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Ovarian cancer (OC) is one of the most lethal gynecologic cancers that is typically diagnosed at the very late stage of disease progression. Thus, there is an unmet need to develop diagnostic probes for early detection of OC. One approach may rely on RNA as a molecular biomarker. In this regard, FLJ22447 lncRNA is an RNA biomarker that is over-expressed in ovarian cancer (OC) and in cancer-associated fibroblasts (CAFs). CAFs appear early on in OC as they provide a metastatic niche for OC progression. FIT-PNAs (forced intercalation-peptide nucleic acids) are DNA analogs that are designed to fluoresce upon hybridization to their complementary RNA target sequence. In recent studies, we have shown that the introduction of cyclopentane PNAs into FIT-PNAs (cpFIT-PNA) results in superior RNA sensors. Herein, we report the design and synthesis of cpFIT-PNAs for the detection of this RNA biomarker in living OC cells (OVCAR8) and in CAFs. cpFIT-PNA was compared to FIT-PNA and the cell-penetrating peptide (CPP) of choice was either a simple one (four L-lysines) or a CPP with enhanced cellular uptake (CLIP6). The combination of CLIP6 with cpFIT-PNA resulted in a superior sensing of FLJ22447 lncRNA in OVCAR8 cells as well as in CAFs. Moreover, incubation of CLIP6-cpFIT-PNA in OVCAR8 cells leads to a significant decrease (ca. 60%) in FLJ22447 lncRNA levels and in cell viability, highlighting the potential theranostic use of such molecules. [ABSTRACT FROM AUTHOR]

Treatment of 1,6-diynes (syntheses described) according to A) proceeds diastereoselectively to produce the important 1,2-trimethylenenorbornane core bearing an exocyclic alkene function. In the case of substrate (VII), the bicyclic compound (VIII) is also formed. It can be slowly converted to (IX) in the presence of the gold catalyst and is assumed to be an intermediate in the process. [ABSTRACT FROM AUTHOR]

Landslide dam failure and induced morphological changes are dependent on the material composition. A bimodal material composition is observed in landslide dams and riverbeds, but its influence on dam failure and morphological changes is poorly understood. In this study, we experimentally investigate landslide dam failure and its effect on local morphology by varying both dam and bed material composition. The results show that the peak discharge and final breach size increase, while the upstream residual water level decreases with increasing fine material (sand) content in the dam material. The effect of the bed material is limited and the whole dam failure process is rather controlled by the dam material. However, erosion surface slope and final erosion depth vary with changes in both dam and bed material. Sediments are deposited unevenly on the erodible bed, resulting in the formation of sandbars after dam failure. Similar topographies are observed with different erodible beds, while the deposition area and the anisotropy of deposition depth increase with increasing sand content in the dam material. The influence of bimodal material on dam failure and morphological changes is related to the incipient motion and transport of sediments, leading to the formation of armour layer and non-uniform bedform after dam failure. A dam failure pattern is proposed by considering the variation of the erosion surface slope caused by the change in erosion rate and the occurrence of deposition during dam failure. This study improves the understanding of landslide dam failure and induced morphological changes, and further aids the hazard management. [ABSTRACT FROM AUTHOR]

• Dulaglutide ameliorated ox-LDL-induced oxidative stress and mitochondrial dysfunction. • Dulaglutide suppressed ox-LDL-induced secretion of IL-1β, IL-6, MCP-1, and HMG-1. • Dulaglutide suppressed ox-LDL-induced reduction of cell viability and release of LDH. • Dulaglutide suppressed attachment of THP-1 to HAECs by inhibiting VCAM-1, E-selectin. • Dulaglutide promoted the expression of KLF2 through inhibiting the activation of p53. Atherosclerosis is a common comorbidity of type II diabetes and a leading cause of death worldwide. The presence of oxidized low-density lipoprotein (ox-LDL) drives atherogenesis by inducing oxidative stress, mitochondrial dysfunction, expression of proinflammatory cytokines and chemokines including interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein 1 (MCP-1), adhesion molecules including vascular cellular adhesion molecule 1 (VCAM-1) and E-selectin, and downregulating expression of the Krüppel-like factor 2 (KLF2) transcription factor. Importantly, ox-LDL induced the attachment of THP-1 monocytes to endothelial cells. In the present study, we demonstrate for the first time that the specific glucagon-like peptide 1 receptor (GLP-1R) agonist dulaglutide may prevent these atherosclerotic effects of ox-LDL by preventing suppression of KLF2 by p53 protein in human aortic endothelial cells. KLF2 has been shown to play a major role in protecting vascular endothelial cells from damage induced by ox-LDL and oscillatory shear, and therefore, therapies capable of mediating KLF2 signaling may be an attractive treatment option for preventing the development and progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

The geometries and material properties of a landslide dam depend on the dam formation process and affect the breaching process. A comprehensive understanding of the entire process of dam formation and breach is necessary for a more accurate analysis of the dam stability and failure characteristics, but little research has been done in this area. In this study, the effects of debris composition, sliding width, and valley shape on dam breaching by considering dam formation features were experimentally investigated. Results reveal that the stability and failure modes of landslide dams are predominantly governed by the debris composition. The dam stability increases with mean grain size, especially the grain size at the overflow location. Dam height and width are largely influenced by debris composition and sliding width, and the lake volume is highly dependent on the valley shape. The arrival time of peak discharge for balance-grained dams is more related to the dam height than the lake volume, while fine-grained dams are the opposite. The peak discharge is significantly influenced by the lake volume and released water volume, while the effects of dam height, downstream slope, and lake shape coefficient are negligible. Balance-grained dams exhibit two longitudinal evolution models in different shaped valleys. The evolution model of fine-grained dams is different from that of balance-grained dams and is independent of valley shape. This study improves our current understanding of the whole process of landslide dams from formation to failure and the effects of dam formation features on dam breaching. [ABSTRACT FROM AUTHOR]

The sudden breach of a landslide dam seriously threatens the safety of people and property downstream. The failure mechanism of landslide dams is significantly affected by the grain size distribution of the dam material. In this study, a series of experiments are conducted to investigate the effects of grain composition on the stability, breach process, and breach parameters of landslide dams. The results show that dams remain stable with seepage for a coarse-dominated dam, fail by overtopping along with piping for a fines-dominated dam, and fail by overtopping alone for a balanced-composition dam. The failure mode is regulated by the composition of dam material, stress condition and hydraulic gradient. Backward erosion occurs for dams with fines contents <5 % due to the movement of debris, during which the width:depth ratio of the cross section first decreases and then increases. By contrast, for dams with fines contents higher than 15 %, headcutting occurs and a step-pool structure develops because the small grains are more easily washed away than the coarse grains. In this scenario, the width:depth ratio first increases and then decreases. Dam longevity nonlinearly increases with increasing fines content. The breach hydrography changes from a single peak to multiple peaks with increasing fines content, and the peak discharge is sensitive to the median diameter of dam material. In addition, the breach degree, defined as the ratio of the releasing potential energy (total potential energy minus the residual potential energy) to the total potential energy of the lake upstream of the landslide dam, is controlled by this median diameter. This study improves our understanding of failure mechanisms and aids the hazard assessment of landslide dams. • The fines content controls the breach pattern, longevity and peak discharge. • The fines content affects the evolution of both longitudinal and cross sections. • The proportions of silt, sand, and gravel affect the stability of landslide dams. • The median diameter of debris controls the morphology of a residual dam. [ABSTRACT FROM AUTHOR]

• Breaching process of landslide dams is controlled by material composition and internal structures. • Four longitudinal evolution patterns are derived to describe the erosion process. • Peak discharge and residual dam parameters for homogeneous dams are sensitive to median diameters. • Breaching and residual dam parameters for inverse grading structure dams are within the values for dams formed by top and bottom layer material. • Employing top layer materials to characterize inverse grading structure dams lead to significant errors in breach parameters analysis. Landslide dams are composed of wide-graded materials characterized by nonuniform structures that govern breaching mechanisms. However, investigations of the failure characteristics of single-structure dams with different material compositions and inverse grading structure dams remain insufficient. In this study, a series of flume experiments are conducted to investigate the influences of noncohesive dam materials and inverse grading structures on the breaching mechanisms, hydraulic characteristics and residual dam parameters during and after landslide dam failures. The results indicate that the dam breach process is controlled by the material composition and dam structure. A coarse-grained dam remains stable with seepage, a medium-grained dam fails by headcutting and backwards erosion, and a fine-grained dam fails due to layered erosion. An inverse grading dam with coarse-grained overburden features backwards erosion or a combination of sliding and backwards erosion, while a dam with medium-grained overburden fails by headcutting and backwards erosion. The maximum erosion rate occurs at the accelerated breaching stage for single-structure dams and at the initial overtopping or accelerated breaching stage for inverse grading structure dams. Four longitudinal evolution patterns are extracted based on the breach process and erosion characteristics. In addition, the outflow discharge during dam failure can be estimated by measuring the breach width, which is defined as the straight line distance between the ends of the breach crest at the overflow face. Both the peak discharge and residual dam parameters for single-structure dams are sensitive to the median diameter of the material. These parameters of inverse grading structure dams fall within the range of values observed for dams formed by the top layer material and the bottom layer material. The initial overtopping and backwards erosion stages account for 10%–35% and 36%–66% of the total breach duration for single-structure and inverse grading structure dams, respectively. Serious errors in the prediction of breach parameters can occur when top layer materials are considered to characterize the material of inverse grading structure dams. [ABSTRACT FROM AUTHOR]

This study aims to accurately predict landslide displacement characterized by a step-like displacement curve, resulting from complex interactions among multiple factors, including periodic and variable elements. Specifically, we propose a framework based on a Convolutional Neural Network (CNN) and optimized Bidirectional Gated Recurrent Unit (BiGRU) with an Attention mechanism, designed to forecast landslide displacement with a step-like curve. Initially, landslide displacements are decomposed into periodic and trend terms utilizing complementary ensemble empirical mode decomposition with adaptive noise (CEEMDAN) algorithm. Subsequently, a CNN layer is constructed to extract intricate high-dimensional features, while a BiGRU layer is established to capture temporal dependencies within historical sequences. Notably, an attention mechanism module is introduced to enhance the impact of key information within rainfall, water level, and historical displacement data. Finally, the nonlinear weighted Huber loss function (NLWHL) evaluation method is introduced to assess the accuracy of the model in predicting mutation states. The results demonstrate that the proposed framework exhibited superior accuracy in predicting landslide displacement in comparison to alternative intelligent algorithms. Regarding total displacement, the CNN-BiGRU-Attention model demonstrates superior predictive capabilities, reducing RMSE values by 12.52%, 14.15%, 15.58%, 21.68%, 21.84%, 32.81%, 58.10%, and 53.81% in the test set compared to CNN-BiGRU, CNN-BiLSTM, BiGRU-Attention, SMA-GRU, SMA-LSTM, SMA-SVM, GRU, and LSTM, respectively. Furthermore, the introduction of NLWHL underscores the remarkable accuracy of the proposed framework in forecasting both creep and mutation states. Assessing the displacement mutation state provides the necessary opportunity for early detection and intervention. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is an ischemic heart disease due to the narrowing of the coronary arteries resulting from atherosclerosis. Blood biomarkers have been well utilized for the diagnosis and prognosis of CAD. However, the value of biomarkers for evaluating coronary atherosclerosis remains to be clarified. This clinical investigation aimed to explore the potential value of biomarkers for evaluating the severity of coronary stenosis in CAD patients. The extent of coronary atherosclerosis was accessed by the angiography-based quantitative measurement Gensini score (GS). Blood levels of Brain natriuretic peptide, Copeptin (CPP), Phosphodiesterase 9A, and Pentraxin3 (PTX3) were measured in 56 patients divided into three levels as low GS (n = 17), intermediate GS (n = 19) and high GS (n = 20) based on GS tertiles. We found that plasma concentrations of CPP and PTX3 were significantly elevated in patients with high GS compared with the low GS group. In addition, Pearson correlation analysis showed that CPP and PTX3 were positively correlated with the GS. Furthermore, Receiver operating characteristics analysis demonstrated that both CPP and PTX3 exhibited discriminative capacities for evaluating the extent of coronary stenosis. Laboratory tests of CPP and PTX3 via non-invasive means may provide novel information for risk stratification and disease management in CAD patients before invasive angiographic approaches. This study opens the door for enormous opportunities to explore new biomarkers with better efficiency, sensitivity and specificity as alternative/additional methods for evaluating the severity of coronary atherosclerosis in CAD patients in future research. [ABSTRACT FROM AUTHOR]

This research proposed a novel deep learning framework that combines the Laplace function sparse regularized continuous deep belief network (LSCDBN) and the Gray Wolf Optimization Algorithm (GWO) and the Whale Optimization Algorithm (WOA), to perform landslide susceptibility assessment. This framework mitigates the challenges of feature homogenization for continuous input variables for landslide condition factors, limited landslide samples, and local optima in the training process. To facilitate this investigation, a meticulous compilation of existing landslide occurrences was used to create a database comprising 18 landslide conditioning factors. To compare the performance of the model, a set of statistical indicators was employed. The results demonstrate the superior performance of both the LSCDBN-GWO model (AUC = 0.952, RMSE = 0.182) and LSCDBN-WOA model (AUC = 0.964, RMSE = 0.174) when compared to the alone LSCDBN model (AUC = 0.913, RMSE = 0.291). It is noteworthy that the performance of the LSCDBN model outperformed that of lone machine learning models (SVM, BP, RF, and LR), lone deep learning models (RNN and CNN), and hybrid deep learning models (CNN-GWO and CNN-WOA). Therefore, it is evident that the proposed LSCDBN-WOA framework can generate models that are optimally suited for landslide susceptibility assessment. [ABSTRACT FROM AUTHOR]

[Display omitted] • At the initial cracking load, the macroscopic crack-zone length increased with increasing fiber-volume fraction, whereas the fracture-process zone (FPZ) length decreased. • At the F MOR , the macroscopic crack and FPZ lengths of specimens were approximately 62.47 and 22.12 mm. • At the 30% F MOR , the macroscopic crack and FPZ lengths of specimens were approximately 75.99 and 18.90 mm. • A linear relationship between fiber pull-out number and equivalent bending stress, as well as between total fiber pull-out length and toughness, was established. • The tension softening curves obtained from the bi-linear softening curve analysis underestimated the experimental results. • The trilinear softening curve analysis exhibited good agreement with the experimental results. Here, the mechanical properties and crack propagation nalysing of functional gradient ultra-high-performance concrete (FGUHPC) were nalysin using the digital image correlation (DIC) method. The fiber layer thickness (0, 25, 50, 75, and 100 mm) was varied to evaluate the impact on the FGUHPC. A quadratic equation was introduced to evaluate the compressive strength of FGUHPC, and a numerical model based on nonlinear fracture mechanics was established to predict the load crack opening displacement (COD) relationship. Results indicated that the maximum contribution of fibers to flexural strength occurred with a fiber layer thickness of 75 mm. The strength enhancement factor (ξ) was 1.139 and the fracture factor (K IC) was 1.5. The crack propagation nalysing of FGUHPC displayed an increasing curvilinear trend as the fiber layer thickness increased. The mid-span vertical displacement and crack opening displacement had a linear relationship, and the scale factor was 0.549. The fiber layer thickness had a limited effect on the fiber dispersion coefficient (α) and the orientation distribution (η θ). The two-parameter exponential function proposed accurately evaluated the probability of fiber distribution. The trilinear matrix softening accurately predicted the load-COD curves. Compared to a fiber layer thickness of 100 mm, the specimen with a thickness of 75 mm reduced cost by 13.3% while only decreasing strength by 4.4%, demonstrating the potential of FGUHPC for practical engineering applications. [ABSTRACT FROM AUTHOR]

Two large successive co-site landslide dams blocked the Jinsha River in the Sichuan Province of China in 2018. A quantitative risk analysis was carried out to quantify potential human and economic losses resulting from the failure of these dams, especially the interaction between the co-site landslide dams, and to further investigate the influence of digging a diversion channel on risk mitigation. Flood routing for three scenarios (i.e. after the first dam formation, when the second landslide mass was added, and with a diversion channel after failures) were simulated using HEC-RAS. The human and economic losses were evaluated using a human risk assessment model together with empirical formulations. The results show that the risk of breaching floods had increased significantly after the second co-site landslide dam formation on the pre-existing loose deposits of the first dam. This amplification effect of outburst floods was so great that the peak outflow resulting from the breaching of the second landslide dams was more important, leading to greater economic losses than those resulting from the breaching of the first dam. However, the expected loss of life caused by the breach of the two landslide dams appeared small because of the sufficient time lag provided by the long distance between the residential area and the dam site. The simulations also outline the importance of the diversion channel in decreasing the peak outflow rate and hence downstream risks. A parametric analysis shows that a deep channel with a moderate longitudinal gradient can significantly decrease the peak outflow discharge at the dam site. Flood intensity and risks to downstream towns did not change because of the relatively small attenuation rate of the peak outflow rate. However, a shorter height of the residual dam can be obtained by optimizing the diversion channel, and the amplification effects of such co-site dam can be significantly reduced in the future. • The human and economic risks caused by the two co-site Baige landslide dams are quantitatively assessed. • The reasons why an amplification effect of flood intensity and downstream risks occurred are systematically investigated. • An optimal diversion channel is obtained based on parametric analysis of the peak outflow rate during dam breach. • The influence of the diversion channel in flood intensity, risks in downstream and risk mitigation is discussed. [ABSTRACT FROM AUTHOR]

Coronary atherosclerosis leading to ischemic artery disease is one of the etiological factors to develop heart failure (HF). This study aimed to investigate potential biomarkers for discriminating HF in atherosclerotic patients. This study included 40 consecutive atherosclerotic patients who underwent angiography. Concentrations of B-type natriuretic peptide (BNP), fibronectin type III domain containing 5 (FNDC5), and Phosphodiesterase 9A (PDE9A) were measured in 20 atherosclerotic patients with HF symptoms/signs and 20 without HF symptoms/signs. Circulating BNP levels were elevated, while FNDC5 levels were reduced in atherosclerotic patients with HF symptoms/signs compared to those without HF symptoms/signs. Pearson correlation analysis showed a significant correlation between FNDC5 and BNP. Receiver Operating Characteristics analysis indicated that both FNDC5 and BNP were able to discriminate HF in atherosclerotic patients. Our findings suggest that FNDC5, along with BNP, has independent value as a biomarker for discriminating HF in patients with coronary atherosclerosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.

The evolution of drug resistance to many antimalarial drugs in the lethal strain of malaria ( Plasmodium falciparum ) has been a great concern over the past 50 years. Among these drugs, artemisinin has become less effective for treating malaria. Indeed, several P. falciparum variants have become resistant to this drug, as elucidated by specific mutations in the pfK13 gene. This study presents the development of a diagnostic kit for the detection of a common point mutation in the pfK13 gene of P. falciparum , namely, the C580Y point mutation. FIT-PNAs (forced-intercalation peptide nucleic acid) are DNA mimics that serve as RNA sensors that fluoresce upon hybridization to their complementary RNA. Herein, FIT-PNAs were designed to sense the C580Y single nucleotide polymorphism (SNP) and were conjugated to biotin in order to bind these molecules to streptavidin-coated plates. Initial studies with synthetic RNA were conducted to optimize the sensing system. In addition, cyclopentane-modified PNA monomers (cpPNAs) were introduced to improve FIT-PNA sensing. Lastly, total RNA was isolated from red blood cells infected with P. falciparum (WT strain - NF54-WT or mutant strain - NF54-C580Y). Streptavidin plates loaded with either FIT-PNA or cpFIT-PNA were incubated with the total RNA. A significant difference in fluorescence for mutant vs WT total RNA was found only for the cpFIT-PNA probe. In summary, this study paves the way for a simple diagnostic kit for monitoring artemisinin drug resistance that may be easily adapted to malaria endemic regions.

Partial endothelial-to-mesenchymal transition (EndMT) is an intermediate phenotype observed in endothelial cells (ECs) undergoing a transition toward a mesenchymal state to support neovascularization during (patho)physiological angiogenesis. Here, we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4 (GTF2H4) as a positive regulator of this process. In addition, we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3 (ERCC3) to co-regulate partial EndMT. Furthermore, by using phosphorylation proteomics and site-directed mutagenesis, we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3 (NCOA3) at serine 1330, which promoted the interaction between NCOA3 and p65, resulting in the transcriptional activation of NF-κB and the NF-κB/Snail signaling axis during partial EndMT. In vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic injury. Collectively, our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Selective incorporation of conformational constraints into thyclotides can be used to modulate their binding to complementary oligonucleotides, increase polarity, and optimize uptake into HCT116 cells without assistance from moieties known to promote cell uptake. The X-ray structure and biophysical studies of a thyclotide-DNA duplex reveal that incorporation of tetrahydrofurans into an aeg PNA backbone promotes a helical conformation that enhances binding to complementary DNA and RNA. Selective incorporation of tetrahydrofurans into the aeg PNA backbone allows polarity to be increased incrementally so that uptake into HCT116 cells can be optimized. The enhanced binding, polarity, and cellular uptake properties of thyclotides were used to demonstrate effective inhibition of microRNA-21 in HCT116 cells., Competing Interests: The authors declare the following competing financial interest(s): Part of this work has been patented (Thyclotide. WO2021211786A1). Inventors: Daniel H. Appella, Hongchao Zheng, Harsha C. Amarasekara, Victor Clausse, George A. Kubi., (Not subject to U.S. Copyright. Published 2023 by American Chemical Society.)

The wild-type p53 induced phosphatase 1 (Wip1), a member of the serine/threonine-specific PP2C family, is overexpressed in numerous human cancers. Wip1 dephosphorylates p53 as well as several kinases (such as p38 MAPK, ATM, Chk1, and Chk2) in the DNA damage response pathway that are responsible for maintaining genomic stability and preventing oncogenic transformation. As a result, Wip1 is an attractive target for synthetic inhibitors that could be further developed into therapeutics to treat some cancers. In this study, we report a series of alkyl-substituted N-methylaryl-N'-aryl-4-aminobenzamides and their inhibitory activity of the Wip1 phosphatase. A straightforward synthetic route was developed to synthesize the target compounds from commercially available starting materials. Three different portions (R 1 , R 2 , R 3 ) of the core scaffold were extensively modified to examine structure-activity relationships. This study revealed interesting trends about a new molecular scaffold to inhibit Wip1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Masson SAS.)

Peptide nucleic acids (PNAs) are promising therapeutic molecules for gene modulation; however, they suffer from poor cell uptake. Delivery of PNAs into cells requires conjugation of the PNA to another large molecule, typically a cell-penetrating peptide or nanoparticle. In this study, we describe a new PNA-based molecule with cyclic tetrahydrofuran (THF) backbone modifications that in some cases considerably improve cell uptake. We refer to these THF-PNA oligomers as thyclotides. With THF groups at every position of the oligomer, the cell uptake of thyclotides targeted to miR-21 is enhanced compared with the corresponding unmodified PNA based on an aminoethylglycine backbone. An optimized thyclotide can efficiently enter cells without the use of cell-penetrating peptides, bind miR-21, its designated microRNA target, decrease expression of miR-21 and increase expression of three downstream targets (PTEN, Cdc25a and KRIT1). Using a plasmid with the PTEN-3'UTR coupled with luciferase, we further confirmed that a miR-21-targeted thyclotide prevents miR-21 from binding to its target RNA. Additionally, the thyclotide shows no cytotoxicity when administered at 200 times its active concentration. We propose that thyclotides be further explored as therapeutic candidates to modulate miRNA levels., (Published by Oxford University Press on behalf of Nucleic Acids Research 2022.)

Oxidized low-density lipoprotein (ox-LDL) accumulation in the vascular wall plays a pivotal role in the development of atherosclerosis and vascular calcification. However, few studies focus on the regulatory roles of microRNAs in ox-LDL stimulated vascular calcification. The aim of the present study was to investigate how miR-33a-5p regulated vascular calcification stimulated by ox-LDL. In the present study, miR-33a-5p was downregulated during vascular smooth muscle cells (VSMCs) calcification and upon ox-LDL treatment. ox-LDL significantly stimulated VSMCs calcification, while miR-33a-5p overexpression by its mimics transfection inhibited alkaline phosphatase (ALP) activity, mineralization and marker genes associated with VSMCs calcification even in the presence of ox-LDL. Methyltransferase like 3 (METTL3) was the target gene of miR-33a-5p. METTL3 was upregulated during VSMCs calcification and upon ox-LDL treatment. When VSMCs were transfected with miR-33a-5p mimics, METTL3 was downregulated. METTL3 downregulation by siRNA method decreased VSMCs calcification even in the presence of ox-LDL. Taken together, these results suggest miR-33a-5p suppresses VSMCs calcification stimulated by ox-LDL via targeting METTL3, highlighting the critical role of miR-33a-5p/METTL3 in vascular calcification., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Inhibition of MER receptor tyrosine kinase (MERTK) causes direct tumor cell killing and stimulation of the innate immune response. Therefore, MERTK has been identified as a therapeutic target in a wide variety of human tumors. Clinical trials targeting MERTK have recently been initiated, however, none of these drugs are MERTK-specific. Herein, we present the discovery of a highly MERTK-selective inhibitor UNC5293 (24). UNC5293 has subnanomolar activity against MERTK with an excellent Ambit selectivity score (S 50 (100 nM) = 0.041). It mediated potent and selective inhibition of MERTK in cell-based assays. Furthermore, it has excellent mouse PK properties (7.8 h half-life and 58% oral bioavailability) and was active in bone marrow leukemia cells in a murine model., Competing Interests: Declaration of competing interest The authors declared the following financial interests/personal relationships which may be considered as potential competing interests: HSE, DKG & SVF report equity ownership and membership on the Meryx Board of Directors. DK, DD & XW report equity ownership in Meryx. HZ, JZ, WZ, SVF & XW report patents from the University of North Carolina., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2 H -1λ 2 -quinoline-2,5(6 H )-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 ( NCATS - SM5637 , NSC 791985 ). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

Cardiac rehabilitation (CR) plays an important role in cardiovascular disease prevention. Understanding the key component of CR such as training intensity and biomarkers reflecting cardiopulmonary functions may help to better target the rehabilitation program. Thirty-four consecutive patients with coronary artery disease after percutaneous coronary intervention participated in the CR program. The difference between intervention group and control group was mainly the training intensity. Cardiopulmonary exercise testing (CPET) and blood biomarker measurements were performed before and after CR. The results demonstrated that it was safe and feasible to perform CR, while sufficient training intensity was required to significantly ameliorate CPET parameters. Among numerous biomarkers tested, vasopressin surrogate marker copeptin (CPP) improved significantly after CR. Moreover, improved CPP was correlated with exercise intensity and peak oxygen uptake, two most important indicators of cardiopulmonary exercise capacities. Therefore, CR may have a novel role in maintaining plasma osmolality and cardiovascular homeostasis. Graphical Abstract Cardiac rehabilitation training improves cardiopulmonary exercise parameters El and PVO 2 which are correlated with reduced CPP level. CPP, copeptin; El, exercise intensity; POV2, peak oxygen uptake.

Background: The RESOLUTE-DIABETES CHINA study was specifically designed to investigate the safety and efficacy of Resolute zotarolimus-eluting stents (ZES; Medtronic, Santa Rosa, CA, USA) in the treatment of diabetic coronary lesions in the Chinese population., Methods: In all, 945 patients with de novo native coronary lesions and type 2 diabetes mellitus were recruited at 32 cardiac centers across the Chinese mainland and were implanted with Resolute ZES. The primary endpoint was target vessel failure (TVF); secondary endpoints were clinical outcomes, namely all-cause death, stroke, bleeding, target lesion revascularization (TLR), target vessel revascularization (TVR), non-TVR, and stent thrombosis (ST). The follow-up period for all endpoints was 12 months after the procedure., Results: In all, 933 patients (98.73%) had clinical follow-up at 12 months. The rate of TVF was 11.60%, whereas the rate of occurrence of secondary endpoints was 5.47%, with four patients (0.43%) having subacute or late ST. There were no significant differences in TVF rates comparing patients with different HbA1c levels or receiving different glucose control treatments (all P > 0.05). Patients with multivessel lesions had higher TVF rates (95% confidence intervals) than those with single-vessel lesions (16.76% [12.10%-22.97%) vs 9.72% [7.79%-12.11%], respectively; P = 0.006). There were no significant differences in TVF rates in patients with or without small vessels, bifurcated lesions, or chronic total occlusions (all P > 0.05). [Correction added on 17 January 2019, after first online publication: in the second sentence of Results section, "TLF" was changed to "TVF".]., Conclusions: Resolute ZES may perform well in the Chinese diabetic population, especially in those with poor glucose control, complex lesions, and certain unfavorable clinical features. Further studies are needed to determine why ZES perform well in this population., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

An efficient synthesis of Fmoc-protected ( S, S)- trans-cyclopentane PNA ( tcypPNA) monomers starting from mono-Boc-protected ( S, S)-1,2-cyclopentanediamine is reported. A general synthetic strategy was developed so that tcypPNA monomers with each nucleobase can be made in sufficient quantity and purity for use in solid-phase peptide synthesis (SPPS). The newly synthesized monomers were then successfully incorporated into 10-residue PNA oligomers using standard Fmoc chemistry for SPPS. The different tcypPNAs allow different positions in the sequence to be conformationally constrained with ( S, S)- trans-cyclopentane to determine the effects on binding to complementary DNA.

Objective: To investigate the mechanisms underlying the therapeutic effects of losartan on hyperuricemia-induced aortic atherosclerosis, in an experimental rabbit model., Methods: Male rabbits (n = 48) were divided into control, hyperuricemia (HU), hypercholesterolemia + hyperuricemia (HC + HU) and high-purine with 30-mg/kg/d losartan (HU + losartan) groups. Serum uric acid (UA) and plasma renin and angiotensin II activities were determined. Aortic tissue specimens were analyzed for histological changes and proliferating cell nuclear antigen (PCNA). Liver tissues were sampled for quantitative analyses of liver low-density lipoprotein receptor (LDLR) mRNA and protein via reverse transcription polymerase chain reaction and western blotting., Results: After 12 weeks, serum UA and plasma renin and plasma angiotensin II activities were enhanced in the HU and HU + HC groups (P < 0.001) compared to the control, whereas in the HU + losartan group plasma renin activity was not different and serum UA concentrations as well as plasma angiotensin II activity were moderately enhanced (P < 0.05). Smooth muscle cell (SMC) PCNA expression increased strongly in the HU and HU + HC groups (P < 0.001), but was less pronounced in the HU + losartan group. In contrast, transcription and expression of LDLR mRNA and protein were significantly higher in the control and HU + losartan groups compared to the HU and HU + HC groups. Both the HU and HU + HC groups had elevated intima thickness and intima areas compared to the control and HU + losartan groups., Conclusions: Losartan can alleviate experimental atherosclerosis induced by hyperuricemia.

An unprecedented gold-catalyzed diastereoselective cycloisomerization of 1,6-diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2-trimethylenenorbornanes, which are important building blocks in the preparations of abiotic and sesquiterpene core structures., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein, the concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied in several classic dipolar [3+2] cycloadditions involving azides, nitrile oxides, and nitrones as partners. These cycloadditions can be used to produce pharmaceutically interesting, small heterocyclic products, such as triazoles, isoxazoles, and isoxazolidines. These cycloadducts are formed directly and include a free carboxylic acid functionality that can be employed for further transformations, thereby avoiding prior masking or functionalization. In all cases, BAC provides faster reactions, under milder conditions, with much improved product yields and regioselectivities. In some instances, such as triazole formation from the reaction of azides with 2-alkynoic acids, catalysis with ortho-nitrophenylboronic acid circumvents the undesirable product decarboxylation observed when using thermal activation. By using NMR spectroscopic studies, the boronic acid catalyst was shown to provide activation by a LUMO-lowering effect in the unsaturated carboxylic acid, likely via a monoacylated hemiboronic ester intermediate.