Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions.

Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds.

High-Throughput Assessment of Bile Salt Export Pump Inhibition Using RapidFire-MS and DESI-MS.

The bile salt export pump (BSEP) assay is widely used to evaluate the potential for drug-induced liver injury (DILI) early in the drug discovery process. While traditional liquid chromatography-mass spectrometry (LC-MS)-based approaches have been utilized for BSEP activity testing, they have intrinsic limitations in either throughput or the requirement for sample preparation and are difficult to scale up in order to screen drug candidates. Here we demonstrate the use of two different high-throughput MS methods based on solid-phase extraction (SPE) and desorption electrospray ionization (DESI) for high-throughput BSEP activity assessment in a label-free manner, with minimal needs for sample workup, at sampling rates of ∼11 and ∼5.

Oxoammonium Salt-Mediated On-DNA Alcohol Oxidation for DEL Synthesis.

On-DNA carboxylic acids are important synthetic intermediates in the synthesis of DNA-encoded library (DEL) structures. Herein, we report an oxoammonium salt-mediated, room temperature, solution-phase oxidation of DNA-linked primary alcohols into carboxylic acids. This method exhibits a wide substrate scope, encompassing aliphatic, benzylic, and heterobenzylic alcohols, and is compatible with DEL encoding strategies.

Hydrophobic Surfactant-DNA Complex (Surf-DNA) Enables DNA-Encoded-Library-Compatible Decarboxylative Arylation under Anhydrous Conditions.

DNA-encoded libraries (DELs) are a key technology for identifying small-molecule hits in both the pharmaceutical industry and academia, but their chemical diversity is largely limited to water-compatible reactions to aid in the solubility and integrity of encoding DNA tags. To broaden the DEL chemical space, we present a workflow utilizing DNA-cationic surfactant complexation that enables dissolution and reactions on-DNA in anhydrous organic solvents. We demonstrate its utility by developing DEL-compatible photoredox decarboxylative C(sp)-C(sp) coupling under water-free conditions.

Treatment of Lumbar Degenerative Disease with a Novel Interlaminar Screw Elastic Spacer Technique: A Finite Element Analysis.

A novel interlaminar elastic screw spacer technique was designed to maintain lumbar mobility in treating lumbar degenerative diseases. A validated finite element model of L4/5 was used to establish an ISES-1/2 model and an ISES-1/3 model based on different insertion points, a unilateral fixation model and a bilateral fixed model based on different fixation methods, and a Coflex-F model based on different implants. The elastic rods were used to fix screws.

Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation.

Development and validation of a predictive model for spinal fracture risk in osteoporosis patients.

Background: Spinal osteoporosis is a prevalent health condition characterized by the thinning of bone tissues in the spine, increasing the risk of fractures. Given its high incidence, especially among older populations, it is critical to have accurate and effective predictive models for fracture risk. Traditionally, clinicians have relied on a combination of factors such as demographics, clinical attributes, and radiological characteristics to predict fracture risk in these patients.

Hydrogen Promotes the Effectiveness of Bone Mesenchymal Stem Cell Transplantation in Rats with Spinal Cord Injury.

Although bone mesenchymal stem cell (BMSC) transplantation has been applied to the treatment of spinal cord injury (SCI), the effect is unsatisfactory due to the specific microenvironment (inflammation and oxidative stress) in the SCI area, which leads to the low survival rate of transplanted cells. Thus, additional strategies are required to improve the efficacy of transplanted cells in the treatment of SCI. Hydrogen possesses antioxidant and anti-inflammatory properties.

Hypoxia regulates adipose mesenchymal stem cells proliferation, migration, and nucleus pulposus-like differentiation by regulating endoplasmic reticulum stress via the HIF-1α pathway.

Objective: Hypoxia can promote stem cell proliferation and migration through HIF-1α. Hypoxia can regulate cellular endoplasmic reticulum (ER) stress. Some studies have reported the relationship among hypoxia, HIF-α, and ER stress, however, while little is known about HIF-α and ER stress in ADSCs under hypoxic conditions.

Global reactivity models are impactful in industrial synthesis applications.

Artificial Intelligence is revolutionizing many aspects of the pharmaceutical industry. Deep learning models are now routinely applied to guide drug discovery projects leading to faster and improved findings, but there are still many tasks with enormous unrealized potential. One such task is the reaction yield prediction.

Photoredox-Mediated Deoxygenative Alkylation of DNA-Tagged Alkenes with Activated Alcohols.

DNA-encoded library (DEL) screens have become a key technology to find small molecule binders to biological targets for drug discovery applications. The development of new DNA-compatible chemistries to expand the accessible DEL chemical space is imperative to enhance screen success across broad target classes and modalities. Additionally, reactions that use commonly available building blocks as well as those that enable the fsp of library members to be increased would have high impact for accessing diverse drug-like structures.

Sagittal imaging study of the lumbar spine with the short rod technique.

Purpose: The short rod technique (SRT) is a novel method for lumbar pedicle screw placement to reduce surgical trauma and avoid damage to the facet joint and articular surface. The core concept is to change the entry point and angle of the screw on the vertebrae at both ends in the sagittal plane to shorten the length of the longitudinal rods. The purpose of this study is to determine the sagittal screw angle (SSA) and its safe Maximum (MAX) value on each lumbar vertebra for the SRT and to observe the shortening effect on the longitudinal rods.

Biomechanical evaluation of a short-rod technique for lumbar fixation surgery.

The purpose of this study was to analyze the stability and instrument-related complications associated with fixation of the lumbar spine using the Short-Rod (SR) technique. Using finite element analysis, this study assessed the stability of a bilateral lumbar fixation system when inserting the pedicle screws at angles of 10°, 15°, and 20° to the endplate in the sagittal plane. Using the most stable construct with a screw angle, the model was then assessed with different rod lengths of 25, 30, 35, and 45 mm.

Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation.

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs-with varying length, polarity, and rigidity-were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity.

Palladium-Mediated Carbonylative Suzuki Coupling for DNA-Encoded Library Synthesis.

Developing new DNA-compatible reactions is key to expanding the accessible chemical space of DNA-encoded library (DEL) technology. Here we disclose the first report of a DNA-compatible carbonylative Suzuki coupling of DNA-conjugated (hetero)aryl iodides with (hetero)aryl boronic acids to access di(hetero)aryl ketones, a valuable structural motif present within several approved or clinically advanced small molecules. The reported DNA-compatible, Pd(OAc)-mediated system is mild, uses a robust protocol, has a wide substrate scope for both coupling partners, is suitable for large-scale DEL productions, and provides a source of previously unexplored chemical matter for DEL screens.

Clinical and Radiographic Outcomes of Modified Posterior Atlantoaxial Temporary Fixation with Preservation of Semispinalis Cervicis: A Comparative Study.

Study Design: Retrospective study.

Objective: Current studies suggested that the posterior cervical deep muscles should be preserved during the atlantoaxial posterior approach. This study aimed to modify the conventional temporary posterior fixation by preserving the semispinalis cervicis and to evaluate the radiographic and clinical outcomes compared with the conventional technique.

Palladium-Mediated C-N Coupling of DNA-Conjugated (Hetero)aryl Halides with Aliphatic and (Hetero)aromatic Amines.

DNA-encoded chemical library (DEL) screens are a powerful hit generation tool in drug discovery, but the diversity of DEL chemical matter is dependent on developing robust reaction conditions that may be used on hundreds to millions of substrate combinations and that are compatible with the platform. Here, we disclose the first report of a general, aqueous, DNA-compatible C-N coupling condition that can now couple aliphatic amines, in addition to (hetero)aromatic amines, with a variety of (hetero)aryl iodides, bromides, and chlorides. The reported BippyPhos-Pd(OAc) catalyst system has a wide substrate scope for both coupling partners, is operationally feasible for large scale DEL productions, uses common DEL building block solution stocks, and enables an expansion of DEL-accessible, drug-like chemical space.

W-Transformer: Accurate Cobb angles estimation by using a transformer-based hybrid structure.

Background: Scoliosis is a type of spinal deformity, which is harmful to a person's health. In severe cases, it can trigger paralysis or death. The measurement of Cobb angle plays an essential role in assessing the severity of scoliosis.

Gait-Based Implicit Authentication Using Edge Computing and Deep Learning for Mobile Devices.

Implicit authentication mechanisms are expected to prevent security and privacy threats for mobile devices using behavior modeling. However, recently, researchers have demonstrated that the performance of behavioral biometrics is insufficiently accurate. Furthermore, the unique characteristics of mobile devices, such as limited storage and energy, make it subject to constrained capacity of data collection and processing.

Cholesterol-Modified Oligonucleotides as Internal Reaction Controls during DNA-Encoded Chemical Library Synthesis.

We report two cholesterol-modified oligonucleotides for use as internal controls for on-DNA reactions during the pooled stages of a DNA-encoded chemical library (DECL) synthesis. As these cholesterol-tagged oligonucleotides are chromatographically separable from normal DECL intermediates, they can be directly monitored by mass spectrometry to track reaction progression within a complex pool of DNA. We observed similar product conversions for reactions on substrates linked to a standard DECL DNA headpiece, to the cholesterol-modified oligonucleotides, and to the cholesterol-modified oligonucleotides while in the presence of pooled DECL synthetic intermediates-validating their use as a representative control.

[Research progress in creep characteristics of lumbar intervertebral disc].

Objective: To summarize the research progress in creep characteristics of lumbar intervertebral disc.

Methods: The relevant literature at home and abroad was systematically searched. Then, the concept and structural basis of lumbar disc creep, the description of creep characteristics, and the latest progress of its influencing factors were summarized and analyzed.

Involvement of circRNA_0007059 in the regulation of postmenopausal osteoporosis by promoting the microRNA-378/BMP-2 axis.

Increasing evidence suggests that postmenopausal osteoporosis (PMO), a severe disturbance, imposes heavy physical, psychosocial, and financial burdens and dramatically influences the quality of life of postmenopausal women. Circular RNAs (circRNAs) and microRNAs (miRs) play important roles in the occurrence and development of PMO. However, the roles of circRNAs and miRs in osteoporosis regulation still need to be further investigated.

Perioperative Coagulation Profile with Thromboelastography in Aspirin-Treated Patients Undergoing Posterior Lumbar Fusion.

Background: It has been generally recommended that platelet function may recover after the recommended 5-day discontinuation period prior to operation. The technique of thromboelastography has been demonstrated to monitor intraoperative platelet function in liver transplantation and coronary bypass surgery. However, there is a dearth of literature that addresses the utility of thromboelastography in aspirin-treated patients undergoing fusion.