Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.

Temporal patterns of organ dysfunction in COVID-19 patients hospitalized in the intensive care unit: A group-based multitrajectory modelling analysis.

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyse the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modelling (GBMTM). RESULTS: 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n=64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n=140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n=117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n=71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.

Effectiveness and safety of Buzzy device in needle-related procedures for children under twelve years of age: A systematic review and meta-analysis.

BACKGROUND: Pain transcends simple physiology, encompassing biological, emotional, psychological, and social facets. Children show pronounced immediate and enduring responses to pain-related procedures. The aim of this meta-analysis is to investigate the efficacy and safety of the Buzzy device for needle-related procedures in children aged twelve years or younger. METHODS: PubMed, Web of Science, and Embase were searched from inception to July 2023. Only randomized controlled trials utilizing the Buzzy device for needle-related procedures in children under twelve years old were included. Two reviewers independently conducted study selection, data extraction, and risk of bias assessment. Random-effects models were utilized, and analyses were performed using mean differences or standardized mean differences as well as risk ratios. RESULTS: A total of 19 studies were included, involving 2846 participants (Buzzy = 1095, Control = 1751). Compared to no intervention, the Buzzy device significantly reduced pain response [self-report SMD = -1.90 (-2.45, -1.36), parental SMD = -3.04 (-4.09, -1.99), observer SMD = -2.88 (-3.75, -2.02)] and anxiety scores [self-report SMD = -1.97 (-3.05, -0.88), parental SMD = -2.01 (-2.93, -1.08), observer SMD = -1.92 (-2.64, -1.19)]. Compared to virtual reality (VR), the Buzzy device reduced self-reported anxiety levels SMD = -0.47 (-0.77, -0.17), and compared to distraction cards, the Buzzy device reduced parental and observer-reported pain [parental SMD = -0.85 (-1.22, -0.48), observer SMD = -0.70 (-1.00, -0.40)] and anxiety [parental SMD = -0.96 (-1.46, -0.47), observer SMD = -0.91 (-1.40, -0.42)]. Subgroup analysis results showed that procedure type, patient age, measurement scales used, and distance of operation were not the reason of heterogeneity. The summarized first puncture attempt success rate did not differ from other interventions. There were no significant adverse events in the included studies. CONCLUSION: The Buzzy device reduces pain and anxiety in children during needle procedures, ensuring success and safety. Additionally, the effectiveness of the Buzzy device in reducing pain during venipuncture is superior when compared to its effectiveness during intramuscular injections.

Phage selection drives resistance-virulence trade-offs in Ralstonia solanacearum plant-pathogenic bacterium irrespective of the growth temperature.

While temperature has been shown to affect the survival and growth of bacteria and their phage parasites, it is unclear if trade-offs between phage resistance and other bacterial traits depend on the temperature. Here, we experimentally compared the evolution of phage resistance-virulence trade-offs and underlying molecular mechanisms in phytopathogenic Ralstonia solanacearum bacterium at 25 °C and 35 °C temperature environments. We found that while phages reduced R. solanacearum densities relatively more at 25 °C, no difference in the final level of phage resistance was observed between temperature treatments. Instead, small colony variants (SCVs) with increased growth rate and mutations in the quorum-sensing (QS) signaling receptor gene, phcS, evolved in both temperature treatments. Interestingly, SCVs were also phage-resistant and reached higher frequencies in the presence of phages. Evolving phage resistance was costly, resulting in reduced carrying capacity, biofilm formation, and virulence in planta, possibly due to loss of QS-mediated expression of key virulence genes. We also observed mucoid phage-resistant colonies that showed loss of virulence and reduced twitching motility likely due to parallel mutations in prepilin peptidase gene, pilD. Moreover, phage-resistant SCVs from 35 °C-phage treatment had parallel mutations in type II secretion system (T2SS) genes (gspE and gspF). Adsorption assays confirmed the role of pilD as a phage receptor, while no loss of adsorption was found with phcS or T2SS mutants, indicative of other downstream phage resistance mechanisms. Additional transcriptomic analysis revealed upregulation of CBASS and type I restriction-modification phage defense systems in response to phage exposure, which coincided with reduced expression of motility and virulence-associated genes, including pilD and type II and III secretion systems. Together, these results suggest that while phage resistance-virulence trade-offs are not affected by the growth temperature, they could be mediated through both pre- and postinfection phage resistance mechanisms.

Single-photon ranging lidar based on multi-repetition-rate pulse train correlation and accumulation.

A single-photon lidar based on multi-repetition-rate pulse train correlation and accumulation is proposed, and a ranging experiment is conducted on a 32 m target. By accumulating the correlation ranging results of pulse trains with internal spacings of 80, 100, and 125 ns, the signal-to-noise ratio of the cross correlation function is improved by about three-fold, which enables our method to improve the ranging precisions by more than 20% compared with the single repetition-rate method, and the shorter the acquisition time, the more obvious the advantage will be. Experimental results show that at an acquisition time of 0.01 s, our method can still achieve a ranging precision of 2.59 cm, while the single repetition-rate method can no longer obtain effective ranging results at this time. This method will be of great significance for realizing high-speed, large-scale unambiguous single-photon lidar ranging.

Optimizing biochar application for enhanced cotton and sugar beet production in Xinjiang: a comprehensive study.

BACKGROUND: Optimizing biochar application is vital for enhancing crop production and ensuring sustainable agricultural production. A 3-year field experiment was established to explore the effects of varying the biochar application rate (BAR) on crop growth, quality, productivity and yields. BAR was set at 0, 10, 50 and 100 t ha-1 in 2018; 0, 10, 25, 50 and 100 t ha-1 in 2019; and 0, 10, 25 and 30 t ha-1 in 2020. Crop quality and growth status and production were evaluated using the dynamic technique for order preference by similarity to ideal solution with the entropy weighted method (DTOPSIS-EW), principal component analysis (PCA), membership function analysis (MFA), gray relation analysis (GRA) and the fuzzy Borda combination evaluation method. RESULTS: Low-dose BAR (≤ 25 t ha-1 for cotton; ≤ 50 t ha-1 for sugar beet) effectively increased biomass, plant height, leaf area index (LAI), water and fertility (N, P and K) productivities, and yield. Biochar application increased the salt absorption and sugar content in sugar beet, with the most notable increases being 116.45% and 20.35%, respectively. Conversely, BAR had no significant effect on cotton fiber quality. The GRA method was the most appropriate for assessing crop growth and quality. The most indicative parameters for reflecting cotton and sugarbeet growth and quality status were biomass and LAI. The 10 t ha-1 BAR consistently produced the highest scores and was the most economically viable option, as evaluated by DTOPSIS-EW. CONCLUSION: The optimal biochar application strategy for improving cotton and sugar beet cultivation in Xinjiang, China, is 10 t ha-1 biochar applied continuously. © 2024 Society of Chemical Industry.

Genetic fusion of CCL11 to antigens enhances antigenicity in nucleic acid vaccines and eradicates tumor mass through optimizing T-cell response.

Nucleic acid vaccines have shown promising potency and efficacy for cancer treatment with robust and specific T-cell responses. Improving the immunogenicity of delivered antigens helps to extend therapeutic efficacy and reduce dose-dependent toxicity. Here, we systematically evaluated chemokine-fused HPV16 E6/E7 antigen to improve the cellular and humoral immune responses induced by nucleotide vaccines in vivo. We found that fusion with different chemokines shifted the nature of the immune response against the antigens. Although a number of chemokines were able to amplify specific CD8 + T-cell or humoral response alone or simultaneously. CCL11 was identified as the most potent chemokine in improving immunogenicity, promoting specific CD8 + T-cell stemness and generating tumor rejection. Fusing CCL11 with E6/E7 antigen as a therapeutic DNA vaccine significantly improved treatment effectiveness and caused eradication of established large tumors in 92% tumor-bearing mice (n = 25). Fusion antigens with CCL11 expanded the TCR diversity of specific T cells and induced the infiltration of activated specific T cells, neutrophils, macrophages and dendritic cells (DCs) into the tumor, which created a comprehensive immune microenvironment lethal to tumor. Combination of the DNA vaccine with anti-CTLA4 treatment further enhanced the therapeutic effect. In addition, CCL11 could also be used for mRNA vaccine design. To summarize, CCL11 might be a potent T cell enhancer against cancer.

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer's disease.

JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.

Identification of molecular subtypes and a prognostic signature based on m6A/m5C/m1A-related genes in lung adenocarcinoma.

Lung cancer, specifically the histological subtype lung adenocarcinoma (LUAD), has the highest global occurrence and fatality rate. Extensive research has indicated that RNA alterations encompassing m6A, m5C, and m1A contribute actively to tumorigenesis, drug resistance, and immunotherapy responses in LUAD. Nevertheless, the absence of a dependable predictive model based on m6A/m5C/m1A-associated genes hinders accurately predicting the prognosis of patients diagnosed with LUAD. In this study, we collected patient data from The Cancer Genome Atlas (TCGA) and identified genes related to m6A/m5C/m1A modifications using the GeneCards database. The "ConsensusClusterPlus" R package was used to produce molecular subtypes by utilizing genes relevant to m6A/m5C/m1A identified through differential expression and univariate Cox analyses. An independent prognostic factor was identified by constructing a prognostic signature comprising six genes (SNHG12, PABPC1, IGF2BP1, FOXM1, CBFA2T3, and CASC8). Poor overall survival and elevated expression of human leukocyte antigens and immune checkpoints were correlated with higher risk scores. We examined the associations between the sets of genes regulated by m6A/m5C/m1A and the risk model, as well as the immune cell infiltration, using algorithms such as ESTIMATE, CIBERSORT, TIMER, ssGSEA, and exclusion (TIDE). Moreover, we compared tumor stemness indices (TSIs) by considering the molecular subtypes related to m6A/m5C/m1A and risk signatures. Analyses were performed based on the risk signature, including stratification, somatic mutation analysis, nomogram construction, chemotherapeutic response prediction, and small-molecule drug prediction. In summary, we developed a prognostic signature consisting of six genes that have the potential for prognostication in patients with LUAD and the design of personalized treatments that could provide new versions of personalized management for these patients.

Critical Solvation Structures Arrested Active Molecules for Reversible Zn Electrochemistry.

Aqueous Zn-ion batteries (AZIBs) have attracted increasing attention in next-generation energy storage systems due to their high safety and economic. Unfortunately, the side reactions, dendrites and hydrogen evolution effects at the zinc anode interface in aqueous electrolytes seriously hinder the application of aqueous zinc-ion batteries. Here, we report a critical solvation strategy to achieve reversible zinc electrochemistry by introducing a small polar molecule acetonitrile to form a "catcher" to arrest active molecules (bound water molecules). The stable solvation structure of [Zn(H2O)6]2+ is capable of maintaining and completely inhibiting free water molecules. When [Zn(H2O)6]2+ is partially desolvated in the Helmholtz outer layer, the separated active molecules will be arrested by the "catcher" formed by the strong hydrogen bond N-H bond, ensuring the stable desolvation of Zn2+. The Zn||Zn symmetric battery can stably cycle for 2250 h at 1 mAh cm-2, Zn||V6O13 full battery achieved a capacity retention rate of 99.2% after 10,000 cycles at 10 A g-1. This paper proposes a novel critical solvation strategy that paves the route for the construction of high-performance AZIBs.

Linear feedback coding scheme for multiple-access fading channels with degraded message sets.

Channel coding technology plays an important role in wireless communication systems, and it serves as a crucial mechanism to reduce interference during the transmission process. As the fifth-generation (5G) and sixth-generation (6G) wireless communication systems rapidly advance, requirements of the users on the quality and security of wireless service are increasing. To solve these problems, it calls for us to explore the new channel coding technologies. In this paper, a linear feedback coding scheme for fading multiple-access channels with degraded message sets (FMAC-DMS) is proposed. In this scheme, the transmitting beamforming and channel splitting are used to transform the channel with complex signals into scalar equivalent sub-channels. Then, the extended Schalkwijk-Kailath coding scheme (SK) is further applied to each sub-channel. The channel capacity, finite blocklength (FBL) sum-rate and FBL secrecy achievable sum-rate of the FMAC-DMS in single-input single-output (SISO) and multi-input single-output (MISO) cases are derived. Finally, we show that the proposed scheme not only provides a FBL coding solution but also guarantees physical layer security(PLS). The numerical and simulation results show the effectiveness of the proposed scheme as a channel coding solution. The study of this paper provides a new method to construct a practical FBL scheme for the FMAC-DMS.

Association between performance measures and clinical outcomes in patients with heart failure in China: Results from the HERO study.

BACKGROUND: There is great heterogeneity in the quality of care among hospitals in China, but studies on the performance measures and prognosis of patients with heart failure (HF) are still deficient. HYPOTHESIS: Performance measures have been used as a guideline to clinicans, however, the association between them and outcomes among HF patients in China remains unclear. METHODS: We analyzed 4497 patients with HF from the Heart Failure Registry of Patient Outcomes study. Performance measures were determined according to the guidelines, and the patients were divided into four groups based on a composite performance score. Multiple imputation and Cox proportional-hazard regression models were used to assess the association between the performance measures and clinical outcomes. RESULTS: Overall, only 12.5% of patients met the top 25% of the performance measures, whereas 33.5% of patients met the bottom 25% of the measures. A total of 992 (22.2%) patients died within 1 year, involving a larger proportion of patients who had met only the bottom 25% of the performance measures than had met the top 25% (27.0% vs. 16.3%, respectively). The patients who met the top 25% of the measures had a lower 1-year mortality rate (adjusted hazard ratio: 0.78, 95% confidence interval: 0.61-0.98). CONCLUSIONS: The association between performance measures and mortality appeared to follow a dose-response pattern with a larger degree of compliance with performance measures being associated with a lower mortality rate in patients with HF. Accordingly, the quality of care for patients with HF in China needs to be further improved.

Body mass index and risk of inflammatory breast disease: a Mendelianrandomization study / Índice de masa corporal y riesgo de mastitis: un estudio de aleatorización mendeliana

Introduction: in previous studies, obesity was identified as a risk factor for inflammatory breast disease, but its causality is uncertain. In thepresent study, we performed a two-sample Mendelian randomization (TSMR) analysis to investigate the causal relationship between obesity andinflammatory breast disease.Methods: we use body mass index (BMI) as a measure of obesity. Data for single nucleotide polymorphisms (SNPs) associated with BMI wereobtained from UK Biobank. Data for single nucleotide polymorphisms (SNPs) associated with mastitis were obtained from FinnGen Biobank. We usedseveral MR analysis methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode to makeour results more convincing. We also performed MR-PRESSO test, MR-Egger test, heterogeneity test, pleiotropy test and leave-one-out analysisto make our analysis results more robust and credible. We used odds ratio (OR) to evaluate the causal relationship between BMI and mastitis.Results: based on the IVW random effects model, we found that a one-standard deviation (SD) increase in BMI increased the risk of mastitis by62.1 % (OR = 1.621, 95 % CI: 1.262-2.083, p = 1.59E-4), which is almost consistent with the results of several other methods.Conclusions: in European individuals, an increase in the number of BMI increases the risk of inflammatory breast disease. People with high BMIneed to control their weight to reduce the incidence of inflammatory breast disease.(AU)

Introducción: en estudios previos, la obesidad se identificó como un factor de riesgo para la enfermedad inflamatoria de mama, pero su cau-salidad es incierta. En el presente estudio, se realizó un análisis de aleatorización mendeliana de dos muestras (TSMR) para investigar la relacióncausal entre la obesidad y la enfermedad inflamatoria de mama.Métodos: se empleó el índice de masa corporal (IMC) como medida de obesidad. Los datos de los polimorfismos de nucleótido único (SNP)asociados con el IMC se obtuvieron del Biobank de Reino Unido y los datos de los polimorfismos de nucleótido único (SNP) asociados con lamastitis se obtuvieron de FinnGen Biobank. Se utilizaron varios métodos de análisis de RM, como la ponderación inversa de la varianza (IVW),RM-Egger, mediana ponderada, modo simple y modo ponderado para que nuestros resultados fueran más convincentes. También se realizaronla prueba MR-PRESSO, la prueba MR-Egger, la prueba de heterogeneidad, el test de pleiotropía y la validación dejando uno fuera (en inglés,leave-one-out) para que los resultados de nuestro análisis fueran más sólidos y creíbles. Se utilizó la odds ratio (OR) para evaluar la relacióncausal entre el IMC y la mastitis.Resultados: basándonos en el modelo de efectos aleatorios IVW, se halló que un aumento de una desviación estándar (DE) en el IMC aumentabael riesgo de mastitis en un 62,1 % (OR = 1,621, IC 95 %: 1,262-2,083, p = 1,59E-4), que es casi consistente con los resultados de otrosdiversos métodos.Conclusiones: en los individuos europeos, un aumento del número de IMC aumenta el riesgo de enfermedad inflamatoria mamaria. Las personascon un IMC elevado deben controlar su peso para reducir la incidencia de enfermedad inflamatoria de la mama.(AU)

The causal effect of hypertension, intraocular pressure, and diabetic retinopathy: a Mendelian randomization study.

Background: Previous research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR); however, the relationship has not been elucidated. In this study, we aim to investigate the causal association of hypertension, IOP, and DR. Methods: The genome-wide association study (GWAS) IDs for DR, hypertension, and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 single-nucleotide polymorphisms (SNPs) and a sample size of 1,030,836 for DR. There were 16,380,466 SNPs and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable, multivariable, and bidirectional Mendelian randomization (MR) studies were conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses. Results: A total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR [p = 0.006, odds ratio (OR) = 1.080]. A total of 95 SNPs at the genome-wide significance level were selected as IVs for IOP-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (p = 0.029, OR = 1.090). The results of reverse MR analysis showed that DR was a risk factor for hypertension (p = 1.27×10-10, OR = 1.119), but there was no causal relationship between DR and IOP (p > 0.05). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (p = 0.001, OR = 1.121 and p = 0.030, OR = 1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension. Conclusion: This study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.

MDM2 provides TOP2 poison resistance by promoting proteolysis of TOP2ßcc in a p53-independent manner.

DNA topoisomerase II (TOP2) is an enzyme that performs a critical function in manipulating DNA topology during replication, transcription, and chromosomal compaction by forming a vital intermediate known as the TOP2-DNA cleavage complex (TOP2cc). Although the TOP2cc is often transient, stabilization can be achieved by TOP2 poisons, a family of anti-cancer chemotherapeutic agents targeting TOP2, such as etoposide (VP-16), and then induce double-strand breaks (DSBs) in cellular DNA. TOP2cc first needs to be proteolyzed before it can be processed by TDP2 for the removal of these protein adducts and to produce clean DNA ends necessary for proper repair. However, the mechanism by which TOP2ßcc is proteolyzed has not been thoroughly studied. In this study, we report that after exposure to VP-16, MDM2, a RING-type E3 ubiquitin ligase, attaches to TOP2ß and initiates polyubiquitination and proteasomal degradation. Mechanistically, during exposure to VP-16, TOP2ß binds to DNA to form TOP2ßcc, which promotes MDM2 binding and subsequent TOP2ß ubiquitination and degradation, and results in a decrease in TOP2ßcc levels. Biologically, MDM2 inactivation abrogates TOP2ß degradation, stabilizes TOP2ßcc, and subsequently increases the number of TOP2ß-concealed DSBs, resulting in the rapid death of cancer cells via the apoptotic process. Furthermore, we demonstrate the combination activity of VP-16 and RG7112, an MDM2 inhibitor, in the xenograft tumor model and in situ lung cancer mouse model. Taken together, the results of our research reveal an underlying mechanism by which MDM2 promotes cancer cell survival in the presence of TOP2 poisons by activating proteolysis of TOP2ßcc in a p53-independent manner, and provides a rationale for the combination of MDM2 inhibitors with TOP2 poisons for cancer therapy.

Impacts of prothioconazole and prothioconazole-desthio on bile acid and glucolipid metabolism: Upregulation of CYP7A1 expression in HepG2 cells.

As an efficient triazole fungicide, prothioconazole (PTC) is widely used for the prevention and control of plant fungal pathogens. It was reported that the residues of PTC and prothioconazole-desthio (PTC-d) have been detected in the environment and crops, and the effects of PTC-d may be higher than that of PTC. Currently, PTC and PTC-d have been proven to induce hepatic metabolic disorders. However, their toxic effects on cellular bile acid (BA) and glucolipid metabolism remain unknown. In this study, HepG2 cells were exposed to 1-500 µM of PTC or PTC-d. High concentrations of PTC and PTC-d were found to induce cytotoxicity; thus, subsequent experimental exposure was conducted at concentrations of 10-50 µM. The expression levels of CYP7A1 and TG synthesis-related genes and levels of TG and total BA were observed to increase in HepG2 cells. Molecular docking analysis revealed direct interactions between PTC or PTC-d and CYP7A1 protein. To further investigate the underlying mechanisms, PTC and PTC-d were treated to HepG2 cells in which CYP7A1 expression was knocked down using siCYP7A1. It was observed that PTC and PTC-d affected the BA metabolism process and regulated the glycolipid metabolism process by promoting the expression of CYP7A1. In summary, we comprehensively analyzed the effects and mechanisms of PTC and PTC-d on cellular metabolism in HepG2 cells, providing theoretical data for evaluating the safety and potential risks associated with these substances.

Genomic evidence for climate-linked diversity loss and increased vulnerability of wild barley spanning 28 years of climate warming.

The information on how plant populations respond genetically to climate warming is scarce. Here, landscape genomic and machine learning approaches were integrated to assess genetic response of 10 wild barley (Hordeum vulgare ssp. spontaneum; WB) populations in the past and future, using whole genomic sequencing (WGS) data. The WB populations were sampled in 1980 and again in 2008. Phylogeny of accessions was roughly in conformity with sampling sites, which accompanied by admixture/introgressions. The 28-y climate warming resulted in decreased genetic diversity, increased selection pressure, and an increase in deleterious single nucleotide polymorphism (dSNP) numbers, heterozygous deleterious and total deleterious burdens for WB. Genome-environment associations identified some candidate genes belonging to peroxidase family (HORVU2Hr1G057450, HORVU4Hr1G052060 and HORVU4Hr1G057210) and heat shock protein 70 family (HORVU2Hr1G112630). The gene HORVU2Hr1G120170 identified by selective sweep analysis was under strong selection during the climate warming of the 28-y, and its derived haplotypes were fixed by WB when faced with the 28-y increasingly severe environment. Temperature variables were found to be more important than precipitation variables in influencing genomic variation, with an eco-physiological index gdd5 (growing degree-days at the baseline threshold temperature of 5 °C) being the most important determinant. Gradient forest modelling revealed higher predicted genomic vulnerability in Sede Boqer under future climate scenarios at 2041-2070 and 2071-2100. Additionally, estimates of effective population size (Ne) tracing back to 250 years indicated a forward decline in all populations over time. Our assessment about past genetic response and future vulnerability of WB under climate warming is crucial for informing conservation efforts for wild cereals and rational use strategies.

In-based coordination polymer-derived carbon nanoribbons with abundant CoP nanoparticles in carbon nanotubes for water oxidation.

The sluggish oxygen evolution reaction (OER) in overall electrocatalytic water splitting poses a significant challenge in hydrogen production. A series of transition metal phosphides are emerging as promising electrocatalysts, effectively modulating the charge distribution of surrounding atoms for OER. In this study, a highly efficient OER electrocatalyst (CoP-CNR-CNT) was successfully synthesized through the pyrolysis and phosphatization of a Co-doped In-based coordination polymer, specifically InOF-25. This process resulted in evenly dispersed CoP nanoparticles encapsulated in coordination polymer-derived carbon nanoribbons. The synthesized CoP-CNR-CNT demonstrated a competitive OER activity with a smaller overpotential (η10) of 295.7 mV at 10 mA cm-2 and a satisfactory long-term stability compared to the state-of-the-art RuO2 (η10 = 353.7 mV). The high OER activity and stability can be attributed to the high conductivity of the carbon network, the abundance of CoP particles, and the intricate nanostructure of nanoribbons/nanotubes. This work provides valuable insights into the rational design and facile preparation of efficient non-precious metal-based OER electrocatalysts from inorganic-organic coordination polymers, with potential applications in various energy conversion and storage systems.