Discovery of : A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition.

Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of , a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles.

Consistency assessment of tissue-level brain injury criteria in FEHM.

Tissue-level brain injury criteria are essential for analyzing brain injuries using finite element head models (FEHMs), but their consistency remains unclear. This study applied the data-driven method previously proposed for maximum principal strain (MPS) injury criterion to determine thresholds for von Mises stress (VMS), pressure, maximum shear stress (MSS), and the rate of MPS. It then assessed the consistency of these criteria in terms of injury status, injury location, and injury overlap rate in 18 impact simulations.

Damage Evolution and Lifetime Prediction of Cement Asphalt Mortar Under High-Speed Train Frequency and Temperature Gradient Load.

Severe damage to cement asphalt mortar (CA mortar) can compromise the stability and safety of high-speed railway operations due to various complex factors during service. The loads from high-speed trains and temperature gradients within the ballastless track structure are significant contributors to this damage. However, most previous studies have focused on laboratory tests or numerical simulations under simple loading conditions, while few have investigated the damage evolution of CA mortar when both train loads and temperature gradients are considered simultaneously.

Global burden of osteoarthritis from 1990 to 2019 attributable to high body mass index.

Introduction: The aim was to examine data from the Global Burden of Disease Study (GBD) 2019 to determine the global burden of osteoarthritis (OA) from 1990 to 2019 that is attributable to high body mass index (BMI).

Material And Methods: Disability-adjusted life years (DALYs) and age-standardized DALY rates, and their corresponding estimated annual percentage changes (EAPCs), were used to compare estimated OA burdens between countries and regions. Moreover, a comparative risk assessment framework was used to estimate the risks attributable to high BMI in terms of DALYs.

Azvudine efficacy in reducing mortality in COVID-19 patients.

Background: Several therapeutic drugs have been authorized for the treatment of patients with Coronavirus disease 2019 (COVID-19). However, further research on the mechanisms of action, efficacy, and target populations of these novel therapeutic drugs are necessary. This study included mild, moderate, severe, and critical COVID-19 patients to evaluate azvudine's effectiveness across different severity levels.

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.

The role of JNK signaling pathway in organ fibrosis.

Background: Fibrosis is a tissue damage repair response caused by multiple pathogenic factors which could occur in almost every apparatus and leading to the tissue structure damage, physiological abnormality, and even organ failure until death. Up to now, there is still no specific drugs or strategies can effectively block or changeover tissue fibrosis. JNKs, a subset of mitogen-activated protein kinases (MAPK), have been reported that participates in various biological processes, such as genetic expression, DNA damage, and cell activation/proliferation/death pathways.

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells.

An Objective Injury Threshold for the Maximum Principal Strain Criterion for Brain Tissue in the Finite Element Head Model and Its Application.

Although the finite element head model (FEHM) has been widely utilized to analyze injury locations and patterns in traumatic brain injury, significant controversy persists regarding the selection of a mechanical injury variable and its corresponding threshold. This paper aims to determine an objective injury threshold for maximum principal strain (MPS) through a novel data-driven method, and to validate and apply it. We extract the peak responses from all elements across 100 head impact simulations to form a dataset, and then determine the objective injury threshold by analyzing the relationship between the combined injury degree and the threshold according to the stationary value principle.

Efficient Production of an Alginate Lyase in with Combined Strategy: Vector and Host Selection, Promoter and Signal Peptide Screening, and Modification of a Translation Initiation Region.

Alginate lyases (ALys) whose degrading products, alginate oligosaccharides, exhibit various outstanding biochemical activities have aroused increasing interest of researchers in the marine bioresource field. However, their predominant sourcing from marine bacteria, with limited yields and unclear genetic backgrounds, presents a challenge for industrial production. In this study, ALys (Aly01) from SK 42.

Influence of centroid acceleration acquisition and filtering class on head injury criterion evaluation.

Background: Although the Head Injury Criteria (HIC) has been widely applied to assess head impact injuries, it faces two outstanding problems: 1) HIC is affected strongly by the cut-off frequency when processing acceleration signals. And these cut-off frequencies are experiential and lack unified guidelines; 2) If the head was impacted on a different part, should the corresponding HIC threshold be the same? If these problems are not resolved, it could potentially lead to a critical misinterpretation of the safety assessment.

Methods: Finite element method was used to reconstruct head impacts.

Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders.

Single-Atom Cu Stabilized on Ultrathin WO Nanowire for Highly Selective and Ultrasensitive ppb-Level Toluene Detection.

Various catalysts are developed to improve the performance of metal oxide semiconductor gas sensors, but achieving high selectivity and response intensity in chemiresistive gas sensors (CGSs) remains a significant challenge. In this study, an in situ-annealing approach to synthesize Cu catalytic sites on ultrathin WO nanowires for detecting toluene at ultralow concentrations (R /R = 1.9 at 10 ppb) with high selectivity is developed.

Improving thermostability of a PL 5 family alginate lyase with combination of rational design strategies.

Alginate lyases with strict substrate specificity possess potential in directed production of alginate oligosaccharides with specific composition. However, their poor thermostability hampered their applications in industry. In this study, an efficient comprehensive strategy including sequence-based analysis, structure-based analysis, and computer-aid ΔΔG value calculation was proposed.

Bidirectional effects of oral anticoagulants on gut microbiota in patients with atrial fibrillation.

Background: The imbalance of gut microbiota (GM) is associated with a higher risk of thrombosis in patients with atrial fibrillation (AF). Oral anticoagulants (OACs) have been found to significantly reduce the risk of thromboembolism and increase the risk of bleeding. However, the OAC-induced alterations in gut microbiota in patients with AF remain elusive.

Hollow-Out FeO-Loaded NiO Heterojunction Nanorods Enable Real-Time Exhaled Ethanol Monitoring under High Humidity.

The analysis of exhaled breath has opened up new exciting avenues in medical diagnostics, sleep monitoring, and drunk driving detection. Nevertheless, the detection accuracy is greatly affected due to high humidity in the exhaled breath. Here, we propose a regulation method to solve the problem of humidity adaptability in the ethanol-monitoring process by building a heterojunction and hollow-out nanostructure.

Characterization of a Novel Polysaccharide Lyase Family 5 Alginate Lyase with PolyM Substrate Specificity.

Alginate lyases (ALyases) have been widely applied in enzymatically degrading alginate for the preparation of alginate oligosaccharides (AOS), which possess a range of excellent physiological benefits including immunoregulatory, antivirus, and antidiabetic properties. Among the characterized ALyases, the number of ALyases with strict substrate specificity which possess potential in directed preparation of AOS is quite small. ALyases of polysaccharides lyase (PL) 5 family have been reported to perform poly--D-mannuronic acid (Poly-M) substrate specificity.

Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors.

The receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, , potently inhibited AXL enzymatic activity with an IC value of 1.

In Operando Investigation of the Concentration Dependent NO Sensing Mechanism of BiS Nanorods at Low Temperatures and the Interference of O.

The demand for gas sensors that can detect gases selectively at low temperatures has increased steadily over recent years. Most devices use semiconducting metal oxides as sensing materials which often require high operation temperatures and suffer from a lack of selectivity. Semiconducting metal sulfides were found to be a reasonable alternative for the application in sensing devices at low temperatures.

Characterization of a phospholipase D from Streptomyces cinnamoneum SK43.003 suitable for phosphatidylserine synthesis.

A phospholipase D high producing strain with transphosphatidylation activity that is suitable for phosphatidylserine synthesis was screened by our laboratory and named as Streptomyces cinnamoneum SK43.003. The enzyme structural and biochemical properties were investigated using the molecular biology method.

Template-Free Construction of Tin Oxide Porous Hollow Microspheres for Room-Temperature Gas Sensors.

Porous hollow microsphere (PHM) materials represent ideal building blocks for realizing diverse functional applications such as catalysis, energy storage, drug delivery, and chemical sensing. This has stimulated intense efforts to construct metal oxide PHMs for achieving highly sensitive and low-power-consumption semiconductor gas sensors. Conventional methods for constructing PHMs rely on delicate reprogramming of templates and may suffer from the structural collapse issue during the removal of templates.