affected by parameters, the variation range was -20.7%-77%. (3) The parameters of inputs that accounted for higher proportions of the NANI were more sensitive than the inputs with lower contributions. The sensitivity indexes of the parameters contained in the fertilizer N applications were higher than those of net food and animal feed imports and agricultural N-fixation. This study quantified the uncertainty and sensitivity of parameters in the process of NANI simulation and provides a reference for global peers in the application and selection of parameters to obtain more accurate simulation results.

Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy.

Dependence of pharmacokinetics and drug effects (efficacy and toxicity) on dosing time has long been recognized. However, significant progress has only recently been made in our understanding of circadian rhythms and their regulation on drug pharmacokinetics, efficacy and toxicity. This review will cover the relevant literature and a series of publications from our work summarizing the effects of circadian rhythms on drug pharmacokinetics, and propose that the influence of circadian rhythms on pharmacokinetics are ultimately translated into therapeutic effects and side effects of drugs. Evidence suggests that daily rhythmicity in expression of drug-metabolizing enzymes and transporters necessary for drug ADME (absorption, distribution, metabolism and excretion) are key factors determining circadian pharmacokinetics. Newly discovered mechanisms for circadian control of the enzymes and transporters are covered. We also discuss how the rhythms of drug-processing proteins are translated into circadian pharmacokinetics and drug chronoefficacy/chronotoxicity, which has direct implications for chronotherapy. More importantly, we will present perspectives on the challenges that are still needed for a breakthrough in translational research. In addition, knowledge of the circadian influence on drug disposition has provided new possibilities for novel pharmacological strategies. Careful application of pharmacokinetics-based chronotherapy strategies can improve efficacy and reduce toxicity. Circadian rhythm-mediated metabolic and transport strategies can also be implemented to design drugs.

E4BP4 Coordinates Circadian Control of Cognition in Delirium.

Improved understanding of the etiologies of delirium, a common and severe neuropsychiatric syndrome, would facilitate the disease prevention and treatment. Here, the authors invesitgate the role of circadian rhythms in the pathogenesis of delirium. They observe perturbance of circadian rhythms in mouse models of delirium and disrupted clock gene expression in patients with delirium. In turn, physiological and genetic circadian disruptions sensitize mice to delirium with aggravated cognitive impairment. Likewise, global deletion of E4bp4 (E4 promoter-binding protein), a clock gene markedly altered in delirium conditions, results in exacerbated delirium-associated cognitive decline. Cognitive decline in delirium models is attributed to microglial activation and impaired long-term potentiation in the hippocampus. Single-cell RNA-sequencing reveals microglia as the regulatory target of E4bp4. E4bp4 restrains microglial activation via inhibiting the ERK1/2 signaling pathway. Supporting this, mice lacking in microglial E4bp4 are delirious prone, whereas mice with E4bp4 specifically deleted in hippocampal CA1 neurons have a normal phenotype. Mechanistically, E4bp4 inhibits ERK1/2 signaling by trans-repressing Mapk1/3 (genes encoding ERK1/2) via direct binding to a D-box element in the promoter region. These findings define a causal role of clock dysfunction in delirium development and indicate E4bp4 as a regulator of cognition at the crosstalk between circadian clock and delirium.

The Clock gene regulates kainic acid-induced seizures through inhibiting ferroptosis in mice.

OBJECTIVES: Temporal lobe epilepsy (TLE) is a common and intractable form of epilepsy. There is a strong need to better understand molecular events underlying TLE and to find novel therapeutic agents. Here we aimed to investigate the role of Clock and ferroptosis in regulating TLE. METHODS: TLE model was established by treating mice with kainic acid (KA). Regulatory effects of the Clock gene on KA-induced seizures and ferroptosis were evaluated using Clock knockout (Clock-/-) mice. mRNA and protein levels were determined by quantitative real-time PCR and western blotting, respectively. Ferroptosis was assessed by measuring the levels of iron, GSH and ROS. Transcriptional regulation was studied using a combination of luciferase reporter, mobility shift and chromatin immunoprecipitation (ChIP) assays. KEY FINDINGS: We found that Clock ablation exacerbated KA-induced seizures in mice, accompanied by enhanced ferroptosis in the hippocampus. Clock ablation reduced the hippocampal expression of GPX4 and PPAR-γ, two ferroptosis-inhibitory factors, in mice and in N2a cells. Moreover, Clock regulates diurnal expression of GPX4 and PPAR-γ in mouse hippocampus and rhythmicity in KA-induced seizures. Consistent with this finding, Clock overexpression up-regulated GPX4 and PPAR-γ and protected against ferroptosis in N2a cells. In addition, luciferase reporter, mobility shift and ChIP assays showed that CLOCK trans-activated Gpx4 and Ppar-γ through direct binding to the E-box elements in the gene promoters. CONCLUSION: CLOCK protects against KA-induced seizures through increased expression of GPX4 and PPAR-γ and inhibition of ferroptosis.

Production Task Allocation Decision Based on Cloud Robot Cell-Line.

Cloud manufacturing is a new service-oriented efficient and low-consumption agile manufacturing mode integrating information, manufacturing, Internet of Things, and other technologies. One of the key decisions of production enterprises is production task allocation based on cloud robot cell-line, which determines the efficiency and flexibility of the production system and affects various production links, such as job-shop logistics, production planning, and production scheduling. This paper explores the production task allocation, from the angle of the optimal combination of cloud manufacturing resources. First, a mathematical model was established, based on the transport cost of different sub-tasks and the tardiness cost of product delivery, and solved by quantum firefly algorithm (QFA). Next, QFA was proved superior to traditional firefly algorithm (FA), improved FA, and the FA optimized by cat swarm optimization (CSO-FA), in terms of time complexity and spatial complexity. The research enriches the theory and methodology of allocating operation-level cloud manufacturing resources based on cloud robot cell-line and provides decision support to manufacturers, which want to implement operation-level allocation of cloud manufacturing resources based on cloud robot cell-line.

Glycinebetaine mitigates tomato chilling stress by maintaining high-cyclic electron flow rate of photosystem I and stability of photosystem II.

KEY MESSAGE: Glycinebetaine alleviates chilling stress by protecting photosystems I and II in BADH-transgenic and GB-treated tomato plants, which can be an effective strategy for improving crop chilling tolerance. Tomato (Solanum lycopersicum) is one of the most cultivated vegetables in the world, but is highly susceptible to chilling stress and does not naturally accumulate glycinebetaine (GB), one of the most effective stress protectants. The protective mechanisms of GB on photosystem I (PSI) and photosystem II (PSII) against chilling stress, however, remain poorly understood. Here, we address this problem through exogenous GB application and generation of transgenic tomatoes (Moneymaker) with a gene encoding betaine aldehyde dehydrogenase (BADH), which is the key enzyme in the synthesis of GB, from spinach. Our results demonstrated that GB can protect chloroplast ultramicrostructure, alleviate PSII photoinhibition and maintain PSII stability under chilling stress. More importantly, GB increased the electron transfer between QA and QB and the redox potential of QB and maintained a high rate of cyclic electron flow around PSI, contributing to reduced production of reactive oxygen species, thereby mitigating PSI photodamage under chilling stress. Our results highlight the novel roles of GB in enhancing chilling tolerance via the protection of PSI and PSII in BADH transgenic and GB-treated tomato plants under chilling stress. Thus, introducing GB-biosynthetic pathway into tomato and exogenous GB application are effective strategies for improving chilling tolerance.