Design, synthesis, and evaluation of quinolin-2(1H)-ones as PDE1 inhibitors for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the entire gastrointestinal tract. The complex etiology of IBD made it difficult to cure. Phosphodiesterases (PDEs) have garnered significant attention due to their involvement in immune and inflammatory responses in IBD.

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood.

A new anti-CRISPR gene promotes the spread of drug-resistance plasmids in Klebsiella pneumoniae.

The Klebsiella pneumoniae (K. pneumoniae, Kp) populations carrying both resistance-encoding and virulence-encoding mobile genetic elements (MGEs) significantly threaten global health. In this study, we identified a new anti-CRISPR gene (acrIE10) on a conjugative plasmid with self-target sequence in K.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet.

Design, Synthesis, and Mode of Action of Thioacetamide Derivatives as the Algicide Candidate Based on Active Substructure Splicing Strategy.

Lakes and reservoirs worldwide are experiencing a growing problem with harmful cyanobacterial blooms (HCBs), which have significant implications for ecosystem health and water quality. Algaecide is an effective way to control HCBs effectively. In this study, we applied an active substructure splicing strategy for rapid discovery of algicides.

A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS.

KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRAS suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes.

Applying Machine Learning Analysis Based on Proximal Femur of Abdominal Computed Tomography to Screen for Abnormal Bone Mass in Femur.

Rationale And Objectives: To evaluate the performance of machine learning analysis based on proximal femur of abdominal computed tomography (CT) scans in screening for abnormal bone mass in femur.

Materials And Methods: 222 patients aged 50 years or older who underwent abdominal CT and dual-energy X-ray absorptiometry scans within 14 days were retrospectively enrolled. The patients were randomly assigned to a training cohort (n = 155) and a testing cohort (n = 67) in a ratio of 7:3.

Correlation between AI-based CT organ features and normal lung dose in adjuvant radiotherapy following breast-conserving surgery: a multicenter prospective study.

Background: Radiation pneumonitis (RP) is one of the common side effects after adjuvant radiotherapy in breast cancer. Irradiation dose to normal lung was related to RP. We aimed to propose an organ features based on deep learning (DL) model and to evaluate the correlation between normal lung dose and organ features.

RNA N6-methyladenosine demethylase FTO inhibits glucocorticoid-induced osteoblast differentiation and function in bone marrow mesenchymal stem cells.

Excess glucocorticoids (GCs) have been reported as key factors that impair osteoblast (OB) differentiation and function. However, the role of RNA N6-methyladenosine (m A) in this process has not yet been elucidated. In this study, we report that both the mRNA and protein expression of fat mass and obesity-associated gene (FTO), a key m A demethylase, were dose-dependently downregulated during OB differentiation by dexamethasone (DEX) in bone marrow mesenchymal stem cells (BMSCs), and FTO was gradually increased during OB differentiation.

Rapid preparation of high efficiency hydrogen evolution catalyst with hydrophilicity.

The electrolytic water method is an outstanding hydrogen production process because of its high stability and no restriction. A low-priced and efficient catalyst for electro-deposition of Ni-Co microspheres and nanoclusters on carbon steel (Ni-Co/CS) has been prepared by the dynamic hydrogen bubble template. In the 6 M KOH solution, Ni-Co/CS only requires an overpotential of 48 mV to provide a current density of 50 mA cm.

Identification of Novel Quinolin-2(1)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1)-ones were designed rationally, leading to compound with an IC of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties.

Design, Synthesis, and Bioassay for the Thiadiazole-Bridged Thioacetamide Compound as Cy-FBP/SBPase Inhibitors Based on Catalytic Mechanism Virtual Screening.

Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase (Cy-FBP/SBPase) was an important regulatory enzyme in cyanobacterial photosynthesis and was a potential target enzyme for screening to obtain novel inhibitors against cyanobacterial blooms. In this study, we developed a novel pharmacophore screening model based on the catalytic mechanism and substrate structure of Cy-FBP/SBPase and screened 26 series compounds with different structures and pharmacophore characteristics from the Specs database by computer-assisted drug screening. These compounds exhibited moderate inhibitory activity against Cy-FBP/SBPase, with 9 compounds inhibiting >50% at 100 μM.

Design, synthesis and mechanism research of novel algicide based on bioactive fragments synthesis strategy.

The frequency and intensity of harmful cyanobacterial blooms (HCBs) are increasing all over the world, their prevention and control have become a great challenge. In this paper, a series of 1,3,4-thiadiazole thioacetamides (T series) were designed and synthesized as potential algaecides. Among them, the compound T3 showed its best algacidal activity against Synechocystis sp.

Structural insight into the substrate-binding mode and catalytic mechanism for MlrC enzyme of sp. ACM-3962 in linearized microcystin biodegradation.

Removing microcystins (MCs) safely and effectively has become an urgent global problem because of their extremely hazardous to the environment and public health. Microcystinases derived from indigenous microorganisms have received widespread attention due to their specific MC biodegradation function. However, linearized MCs are also very toxic and need to be removed from the water environment.

Crystal structural analysis and characterization for MlrC enzyme of Sphingomonas sp. ACM-3962 involved in linearized microcystin degradation.

Microcystinase C (MlrC), one key hydrolase of the microcystinase family, plays an important role in linearized microsystin (L-MC) degradation. However, the three-dimensional structure and structural features of MlrC are still unclear. This study obtained high specific activity and high purity of MlrC by heterologous expression, and revealed that MlrC derived from Sphingomonas sp.

A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.

Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strategy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was associated with susceptibility to Zika virus (ZIKV) infection.

Development of a Potentially New Algaecide for Controlling Harmful Cyanobacteria Blooms Which is Ecologically Safe and Selective.

Harmful cyanobacterial blooms (HCBs) caused by are of great concern as they negatively affect the aquatic environment and human health. Chemical methods could rapidly eradicate HCBs and have been used for many decades. However, many chemical reagents are not recommended to eliminate HCBs in the long term, given the possible destructive and toxic effects of the chemicals employed on non-target aquatic organisms.

Universal Preparation Strategy for Ultradurable Antibacterial Fabrics through Coating an Adhesive Nanosilver Glue.

Microbiological protection textile materials played an important role in the battle against the epidemic. However, the traditional active antimicrobial treatment of textiles suffers from narrow textile applicability, low chemical stability, and poor washability. Here, a high-strength adhesive nanosilver glue was synthesized by introducing nontoxic water-soluble polyurethane glue as a protectant.

Strain-boosted hyperoxic graphene oxide efficiently loading and improving performances of microcystinase.

Harmful blooms (HMBs) and microcystins (MCs) that are produced by  seriously threaten water ecosystems and human health. This study demonstrates an eco-friendly strategy for simultaneous removal of MCs and HMBs by adopting unique hyperoxic graphene oxides (HGOs) as carrier and pure microcystinase A (PMlrA) as connecting bridge to form stable HGOs@MlrA composite. After oxidation, HGOs yield inherent structural strain effects for boosting the immobilization of MlrA by material characterization and density functional theory calculations.

Design, synthesis, high algicidal potency, and putative mode of action of new 2-cyclopropyl-4-aminopyrimidine hydrazones.

Control of cyanobacteria harmful algal blooms remains a global challenge. In the present study, a series of novel 2-cyclopropyl-4-aminopyrimidine hydrazones were designed and synthesized as potential algicides. Compounds 4a, 4b, 4h, 4j, 4k, 4l, and 4m showed potent inhibition against Synechocystis sp.

Clinical features and functions of a novel Lpl mutation C.986A>C (p.Y329S) in patient with hypertriglyceridemia.

Objective: To investigate and assess the clinical features and functions of a new lipoprotein lipase (Lpl) gene mutation c.986A>C (p.Y329S) found in hypertriglyceridemia(HTG) patients from a Chinese family.

Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulated arc therapy.

Purpose: To explore clinical and dosimetric predictors of acute hematologic toxicity (HT) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy (VMAT).

Methods And Materials: We retrospectively reviewed the clinical data of 184 cervical cancer patients who had concurrent chemotherapy and VMAT. Hematological parameters were collected during the treatment period.