Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression.

TGF-ß signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-ß regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP2A-BP encoded by LINC00665, whose translation was downregulated by TGF-ß in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-ß-activated Smad signaling pathway induced the expression of translation inhibitory protein 4E-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.

Robust and Corrosion-Resistant Overall Water Splitting Electrode Enabled by Additive Manufacturing.

Electrolysis of water has emerged as a prominent area of research in recent years. As a promising catalyst support, copper foam is widely investigated for electrolytic water, yet the insufficient mechanical strength and corrosion resistance render it less suitable for harsh working conditions. To exploit high-performance catalyst supports, various metal supports are comprehensively evaluated, and Ti6 Al4 V (Ti64) support exhibited outstanding compression and corrosion resistance. With this in mind, a 3D porous Ti64 catalyst support is fabricated using the selective laser sintering (SLM) 3D printing technology, and a conductive layer of nickel (Ni) is coated to increase the electrical conductivity and facilitate the deposition of catalysts. Subsequently, Co0.8 Ni0.2 (CO3 )0.5 (OH)·0.11H2 O (CoNiCH) nanoneedles are deposited. The resulting porous Ti64/Ni/CoNiCH electrode displayed an impressive performance in the oxygen evolution reaction (OER) and reached 30 mA cm-2 at an overpotential of only 200 mV. Remarkably, even after being compressed at 15.04 MPa, no obvious structural deformation is observed, and the attenuation of its catalytic efficiency is negligible. Based on the computational analysis, the CoNiCH catalyst demonstrated superior catalytic activity at the Ni site in comparison to the Co site. Furthermore, the electrode reached 30 mA cm-2 at 1.75 V in full water splitting conditions and showed no significant performance degradation even after 60 h of continuous operation. This study presents an innovative approach to robust and corrosion-resistant catalyst design.

Synthesis of Amides via the Amination of Aldehydes with Hydroxylamines Promoted by TBAF·3H2O.

A metal-free, mild, and efficient method for the synthesis of amides has been developed from the amination of aldehydes with hydroxylamines promoted by TBAF·3H2O in the presence of KOH. Control experiments showed that the nitrone was the intermediate of this amination. By this method, a series of amides, biologically active compounds bebenil and a COX inhibitor were obtained in moderate to good yields.

A Data-Driven Computational Framework for Assessing the Risk of Placental Exposure to Environmental Chemicals.

A computational framework based on placental gene networks was proposed in this work to improve the accuracy of the placental exposure risk assessment of environmental compounds. The framework quantitatively characterizes the ability of compounds to cross the placental barrier by systematically considering the interaction and pathway-level information on multiple placental transporters. As a result, probability scores were generated for 307 compounds crossing the placental barrier based on this framework. These scores were then used to categorize the compounds into different levels of transplacental transport range, creating a gradient partition. These probability scores not only facilitated a more intuitive understanding of a compound's ability to cross the placental barrier but also provided valuable information for predicting potential placental disruptors. Compounds with probability scores greater than 90% were considered to have significant transplacental transport potential, whereas those with probability scores less than 80% were classified as unlikely to cross the placental barrier. Furthermore, external validation set results showed that the probability score could accurately predict the compounds known to cross the placental barrier. In conclusion, the computational framework proposed in this study enhances the intuitive understanding of the ability of compounds to cross the placental barrier and opens up new avenues for assessing the placental exposure risk of compounds.

Assessment of Fetal Exposure and Elimination of Perfluoroalkyl and Polyfluoroalkyl Substances: New Evidence from Paired Serum, Placenta, and Meconium Samples.

Multiple pieces of evidence have shown that prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is closely related to adverse birth outcomes for infants. However, difficult access to human samples limits our understanding of PFASs transport and metabolism across the human placental barrier, as well as the accurate assessment of fetal PFASs exposure. Herein, we assess fetal exposure to 28 PFASs based on paired serum, placenta, and meconium samples. Overall, 21 PFASs were identified first to be exposed to the fetus prenatally and to be metabolized and excreted by the fetus. In meconium samples, 25 PFASs were detected, with perfluorooctane sulfonate and perfluorohexane sulfonic acid being the dominant congeners, suggesting the metabolism and excretion of PFASs through meconium. Perfluoroalkyl sulfonic acids might be more easily eliminated through the meconium than perfluorinated carboxylic acids. Importantly, based on molecular docking, MRP1, OATP2B1, ASCT1, and P-gp were identified as crucial transporters in the dynamic placental transfer of PFASs between the mother and the fetus. ATSC5p and PubchemFP679 were recognized as critical structural features that affect the metabolism and secretion of PFASs through meconium. With increasing carbon chain length, both the transplacental transfer efficiency and meconium excretion efficiency of PFASs showed a structure-dependent manner. This study reports, for the first time, that meconium, which is a noninvasive and stable biological matrix, can be strong evidence of prenatal PFASs exposure.

Transcriptome analysis reveals transforming growth factor-ß1 prevents extracellular matrix degradation and cell adhesion during the follicular-luteal transition in cows.

Ovarian angiogenesis is an extremely rapid process that occurs during the transition from follicle to corpus luteum (CL) and is crucial for reproduction. It is regulated by numerous factors including transforming growth factor-ß1 (TGFB1). However, the regulatory mechanism of TGFB1 in ovarian angiogenesis is not fully understood. To address this, in this study we obtained high-throughput transcriptome analysis (RNA-seq) data from bovine luteinizing follicular cells cultured in a system mimicking angiogenesis and treated with TGFB1, and identified 455 differentially expressed genes (DEGs). Quantitative real-time PCR results confirmed the differential expression patterns of the 12 selected genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified that the MAPK and ErbB pathways, cell adhesion molecules (CAMs), and extracellular matrix (ECM)-receptor interactions may play pivotal roles in TGFB1-mediated inhibition of CL angiogenesis. TGFB1 phosphorylated ERK1/2 (MAPK1/3) and Akt, indicating that these pathways may play an important role in the regulation of angiogenesis. Several genes with specific functions in cell adhesion and ECM degradation were identified among the DEGs. In particular, TGFB1-induced upregulation of syndecan-1 (SDC1) and collagen type I alpha 1 chain (COL1A1) expression may contribute to the deposition of type I collagen in luteinizing follicular cells. These results indicate that TGFB1 inhibits cell adhesion and ECM degradation processes involving ERK1/2, ErbB, and PI3K/Akt signaling pathways, and leads to inhibition of angiogenesis during the follicular-luteal transition. Our results further reveal the molecular mechanisms underlying the actions of TGFB1 in early luteinization.

Monochromatic Green Light Stimulation during Incubation Alters Hepatic Glucose Metabolism That Improves Embryonic Development in Yangzhou Goose Eggs.

The influence of monochromatic green light stimulation on hatching performance and embryo development has been studied in chickens, but not geese. The liver has crucial functions in the regulation of energy metabolism during embryogenesis, but its involvement in green light transduction is still unidentified. We aimed to determine the influence of monochromatic green light on Yangzhou goose hatching performance and embryo development. We also investigated the metabolomics and transcriptomic responses of the embryonic liver to green light to determine the underlying molecular mechanisms. Eggs were incubated under either 12 h of monochromatic green light/dark (12 L:12D) cycles or 24 h of darkness (0G:24D). Green light promoted embryonic development and hatching performance, also affected the expression of myogenic regulatory factors associated with muscle development. It also shortened hatching time and elevated plasma levels of growth hormone and insulin-like growth factor-1. Metabolomics and transcriptomic results revealed differentially expressed genes and metabolites with enhanced gluconeogenesis/glycolysis and increased plasma glucose and pyruvate levels under green light. Hence, the growth-promoting effect possibly through regulating energy metabolism in the liver and myogenic regulatory factors in muscle. Our findings provide important and novel insights into the mechanisms underlying the beneficial effects of green light on goose embryos.

Simulation of Acute Pulmonary Hypertension in Beagle Dogs.

Acoustic cardiography (AC) combined with heart sound (HS) recording and electrocardiogram (ECG) provides a noninvasive and inexpensive way to understand the electrical mechanical activity of the heart. Pulmonary artery stenosis can cause hemodynamic abnormalities that might lead to pulmonary hypertension (PH). In this paper, we examined the relationships between the acoustic characteristics of the AC and hemodynamic changes in a beagle dog model of PH.Four healthy beagle dogs were injected with the prostaglandin endoperoxide receptor agonist U-44069 to induce acute PH states. AC was employed to analyze the process of pre-PH, intra-PH, and post-PH. Right ventricular blood pressure (RVBP) was measured via right cardiac catheterization, an invasive method performed in parallel for comparative hemodynamic evaluation. As RVBP increased or decreased, the HS features changed accordingly during acute PH occurrence and development. Right ventricular systolic blood pressure (RVSBP) significantly correlated with the minimum of the first HS (S1) amplitude (correlation coefficient (CC) = -0.82), energy of the S1 (CC = 0.86), energy of the second HS (S2) (CC = 0.67), entropy of the S1 (CC = -0.94), and ratio of electromechanical systolic time (EMST) to the cardiac cycle time (CC = 0.81). The two techniques (AC [HSs and ECG] versus right cardiac catheterization [RVBP]) were significantly correlated. Especially, the diastolic filling time (DFT) had a significant relationship with the right ventricular diastolic time (RVDT) (CC = 0.97), perfusion time (PT) (CC = 0.96), and cardiac cycle time (RR) (CC = 0.96). The CCs between the RVDT and the max dp/dt to min dp/dt, the EMST and the Q to min dp/dt, and the electromechanical activation time and the Q to max dp/dt were 0.95, 0.99, and 0.86, respectively. Furthermore, the logistic regression model with different combinations was used to identify the effective features for monitoring hemodynamic and pathophysiologic conditions.AC provided significant insight into mechanical dysfunction in a rapid and noninvasive way that could be used for early screening of PH.

Dehydrated UiO-66(SH)2 : The Zr-O Cluster and Its Photocatalytic Role Mimicking the Biological Nitrogen Fixation.

This work reports the dehydrated Zr-based MOF UiO-66(SH)2 as a visible-light-driven photocatalyst to mimic the biological N2 fixation process. The 15 N2 and other control experiments demonstrated that the new photocatalyst is highly efficient in converting N2 to ammonia. In-situ TGA, XPS, and EXAFS as well as first-principles simulations were used to demonstrate the role of the thermal treatment and the changes of the local structures around Zr due to the dehydration. It was shown that the dehydration opened a gate for the entry of N2 molecules into the [Zr6 O6 ] cluster where the strong N≡N bond was broken stepwise by µ-N-Zr type interactions driven by the photoelectrons aided by the protonation. This mechanism was discussed in comparison with the Lowe-Thorneley mechanism proposed for the MoFe nitrogenase, and with emphasis on the [Zr6 O6 ] cluster effect and the leading role of photoelectrons over the protonation. The results shed new light on understanding the catalytic mechanism of biological N2 fixation and open a new way to fix N2 under mild conditions.

DGAT1 inhibitors protect pancreatic ß-cells from palmitic acid-induced apoptosis.

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic ß-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic ß-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 µM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic ß-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 µM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic ß-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

Selective Photocatalytic Oxidation of Thioanisole on DUT-67(Zr) Mediated by Surface Coordination.

DUT-67(Zr) was obtained by a solvothermal route and applied to photocatalytic selective synthesis of thioanisole under light illuminating. The conversion of thioanisole is up to 95%, and the selectivity of methyl phenyl sulfoxide is 98%. The activity of DUT-67(Zr) is over 10 times higher than that of UiO-66. This great increased activity is attributed to the high percentages of oxygen vacancies on DUT-67(Zr). The ESR result shows there are more oxygen vacancies that can expose high density unsaturated Zr sites on DUT-67(Zr). The in situ FTIR reveals that unsaturated Zr sites on DUT-67(Zr) possess Lewis acidity which facilitate the adsorption of the substrates to form the coordination species, promoting the activation of thioanisole. The absorption edge of DUT-67(Zr) with coordination species red-shifts to 360 nm, which can be presented by DRS. Furthermore, the oxygen molecules can be activated by excited electrons to form •O2-. Finally, a possible photocatalytic process of oxidating thioanisole to methyl phenyl sulfoxide based on the coordination effect between DUT-67(Zr) and thioanisole is proposed at a molecular level.

Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma.

BACKGROUND: Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. METHODS: We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB. RESULTS: We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. CONCLUSIONS: Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

X chromosome-linked long noncoding RNA lnc-XLEC1 regulates c-Myc-dependent cell growth by collaborating with MBP-1 in endometrial cancer.

LncRNAs (long noncoding RNAs) are noncoding transcripts that are more than 200 nt long and have been described as the largest subclass in the noncoding transcriptome in humans. Although studies of lncRNAs in cancer have been continuing for a long time, no much has been known about X chromosome-linked lncRNAs. Here, by using RNA-seq we report the identification of a new X chromosome-linked lncRNA (lnc-XLEC1) that is aberrantly downregulated during the development of endometrial carcinoma (EC). The overexpression of lnc-XLEC1 reduces the migration and proliferation of EC cells. Flow cytometry analysis indicated that lnc-XLEC1 overexpression resulted in a substantial accumulation of EC cells in the G1 phase. In addition, lnc-XLEC1 had inhibitive effects that may result from its collaboration with MBP-1 during the suppression of the c-Myc expression and the negative regulating of the Cdk/Rb/E2F pathway. The anti-tumor effects of lnc-XLEC1 on EC progression suggest that lnc-XLEC1 has some potential value in anti-carcinoma therapies and deserves further investigation. Our study reported for the first time that the lnc-XLEC1 might be related to the incidence and prognosis of EC. Moreover, we discovered that this process might be related to somatic X dosage compensation and skewed X chromosome inactivation (SXCI).

Concise and Gram-Scale Total Synthesis of Lansiumamides A and B and Alatamide.

The total synthesis of potent anti-obesity lansiumamide B was accomplished in four steps using commercially available materials. The synthetic strategy, featured with copper-catalyzed Buchwald coupling, is concise, convergent, practical and can be carried out on a one-gram scale. This approach could give either Z- or E-configured enamide moiety in natural products with absolute stereocontrol and was applied in the total synthesis of natural products.

Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety.

A series of diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors with a picolinoylpyrrolidine-2-carboxylic acid moiety were designed and synthesized. Of these compounds, compound 22 exhibited excellent DGAT-1-inhibitory activity (hDGAT-1 enzyme assay, 50% inhibitory concentration [IC50]=3.5±0.9nM) and effectively reduced the intracellular triglyceride contents in 3T3-L1, HepG2 and Caco-2 cells. A preliminary study of the plasma and tissue distributions of compound 22 in mice revealed low plasma exposure and high concentrations in different segments of the intestine and liver, which may facilitate targeting DGAT-1. Furthermore, in an acute lipid challenge test, compound 22 showed a dose-dependent inhibitory effect on high-serum triglycerides in C57/KSJ mice induced by olive oil (1, 3, and 10mg/kg, i.g.).

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors.

The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 µmol/L, which was lower than that of vemurafenib (0.13 µmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

Chlorogenic acid analogues from Gynura nepalensis protect H9c2 cardiomyoblasts against H2O2-induced apoptosis.

AIM: Chlorogenic acid has shown protective effect on cardiomyocytes against oxidative stress-induced damage. Herein, we evaluated nine caffeoylquinic acid analogues (1-9) isolated from the leaves of Gynura nepalensis for their protective effect against H2O2-induced H9c2 cardiomyoblast damage and explored the underlying mechanisms. METHODS: H9c2 cardiomyoblasts were exposed to H2O2 (0.3 mmol/L) for 3 h, and cell viability was detected with MTT assay. Hoechst 33342 staining was performed to evaluate cell apoptosis. MMPs (mitochondrial membrane potentials) were measured using a JC-1 assay kit, and ROS (reactive oxygen species) generation was measured using CM-H2 DCFDA. The expression levels of relevant proteins were detected using Western blot analysis. RESULTS: Exposure to H2O2 markedly decreased the viability of H9c2 cells and catalase activity, and increased LDH release and intracellular ROS production; accompanied by a loss of MMP and increased apoptotic rate. Among the 9 chlorogenic acid analogues as well as the positive control drug epigallocatechin gallate (EGCG) tested, compound 6 (3,5-dicaffeoylquinic acid ethyl ester) was the most effective in protecting H9c2 cells from H2O2-induced cell death. Pretreatment with compound 6 (1.56-100 µmol/L) dose-dependently alleviated all the H2O2-induced detrimental effects. Moreover, exposure to H2O2 significantly increased the levels of Bax, p53, cleaved caspase-8, and cleaved caspase-9, and decreased the level of Bcl-2, resulting in cell apoptosis. Exposure to H2O2 also significantly increased the phosphorylation of p38, JNK and ERK in the H9c2 cells. Pretreatment with compound 6 (12.5 and 25 µmol/L) dose-dependently inhibited the H2O2-induced increase in the level of cleaved caspase-9 but not of cleaved caspase-8. It also dose-dependently suppressed the H2O2-induced phosphorylation of JNK and ERK but not that of p38. CONCLUSION: Compound 6 isolated from the leaves of Gynura nepalensis potently protects H9c2 cardiomyoblasts against H2O2-induced apoptosis, possibly by inhibiting intrinsic apoptosis and the ERK/JNK pathway.

Identification of autoreactive CD8+ T cell responses targeting chromogranin A in humanized NOD mice and type 1 diabetes patients.

ChgA has recently been identified as the autoantigen for diabetogenic CD4(+) T cells in NOD mice and T1D patients. However, autoreactive CD8(+) T-cell responses targeting ChgA haven't been studied yet. Here several HLA-A*0201-restricted peptides derived from mChgA and hChgA were selected by an integrated computational prediction approach, followed by an HLA-A*0201 binding assay. MChgA10-19 and mChgA(43-52) peptides, which bound well with HLA-A*0201 molecule, induced significant proliferation and IFN-γ-releasing of splenocytes from diabetic NOD.ß2m(null).HHD mice. Notably, flow cytometry analysis found that mChgA(10-19) and mChgA(43-52) stimulated the production of IFN-γ, perforin, and IL-17 by splenic CD8(+) T cells of diabetic NOD.ß2m(null).HHD mice. Furthermore, hChgA(10-19) and hChgA(43-52)-induced IFN-γ releasing by specific CD8(+) T cells were frequently detected in recent-onset HLA-A*0201-positive T1D patients. Thus, this study demonstrated that autoreactive CD8(+) T cells targeting ChgA were present in NOD.ß2m(null).HHD mice and T1D patients, and might contribute to pathogenesis of T1D through secreting proinflammatory cytokines and cytotoxic molecules.

Ebselen and TPI-1, as RecG helicase inhibitors, potently enhance the susceptibility of Pseudomonas aeruginosa to DNA damage agents.

Holliday junction (HJ) is a four-way structured DNA intermediate in processes of homologous recombination and DNA double-stranded break (DSB) repair. In bacteria, HJs are processed via either the RuvABC or RecG-dependent pathways. In addition, RecG also plays a critical role in the reactivation of stalled replication forks, making it an attractive target for antibacterial drug development. Here, we conducted a high-throughput screening targeting the RecG helicase from a common opportunistic pathogen Pseudomonas aeruginosa (Pa). From a library containing 7920 compounds, we identified Ebselen and TPI-1 (2',5'-Dichloro-[1,1'-biphenyl]-2,5-dione) as two potent PaRecG inhibitors, with IC50 values of 0.31 ± 0.02 µM and 1.16 ± 0.06 µM, respectively. Further biochemical analyses suggested that both Ebselen and TPI-1 inhibited the ATPase activity of PaRecG, and hindered its binding to HJ DNA with high selectivity. These compounds, when combined with our previously reported RuvAB inhibitors, resulted in more severe DNA repair defects than the individual treatment, and potently enhanced the susceptibility of P. aeruginosa to the DNA damage agents. This work reports novel small molecule inhibitors of RecG, offering valuable chemical tools for advancing our understanding of RecG's function and mechanism. Additionally, these inhibitors might be further developed as promising antibacterial agents in the fight against P. aeruginosa infections.

Research Note: Effect of different photoperiodic programs from rearing period on the reproductive performance and hormone secretion of White King pigeons.

The photoperiod is an important factor during rearing and laying period that affects age and body weight at sexual maturation and reproductive performance in poultry; however relevant research on this factor in pigeons is still lacking. Thus, this study investigated the effects of different photoperiodic programs on the reproductive performance and hormonal profile in White King pigeons. From 101 d of age, the pigeons in the control group were exposed to a natural photoperiod until 160 d, and then to a photoperiod of 16 h (16 light [L]: 8 dark [D]) and lasted for 200 d. Pigeons in the 3 experimental groups were exposed to a short photoperiod of 8L: 16D until 160 d, and then to 14L: 10D, 16L: 8D, and 18L: 6D, respectively. The results showed that light-restriction (8L: 16D) during the rearing period and then 14L: 10D or 16L: 8D photostimulation delayed the age at first egg laying in pigeons. However, 16L: 8D after an 8L: 16D photoperiod during the breeding period ensured maximum photosensitivity, and significantly improved the reproductive performance (egg production and fertility rates) in pigeons. Moreover, the highest reproductive performance in group under16L: 8D after 8L: 16D photoperiodic program was accompanied by improved follicle-stimulating hormone and estradiol levels and reduced prolactin hormone levels. The results indicated that photoperiodic programs from rearing to laying period are closely related to the reproductive performance of White King pigeons. The results provide information that 8L: 16D during rearing period and 16L: 8D during laying period can be used to enhance reproductive performance in the pigeon industry.