Molecular interaction mechanisms on (-)-epigallocatechin-3-gallate improving activities of inhibited acetylcholinesterase by selected organophosphorus pesticides in vitro & vivo.

(-)-Epigallocatechin-3-gallate (EGCG) is reported to have benefits for the treatment of Alzheimer's disease by binding with acetylcholinesterase (AChE) to enhance the cholinergic neurotransmission. Organophosphorus pesticides (OPs) inhibited AChE and damaged the nervous system. This study investigated the combined effects of EGCG and OPs on AChE activities in vitro & vivo. The results indicated that EGCG significantly reversed the inhibition of AChE caused by OPs. In vitro, EGCG reactived AChE in three group tubes incubated for 110 min, and in vivo, it increased the relative activities of AChE from less than 20% to over 70% in brain and vertebral of zebrafish during the exposure of 34 h. The study also proposed the molecular interaction mechanisms through the reactive kinetics and computational analyses of density functional theory, molecular docking, and dynamic modeling. These analyses suggested that EGCG occupied the key residues, preventing OPs from binding to the catalytic center of AChE, and interfering with the initial affinity of OPs to the central active site. Hydrogen bonding, conjugation, and steric interactions were identified as playing important roles in the molecular interactions. The work suggests that EGCG antagonized the inhibitions of OPs on AChE activities and potentially offered the neuroprotection against the induced damage.

Breastfeeding in infancy and cardiovascular disease in middle-aged and older adulthood: a prospective study of 0.36 million UK Biobank participants.

BACKGROUND: Cardiovascular disease originates in early life. We aimed to investigate the association between breastfeeding in infancy and cardiovascular disease in adult life. METHODS: We followed 364,240 participants from UK Biobank aged 40-73 years from 2006 - 2010 to 2021. Information on breastfeeding in infancy was self-reported by questionnaire. Cox proportional hazard regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between breastfeeding and cardiovascular disease in middle-aged and older adulthood. The multivariable Cox models were used by adjusting for the age (used as the time scale), sex, ethnicity, assessment centre, birth weight, multiple birth status, maternal smoking during pregnancy, Townsend deprivation index, smoking status, alcohol drinker status, physical activity, and menopausal status for women. Binary and multinomial multivariable logistic regression models were used to explore the associations of breastfeeding in infancy with cardiovascular disease risk factors including obesity, body composition, metabolic and inflammatory disorders. RESULTS: During a median of 12.6 years of follow-up, we documented 29,796 new cases of cardiovascular disease, including 24,797 coronary heart disease and 6229 stroke. The multivariable adjusted HRs for breastfed versus non-breastfed were 0.94 (95% CI: 0.91, 0.96) for cardiovascular disease, 0.94 (95% CI: 0.91, 0.96) for coronary heart disease, and 0.95 (95% CI: 0.89, 1.01) for stroke. Furthermore, the strength of observed association between breastfeeding and cardiovascular disease seems to decrease with age (P for interaction <0.001), and increase with polygenic risk for cardiovascular disease (P for interaction <0.001). Consistently, breastfeeding in infancy was associated with cardiovascular disease risk factors including lower body mass index 0.92 (95% CI: 0.89, 0.95), body fat percentage 0.85 (95% CI: 0.83, 0.87), android to gynoid fat ratio 0.89 (95% CI: 0.83, 0.96), visceral adipose tissue 0.92 (95% CI: 0.84, 1.01), as well as lower C-reactive protein level 0.95 (95% CI: 0.94, 0.97) and a lower risk of metabolic syndrome 0.89 (95% CI: 0.85, 0.92). CONCLUSIONS: Breastfeeding in infancy was associated with a lower risk of cardiovascular disease in middle-aged and older adulthood. Promoting breastfeeding is vital not only for promoting child health, but also for halting the increasing trend of cardiovascular disease in adults.

Diagnostic and prognostic value of the HFA-PEFF score for heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Aim: To assess the diagnostic and prognostic performances of the Heart Failure Association Pre-test Assessment, Echocardiography & Natriuretic Peptide, Functional Testing, Final Etiology (HFA-PEFF) score for heart failure with preserved ejection fraction (HFpEF) in a comprehensive manner. Methods: PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched from the inception to June 12, 2023. Studies using the "Rule-out" or "Rule-in" approach for diagnosis analysis or studies on cardiovascular events and all-cause death for prognosis analysis were included. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was adopted to assess the quality of diagnostic accuracy studies. The sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (SROC) curve (AUC) were presented with 95% confidence intervals (CIs). For CVEs and all-cause death, the hazard ratio (HR) values were calculated. Results: Fifteen studies involving 6420 subjects were included, with 9 for diagnosis analysis, and 7 for prognosis analysis. For the diagnostic performance of the HFA-PEFF score, with the "Rule-out" approach, the pooled SEN was 0.96 (95%CI: 0.94, 0.97), the pooled SPE was 0.39 (95%CI: 0.37, 0.42), and the pooled AUC was 0.85 (95%CI: 0.67, 1.00), and with the "Rule-in" approach, the pooled SEN was 0.59 (95%CI: 0.56, 0.61), the pooled SPE was 0.86 (95%CI: 0.84, 0.88), and the pooled AUC was 0.83 (95%CI: 0.79, 0.87). For the predictive performance of the HFA-PEFF score, regarding CVEs, the pooled SEN was 0.63 (95%CI: 0.58, 0.67), the pooled SPE was 0.53 (95%CI: 0.49, 0.58), and the pooled AUC was 0.65 (95%CI: 0.40, 0.90), and concerning All-cause death, the pooled SEN was 0.85 (95%CI: 0.81, 0.88), the pooled SPE was 0.48 (95%CI: 0.44, 0.52), and the pooled AUC was 0.65 (95%CI: 0.47, 0.83). A higher HFA-PEFF score was associated with a higher risk of all-cause death (HR 1.390, 95%CI 1.240, 1.558, P < 0.001). Conclusion: The HFA-PEFF score might be applied in HFpEF diagnosis and all-cause death prediction. More studies are required for finding validation.

The PHYB-FOF2-VOZ2 module functions to fine-tune flowering in response to changes in light quality by modulating FLC expression in Arabidopsis.

Proper timing of flowering under different environmental conditions is critical for plant propagation. Light quality is a pivotal environmental cue that plays a critical role in flowering regulation. Plants tend to flower late under light with a high red (R)/far-red (FR) light ratio but early under light with a low R/FR light ratio. However, how plants fine-tune flowering in response to changes in light quality is not well understood. Here, we demonstrate that F-box of Flowering 2 (FOF2), an autonomous pathway-related regulator, physically interacts with VASCULAR PLANT ONE-ZINC FINGER 1 and 2 (VOZ1 and VOZ2), which are direct downstream factors of the R/FR light receptor phytochrome B (PHYB). We show that PHYB physically interacts with FOF2, mediates stabilization of the FOF2 protein under FR light and end-of-day FR light, and enhances FOF2 binding to VOZ2, which leads to degradation of VOZ2 by SCFFOF2 E3 ligase. By contrast, PHYB mediates degradation of FOF2 protein under R light and end-of-day R light. Genetic interaction studies demonstrated that FOF2 functions downstream of PHYB to promote FLC expression and inhibit flowering under both high R/FR light and simulated shade conditions, processes that are partially dependent on VOZ proteins. Taken together, our findings suggest a novel mechanism whereby plants fine-tune flowering time through a PHYB-FOF2-VOZ2 module that modulates FLC expression in response to changes in light quality.

Photosynthetic characteristics and genetic mapping of a new yellow leaf mutant crm1 in Brassica napus.

Chlorophyll is one of the key factors for photosynthesis and plays an important role in plant growth and development. We previously isolated an EMS mutagenized rapeseed chlorophyll-reduced mutant (crm1), which had yellow leaf, reduced chlorophyll content and fewer thylakoid stacks. Here, we found that crm1 showed attenuated utilization efficiency of both light energy and CO2 but enhanced heat dissipation efficiency and greater tolerance to high-light intensity. BSA-Seq analysis identified a single nucleotide change (C to T) and (G to A) in the third exon of the BnaA01G0094500ZS and BnaC01G0116100ZS, respectively. These two genes encode the magnesium chelatase subunit I 1 (CHLI1) that catalyzes the insertion of magnesium into protoporphyrin IX, a pivotal step in chlorophyll synthesis. The mutation sites resulted in an amino acid substitution P144S and G128E within the AAA+ domain of the CHLI1 protein. Two KASP markers were developed and co-segregated with the yellow leaf phenotype in segregating F2 population. Loss of BnaA01.CHLI1 and BnaC01.CHLI1 by CRISPR/Cas9 gene editing recapitulated the mutant phenotype. BnaA01.CHLI1 and BnaC01.CHLI1 were located in chloroplast and highly expressed in the leaves. Furthermore, RNA-seq analyses revealed the expression of chlorophyll synthesis-related genes were upregulated in the crm1 mutant. These findings provide a new insight into the regulatory mechanism of chlorophyll synthesis in rapeseed and suggest a novel target for improving the photosynthetic efficiency and tolerance to high-light intensity in crops. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01429-6.

GC-biased gene conversion drives accelerated evolution of ultraconserved elements in mammalian and avian genomes.

Ultraconserved elements (UCEs) are the most conserved regions among the genomes of evolutionarily distant species and are thought to play critical biological functions. However, some UCEs rapidly evolved in specific lineages, and whether they contributed to adaptive evolution is still controversial. Here, using an increased number of sequenced genomes with high taxonomic coverage, we identified 2191 mammalian UCEs and 5938 avian UCEs from 95 mammal and 94 bird genomes, respectively. Our results show that these UCEs are functionally constrained and that their adjacent genes are prone to widespread expression with low expression diversity across tissues. Functional enrichment of mammalian and avian UCEs shows different trends indicating that UCEs may contribute to adaptive evolution of taxa. Focusing on lineage-specific accelerated evolution, we discover that the proportion of fast-evolving UCEs in nine mammalian and 10 avian test lineages range from 0.19% to 13.2%. Notably, up to 62.1% of fast-evolving UCEs in test lineages are much more likely to result from GC-biased gene conversion (gBGC). A single cervid-specific gBGC region embracing the uc.359 allele significantly alters the expression of Nova1 and other neural-related genes in the rat brain. Combined with the altered regulatory activity of ancient gBGC-induced fast-evolving UCEs in eutherians, our results provide evidence that synergy between gBGC and selection shaped lineage-specific substitution patterns, even in the most constrained regulatory elements. In summary, our results show that gBGC played an important role in facilitating lineage-specific accelerated evolution of UCEs, and further support the idea that a combination of multiple evolutionary forces shapes adaptive evolution.

Evaluation of Internet-based pharmaceutical care effect on young and middle-aged patients with hypertension by the principal component analysis and the Markov cohort during COVID-19 pandemic.

BACKGROUND: Pharmaceutical care has the potential to improve hypertension control rates in young and middle-aged patients. Due the COVID-19 epidemic, standard intervention methods may not be applicable. We propose establishing an internet-based pharmaceutical care (IPC) route to improve blood pressure control in young and middle-aged patients with hypertension. An evaluation method based on Principal Component Analysis (PCA) and Orthogonal Partial Least-Discriminant Analysis (OPLS-DA) was established to evaluate the effect of the IPC method. METHODS: 1) Internet-based Pharmaceutical care (IPC) was provided by pharmacists mainly using Wechat software for one year after enrollment; 2) PCA and OPLS-DA were applied to analyze questionnaire reliability and data variability; 3) Markov cohort was used to evaluate the IPC effect. RESULTS: Ninety-seven young and middle-aged patients were enrolled. 96 patients received the IPC. 1) The blood pressure control rate increased to 71.88% after IPC in 96 patients. 2) After conducting PCA and OPLS-DA analysis, 10 questions in the questionnaire were significantly improved after the IPC. 3) Markov cohort results showed that patient survival after 28 cycles was 18.62 years and the quality-adjusted life year (QALY) was extended by 5.40 years. The cumulative cost-effectiveness ratio was ¥87.10 per QALY. CONCLUSIONS: The IPC method could significantly improve the blood pressure control rate of patients. The questionnaire analysis method based on PCA and OPLS-DA is an effective method to evaluate the effect of the IPC method. The Markov cohort showed that the IPC had an effect on blood pressure control rate changes. Patients had a strong willingness to pay for IPC.

Chromatin accessibility memory of donor cells disrupts bovine somatic cell nuclear transfer blastocysts development.

The post-transfer developmental capacity of bovine somatic cell nuclear transfer (SCNT) blastocysts is reduced, implying that abnormalities in gene expression regulation are present at blastocyst stage. Chromatin accessibility, as an indicator for transcriptional regulatory elements mediating gene transcription activity, has heretofore been largely unexplored in SCNT embryos, especially at blastocyst stage. In the present study, single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) of in vivo and SCNT blastocysts were conducted to segregate lineages and demonstrate the aberrant chromatin accessibility of transcription factors (TFs) related to inner cell mass (ICM) development in SCNT blastocysts. Pseudotime analysis of lineage segregation further reflected dysregulated chromatin accessibility dynamics of TFs in the ICM of SCNT blastocysts compared to their in vivo counterparts. ATAC- and ChIP-seq results of SCNT donor cells revealed that the aberrant chromatin accessibility in the ICM of SCNT blastocysts was due to the persistence of chromatin accessibility memory at corresponding loci in the donor cells, with strong enrichment of trimethylation of histone H3 at lysine 4 (H3K4me3) at these loci. Correction of the aberrant chromatin accessibility through demethylation of H3K4me3 by KDM5B diminished the expression of related genes (e.g., BCL11B) and significantly improved the ICM proliferation in SCNT blastocysts. This effect was confirmed by knocking down BCL11B in SCNT embryos to down-regulate p21 and alleviate the inhibition of ICM proliferation. These findings expand our understanding of the chromatin accessibility abnormalities in SCNT blastocysts and BCL11B may be a potential target to improve SCNT efficiency.

Convergent molecular evolution of thermogenesis and circadian rhythm in Arctic ruminants.

The muskox and reindeer are the only ruminants that have evolved to survive in harsh Arctic environments. However, the genetic basis of this Arctic adaptation remains largely unclear. Here, we compared a de novo assembled muskox genome with reindeer and other ruminant genomes to identify convergent amino acid substitutions, rapidly evolving genes and positively selected genes among the two Arctic ruminants. We found these candidate genes were mainly involved in brown adipose tissue (BAT) thermogenesis and circadian rhythm. Furthermore, by integrating transcriptomic data from goat adipose tissues (white and brown), we demonstrated that muskox and reindeer may have evolved modulating mitochondrion, lipid metabolism and angiogenesis pathways to enhance BAT thermogenesis. In addition, results from co-immunoprecipitation experiments prove that convergent amino acid substitution of the angiogenesis-related gene hypoxia-inducible factor 2alpha (HIF2A), resulting in weakening of its interaction with prolyl hydroxylase domain-containing protein 2 (PHD2), may increase angiogenesis of BAT. Altogether, our work provides new insights into the molecular mechanisms involved in Arctic adaptation.

Simulated Gastric Acid Promotes the Horizontal Transfer of Multidrug Resistance Genes across Bacteria in the Gastrointestinal Tract at Elevated pH Levels.

The assessment of factors that can promote the transmission of antibiotic resistance genes (ARGs) across bacteria in the gastrointestinal tract is in great demand to understand the occurrence of infections related to antibiotic-resistant bacteria (ARB) in humans. However, whether acid-resistant enteric bacteria can promote ARG transmission in gastric fluid under high-pH conditions remains unknown. This study assessed the effects of simulated gastric fluid (SGF) at different pH levels on the RP4 plasmid-mediated conjugative transfer of ARGs. Moreover, transcriptomic analysis, measurement of reactive oxygen species (ROS) levels, assessment of cell membrane permeability, and real-time quantitative assessment of the expression of key genes were performed to identify the underlying mechanisms. The frequency of conjugative transfer was the highest in SGF at pH 4.5. Antidepressant consumption and certain dietary factors further negatively impacted this situation, with 5.66-fold and 4.26-fold increases in the conjugative transfer frequency being noted upon the addition of sertraline and 10% glucose, respectively, compared with that in the control group without any additives. The induction of ROS generation, the activation of cellular antioxidant systems, increases in cell membrane permeability, and the promotion of adhesive pilus formation were factors potentially contributing to the increased transfer frequency. These findings indicate that conjugative transfer could be enhanced under certain circumstances in SGF at elevated pH levels, thereby facilitating ARG transmission in the gastrointestinal tract. IMPORTANCE The low pH of gastric acid kills unwanted microorganisms, in turn affecting their inhabitation in the intestine. Hence, studies on the factors that influence antibiotic resistance gene (ARG) propagation in the gastrointestinal tract and on the underlying mechanisms are limited. In this study, we constructed a conjugative transfer model in the presence of simulated gastric fluid (SGF) and found that SGF could promote the dissemination of ARGs under high-pH conditions. Furthermore, antidepressant consumption and certain dietary factors could negatively impact this situation. Transcriptomic analysis and a reactive oxygen species assay revealed the overproduction of reactive oxygen species as a potential mechanism by which SGF could promote conjugative transfer. This finding can help provide a comprehensive understanding of the bloom of antibiotic-resistant bacteria in the body and create awareness regarding the risk of ARG transmission due to certain diseases or an improper diet and the subsequent decrease in gastric acid levels.

Antidepressant exposure as a source of disinfectant resistance in waterborne bacteria.

The emergence of disinfectant-resistant pathogens in water is a major threat to public health. However, whether human-consumed pharmaceuticals can induce bacterial resistance to disinfectants remains unclear. Herein, Escherichia coli was exposed to 12 antidepressants, and susceptibility of antidepressant-induced chloramphenicol (CHL)-resistant mutants to disinfectants was tested. Whole genome sequencing, global transcriptomic sequencing, and real-time quantitative polymerase chain reaction were used to elucidate the underlying mechanisms. We observed that duloxetine, fluoxetine, amitriptyline, and sertraline significantly increased the mutation frequency of E. coli against CHL by 15- to 2948-fold. The resultant mutants increased the average MIC50 of sodium hypochlorite, benzalkonium bromide, and triclosan roughly 2- to 8-fold. Consistently, marRAB and acrAB-tolC genes, together with ABC transporter genes (e.g., yddA, yadG, yojI, and mdlA), were triggered to increase the efflux of disinfectants out of the cell, while ompF was inhibited, reducing disinfectant penetration into the cell. Additionally, the occurrence of DNA mutations in marR and acrR in the mutants was observed, potentially resulting in increased synthesis of the AcrAB-TolC pump. This study indicates that pharmaceutical exposure may create disinfectant-resistant bacteria, which may then be released into water systems, providing novel insights into the potential source of water-borne disinfectant-resistant pathogens.

Automated quantification of measurable residual disease in chronic lymphocytic leukemia using an artificial intelligence-assisted workflow.

Detection of measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is an important prognostic marker. The most common CLL MRD method in current use is multiparameter flow cytometry, but availability is limited by the need for expert manual analysis. Automated analysis has the potential to expand access to CLL MRD testing. We evaluated the performance of an artificial intelligence (AI)-assisted multiparameter flow cytometry (MFC) workflow for CLL MRD. We randomly selected 113 CLL MRD FCS files and divided them into training and validation sets. The training set (n = 41) was gated by expert manual analysis and used to train the AI model. We then compared the validation set (n = 72) MRD results obtained by the AI-assisted analysis versus those by expert manual analysis using the Pearson correlation coefficient and Bland-Altman plot method. In the validation set, the AI-assisted analysis correctly categorized cases as MRD-negative versus MRD-positive in 96% of cases. When comparing the AI-assisted analysis versus the expert manual analysis, the Pearson r was 0.8650, mean bias was 0.2237 log10 units, and the 95% limit of agreement (LOA) was ±1.0282 log10 units. The AI-assisted analysis performed sub-optimally in atypical immunophenotype CLL and in cases lacking residual normal B cells. When excluding these outlier cases, the mean bias improved to 0.0680 log10 units and the 95% LOA to ±0.2926 log10 units. An automated AI-assisted workflow allows for the quantification of MRD in CLL with typical immunophenotype. Further work is required to improve performance in atypical immunophenotype CLL.

Convergent Genomic Signatures of Cashmere Traits: Evidence for Natural and Artificial Selection.

Convergent evolution provides powerful opportunities to investigate the genetic basis of complex traits. The Tibetan antelope (Pantholops hodgsonii) and Siberian ibex (Capra sibirica) belong to different subfamilies in Bovidae, but both have evolved similar superfine cashmere characteristics to meet the cold temperature in plateau environments. The cashmere traits of cashmere goats underwent strong artificial selection, and some traces of domestication also remained in the genome. Hence, we investigated the convergent genomic signatures of cashmere traits between natural and artificial selection. We compared the patterns of convergent molecular evolution between Tibetan antelope and Siberian ibex by testing positively selected genes, rapidly evolving genes and convergent amino acid substitutions. In addition, we analyzed the selected genomic features of cashmere goats under artificial selection using whole-genome resequencing data, and skin transcriptome data of cashmere goats were also used to focus on the genes involved in regulating cashmere traits. We found that molecular convergent events were very rare, but natural and artificial selection genes were convergent enriched in similar functional pathways (e.g., ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway) in a variety of gene sets. Type IV collagen family genes (COL4A2, COL4A4, COL4A5, COL6A5, COL6A6) and integrin family genes (ITGA2, ITGA4, ITGA9, ITGB8) may be important candidate genes for cashmere formation and development. Our results provide a comprehensive approach and perspective for exploring cashmere traits and offer a valuable reference for subsequent in-depth research on the molecular mechanisms regulating cashmere development and fineness.

Effects of post-discharge telemonitoring on 30-day chronic obstructive pulmonary disease readmissions and mortality.

INTRODUCTION: Much attention has been focused on decreasing chronic obstructive pulmonary disease (COPD) hospital readmissions. The US health system has struggled to meet this goal. The objective of this study was to assess the efficacy of telehealth services on the reduction of hospital readmission and mortality rates for COPD. METHODS: We used a cross-sectional design to examine the association between hospital risk-adjusted readmission and mortality rates for COPD and hospital use of post-discharge telemonitoring (TM). Data for 777 hospitals were sourced from the Centers for Medicare & Medicaid Services and the American Hospital Association annual surveys. Propensity score matching using the kennel weights method was applied to calculate the weighted probability of being a hospital that offers post-discharge TM services. RESULTS: Hospitals with post-discharge TM had about 34% significantly higher odds (adjusted odds ratio (AOR) = 1.34; 95% confidence interval (CI) 1.06-1.70) of 30-day COPD readmission and 33% significantly lower odds (AOR = 0.67; 95% CI 0.50-0.90) of 30-day COPD mortality compared to hospitals without post-discharge TM services. DISCUSSION: Overall, hospitals that offer post-discharge TM services have seen an improvement in 30-day COPD mortality rates. However, those same hospitals have also experienced a significant increase in 30-day COPD readmissions. TM can potentially decrease mortality in patients recently admitted for acute exacerbation of COPD. The results provide further evidence that readmissions present a problematic assessment of health-care quality, as the need for readmission may or may not be directly related to the quality of care received while in hospital.

The blue light receptor CRY1 interacts with FIP37 to promote N6 -methyladenosine RNA modification and photomorphogenesis in Arabidopsis.

Light is a particularly important environmental cue that regulates a variety of diverse plant developmental processes, such as photomorphogenesis. Blue light promotes photomorphogenesis mainly through the activation of the photoreceptor cryptochrome 1 (CRY1). However, the mechanism underlying the CRY1-mediated regulation of growth is not fully understood. Here, we found that blue light induced N6 -methyladenosine (m6 A) RNA modification during photomorphogenesis partially via CRY1. Cryptochrome 1 mediates blue light-induced expression of FKBP12-interacting protein 37 (FIP37), which is a component of m6 A writer. Moreover, we showed that CRY1 physically interacted with FIP37 in vitro and in vivo, and mediated blue light activation of FIP37 binding to RNA. Furthermore, CRY1 and FIP37 modulated m6 A on photomorphogenesis-related genes PIF3, PIF4, and PIF5, thereby accelerating the decay of their transcripts. Genetically, FIP37 repressed hypocotyl elongation under blue light, and fip37 mutation could partially rescue the short-hypocotyl phenotype of CRY1-overexpressing plants. Together, our results provide a new insight into CRY1 signal in modulating m6 A methylation and stability of PIFs, and establish an essential molecular link between m6 A modification and determination of photomorphogenesis in plants.

A Routing Optimization Method for Software-Defined Optical Transport Networks Based on Ensembles and Reinforcement Learning.

Optical transport networks (OTNs) are widely used in backbone- and metro-area transmission networks to increase network transmission capacity. In the OTN, it is particularly crucial to rationally allocate routes and maximize network capacities. By employing deep reinforcement learning (DRL)- and software-defined networking (SDN)-based solutions, the capacity of optical networks can be effectively increased. However, because most DRL-based routing optimization methods have low sample usage and difficulty in coping with sudden network connectivity changes, converging in software-defined OTN scenarios is challenging. Additionally, the generalization ability of these methods is weak. This paper proposes an ensembles- and message-passing neural-network-based Deep Q-Network (EMDQN) method for optical network routing optimization to address this problem. To effectively explore the environment and improve agent performance, the multiple EMDQN agents select actions based on the highest upper-confidence bounds. Furthermore, the EMDQN agent captures the network's spatial feature information using a message passing neural network (MPNN)-based DRL policy network, which enables the DRL agent to have generalization capability. The experimental results show that the EMDQN algorithm proposed in this paper performs better in terms of convergence. EMDQN effectively improves the throughput rate and link utilization of optical networks and has better generalization capabilities.

Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats.

INTRODUCTION: Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown. METHODS: (1) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-ß-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study). RESULTS: (1) Rapid drug elimination was observed 24 h after intragastric administration. The total cumulative excretion in urine and feces within 168 h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72 h. The drug-related substances were extensively distributed to the tissues within 48 h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The Kp,uu,brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01). CONCLUSIONS: CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.

Super-enhancers conserved within placental mammals maintain stem cell pluripotency.

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.

Roles of H19/miR-29a-3p/COL1A1 axis in COE-induced lung cancer.

Occupational lung cancer caused by coke oven emissions (COE) has attracted increasing attention, but the mechanism is not clear. Many evidences show ceRNA (competing endogenous RNA) networks play important regulatory roles in cancers. In this study, we aimed to construct and verify the ceRNA regulatory network in the occurrence of COE-induced lung squamous cell carcinoma (LUSC). We performed RNA sequencing with lung bronchial epithelial cell (16HBE) and COE induced malignant transformed cell (Rf). Furthermore, we analyzed RNA sequencing data of LUSC and adjacent tissues in the cancer genome atlas (TCGA) database. Combined our data and TCGA data to determine the differentially expressed lncRNAs, miRNAs, mRNAs. lncBASE, miRDB and miRTarBase were used to predict the binding relationship between lncRNA and miRNA, miRNA and mRNA. Based on these, we construct the ceRNA network. FREMSA, dual-luciferase reporter assay, quantitative real-time PCR (qRT-PCR), western-blot were used to verify the regulatory axis. CCK8 assay, phalloidin staining, p53 detection were used to explore the roles of this axis in the COE induced malignant transformation. Results showed 7 lncRNAs, 7 miRNAs and 146 mRNAs were identified. Among these, we constructed a ceRNA network including 1 lncRNA, 2 miRNAs and 9 mRNAs. Further verification confirmed the trend of lncRNA H19, miR-29a-3p and COL1A1 were consistent with sequencing results. H19 and COL1A1 were significantly higher in Rf than in 16HBE and miR-29a-3p was reverse. Regulatory investigation revealed H19 increased COL1A1 expression by sponging miR-29a-3p. Knockdown of H19, COL1A1 or overexpression of miR-29a-3p in Rf cells could inhibit cell proliferation, increased cell adhesion and p53 level. However, knockdown of H19 while suppressing the miR-29a-3p partially rescue the malignant phenotype of Rf caused by H19. In conclusion, all these indicated H19 functioned as a ceRNA to increase COL1A1 by sponging miR-29a-3p and promoted COE-induced cell malignant transformation.

Impacts of Rotation-Fallow Practices on Bacterial Community Structure in Paddy Fields.

Soil nutrients and microbial community play a central role in determining crop productivity in agroecosystems. However, the relationship between microbial community structure and soil nutrients in various crop rotation-fallow systems remains unclear. Thus, we designed a 3-year crop rotation-fallow field with five cropping systems (one continuous cropping, three rotational cropping, and one fallow system). We conducted a comprehensive analysis by evaluating crop yield, soil physicochemical properties, and overall bacteria composition. Our results showed that rotation-fallow treatments markedly influenced the crop yield and soil physicochemical properties. Proteobacteria, Acidobacteriota, and Chloroflexi were the dominant phyla in all rotation-fallow treatments. pH, available-phosphorus, total nitrogen, and soil organic matter had considerable effects on the soil bacterial community structure in 2019; however, only available-phosphorus had an impact on soil bacterial community in each treatment in 2020. In summary, with the increase of tillage years, different rotational fallow systems can increase paddy yield by promoting soil nutrient uptake and increasing the relative abundances of bacteria in paddy fields. IMPORTANCE Soil nutrients and microbial community play a central role in determining crop productivity. Therefore, elucidating the microbial mechanisms associated with different cropping systems is indispensable for understanding the sustainability of agroecosystem. In the present study, we designed a 3-year field rotation experiment using five cropping systems, including one continuous cropping, three rotational cropping, and one fallow system, to indagate the outcomes of soil microbial community structures in the different tillage systems. Our results showed that the different rotational fallow systems had positive impacts on crop yield, soil physicochemical properties, and bacterial community structure and that available phosphorus might be a key determinant for the limited bacterial community structure in various rotation-fallow systems following a 3-year field experiment. This study suggests that crop rotation-fallow systems play critical roles in improving bacterial community structure.