Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC.

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report a platform named Auto-RapTAC. Based on the modular characteristic of the PROTAC molecule, a streamlined workflow that integrates lab automation with "click chemistry" joint building-block libraries was constructed.

An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti-Solid Tumor Immunity.

Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti-tumor immune response. Here, this work develops an oral proteolysis targeting chimera (PROTAC) targeting HPK1 to efficiently and selectively degrade HPK1 to augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally-administrated PROTAC can reach tumors, down-regulate HPK1 levels in locally-administrated CAR-T cells, and promote their efficiency in inhibiting solid tumor recurrence, achieving 50% partial response (PR) and 50% complete response (CR).

Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia.

BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the development of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase.

Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy.

HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. demonstrated significant HPK1 degradation with a DC of 21.

Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells.

Generation, Maintenance, and Identification of Germ-Free Zebrafish Models from Larvae to Juvenile Stages.

Zebrafish serve as valuable models for research on growth, immunity, and gut microbiota due to their genomic similarities with mammals, transparent embryos developed in a relatively clean chorion environment, and extremely rapid development of larvae compared to rodent models. Germ-free (GF) zebrafish (Danio rerio) are crucial for evaluating pollutant toxicity and establishing human-like disease models related to microbial functions. In comparison to conventionally raised (CR) models (fish in common husbandry), GF zebrafish allow for more accurate manipulation of the host microbiota, aiding in determining the causal relationship between microorganisms and hosts.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability.

Metabolome evidence of CKDu risks after chronic exposure to simulated Sri Lanka drinking water in zebrafish.

It is still a serious public health issue that chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka poses challenges in identification, prevention, and treatment. What environmental factors in drinking water cause kidney damage remains unclear. This study aimed to investigate the risks of various environmental factors that may induce CKDu, including water hardness, fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM).

Control effect and field application of four predatory Orius species on Megalurothrips usitatus (Thysanoptera: Thripidae).

Megalurothrips usitatus (Bagrall) is one of the most important pests of cowpea, Vigna unguiculata (Linn.) Walp in South China. Four Orius species, including Orius minutus (L.

Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody.

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy.

Rational Identification of Novel Antibody-Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors.

Bystander-killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody-drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander-killing payloads, this model is utilized for score-directed exatecan derivatives design.

Investigation of Phenolic Resin-Modified Asphalt and Its Mixtures.

This study comprehensively examines the influence of phenol-formaldehyde resin (PF) on the performance of base asphalt and its mixtures for road applications, emphasizing its innovative use in enhancing pavement quality. Optimal PF content was determined through the evaluation of standard indicators and rotational viscosity. In-depth analyses of PF-modified asphalt's high- and low-temperature rheological properties and viscoelastic behavior were conducted using dynamic shear rheometers and bending beam rheometers.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work.

Improved Environmental Stimulus and Biological Competition Tactics Interactive Artificial Ecological Optimization Algorithm for Clustering.

An interactive artificial ecological optimization algorithm (SIAEO) based on environmental stimulus and a competition mechanism was devised to find the solution to a complex calculation, which can often become bogged down in local optimum because of the sequential execution of consumption and decomposition stages in the artificial ecological optimization algorithm. Firstly, the environmental stimulus defined by population diversity makes the population interactively execute the consumption operator and decomposition operator to abate the inhomogeneity of the algorithm. Secondly, the three different types of predation modes in the consumption stage were regarded as three different tasks, and the task execution mode was determined by the maximum cumulative success rate of each individual task execution.

Discovery of new macrophage M2 polarization modulators as multiple sclerosis treatment agents that enable the inflammation microenvironment remodeling.

The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities.

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma.

Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs.

C-scheme electron transfer mechanism: An efficient ternary heterojunction photocatalyst carbon quantum dots/Bi/BiOBr with full ohmic contact.

With a facile one-pot solvothermal method, an efficient ternary heterojunction photocatalyst carbon quantum dots (CQDs)/Bi/BiOBr is firstly prepared. Ethylene glycol (EG) is used as the solvent and carbon source for the first time. At 190 °C for 3 h, while BiOBr is synthesized, EG is employed to prepare CQDs through bottom-up method.

Bisphenol A impairs macrophages through inhibiting autophagy via AMPK/mTOR signaling pathway and inducing apoptosis.

Bisphenol A (BPA) is a widespread endocrine disruptor that induces the impairment of immune cells, but the mechanism remains unknown. Macrophages are one of the most important immune cells in innate and adaptive immunity. In this study, we aimed to probe the effects of BPA on the damage of RAW264.

Overseas immigration of fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), invading Korea and Japan in 2019.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith), spread rapidly in Africa and Asia recently, causing huge economic losses in crop production.

3-B-RUT, a derivative of RUT, protected against alcohol-induced liver injury by attenuating inflammation and oxidative stress.

Alcoholic liver disease (ALD) is the most common chronic liver disease worldwide. Currently, there is no definitive treatment for alcohol-induced liver injury (ALI). Inflammatory response and oxidative stress play a crucial role in ALI.

A Joint 2D-3D Complementary Network for Stereo Matching.

Stereo matching is an important research field of computer vision. Due to the dimension of cost aggregation, current neural network-based stereo methods are difficult to trade-off speed and accuracy. To this end, we integrate fast 2D stereo methods with accurate 3D networks to improve performance and reduce running time.

Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease.

A series of 7-O-amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase, of which compound 7c (7-O-(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC = 0.28 ± 0.

Design and synthesis of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives as novel GSK-3β inhibitors and evaluation of their potential as multifunctional anti-Alzheimer agents.

Pleiotropic intervention has prominent advantages for complex pathomechanisms, such as Alzheimer's disease (AD). In this study, a series of novel 3-(4-pyridyl)-5-(4- sulfamido-phenyl)-1,2,4-oxadiazole derivatives were designed and synthesized following the multitarget-directed ligand-based strategy. All compounds were evaluated for glycogen synthase kinase 3β (GSK-3β) inhibition and antineuroinflammatory and neuroprotective activities.