Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule exhibited pronounced Brd4 protein degradation with low nM DC values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines.

Combined effect of confinement and dielectric exclusion on ion adsorption in slits, pores, and cavities.

We present simulation results for the Donnan equilibrium between a homogeneous bulk reservoir and inhomogeneous confining geometries with varying number of restricted dimensions, . Planar slits ( = 1), cylindrical pores ( = 2), and spherical cavities ( = 3) are considered. The walls have a negative surface charge density.

Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in preeclampsia.

Background: Preeclampsia (PE) is a pregnancy complication characterized by hypertension, proteinuria, endothelial dysfunction, and complement dysregulation. Placenta-derived extracellular vesicles (EVs), necessary in maternal-fetal communication, might contribute to PE pathogenesis. Moreover, neutrophil extracellular traps (NETs) play a pathogenic role in other complement-mediated pathologies, and their contribution in PE remains unexplored.

Intrinsic brain activity differences in drug-resistant epilepsy and well-controlled epilepsy patients: an EEG microstate analysis.

Background: Drug-resistant epilepsy (DRE) patients exhibit aberrant large-scale brain networks.

Objective: The purpose of investigation is to explore the differences in resting-state electroencephalogram (EEG) microstates between patients with DRE and well-controlled (W-C) epilepsy.

Design: Retrospective study.

Assuring assistance to healthcare and medicine: Internet of Things, Artificial Intelligence, and Artificial Intelligence of Things.

Introduction: The convergence of healthcare with the Internet of Things (IoT) and Artificial Intelligence (AI) is reshaping medical practice with promising enhanced data-driven insights, automated decision-making, and remote patient monitoring. It has the transformative potential of these technologies to revolutionize diagnosis, treatment, and patient care.

Purpose: This study aims to explore the integration of IoT and AI in healthcare, outlining their applications, benefits, challenges, and potential risks.

Disparities in PrEP use and unmet need across PEPFAR-supported programs: doubling down on prevention to put people first and end AIDS as a public health threat by 2030.

Background: In 2023, an estimated 1.3 million people newly acquired HIV. In the same year, 3.

Special Section Guest Editorial: Introduction to the JMI Special Section on Augmented and Virtual Reality in Medical Imaging.

The editorial introduces the JMI Special Section on Augmented and Virtual Reality in Medical Imaging.

Targeting AURKA with multifunctional nanoparticles in CRPC therapy.

Castration-resistant prostate cancer (CRPC) presents significant therapeutic challenges due to its aggressive nature and poor prognosis. Targeting Aurora-A kinase (AURKA) has shown promise in cancer treatment. This study investigates the efficacy of ART-T cell membrane-encapsulated AMS@AD (CM-AMS@AD) nanoparticles (NPs) in a photothermal-chemotherapy-immunotherapy combination for CRPC.

The under-representation of women in cardiovascular clinical trials: State-of-the-art review and ethical considerations.

This review describes and evaluates the representation of women in cardiovascular randomized controlled trials (RCT), it reports significant under-representation of women in clinical trials both as participants and researchers and discusses the ethical implications of under-representation. The under-representation of women as participants in cardiovascular RCTs is evident in trials investigating cardiovascular drugs, acute coronary syndrome, heart failure and interventional procedures and devices. Under-representation of women is also evident in the authorship of cardiovascular clinical trials and in trial leadership roles, and under-representation of women as trial investigators is independently associated with under- recruitment of women as trial participants.

The Feasibility of Personalized Endpoints in Assessing Treatment Outcomes in Rare Disease: A Pilot Study of Goal Attainment Scaling in SCN2A-Associated Developmental Epileptic Encephalopathy.

Objectives: For individuals living with rare neurodevelopmental disorders, especially those who are at the most severe end of the spectrum, standardized outcome measures may lack the sensitivity to capture small but meaningful changes. Personalized endpoints such as Goal Attainment Scaling (GAS) allow the assessment of treatment response across variable baseline states and disease manifestations and thus provide a highly sensitive measure of efficacy. The current study tested the feasibility of using GAS in rare SCN2A-associated developmental and epileptic encephalopathy (SCN2A-DEE).

Multi-modal cross-domain self-supervised pre-training for fMRI and EEG fusion.

Neuroimaging techniques including functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) have shown promise in detecting functional abnormalities in various brain disorders. However, existing studies often focus on a single domain or modality, neglecting the valuable complementary information offered by multiple domains from both fMRI and EEG, which is crucial for a comprehensive representation of disorder pathology. This limitation poses a challenge in effectively leveraging the synergistic information derived from these modalities.

Missing History: Anarcha, Betsey, and Lucy's Legacy in Gynecologic Textbooks.

The legacy of J. Marion Sims as the "father of gynecology" has become widely controversial among medical professionals and lay public because of ethical concerns surrounding the development of his surgical techniques and his exploitation of enslaved women for his experiments. Notably, in April 2018, the City of New York relocated a commemorative statue of Sims from Central Park following an art commission's investigation of his controversial practices.

Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA.

A novel development of optimized hybrid MPPT controller for fuel cell systems with high voltage transformation ratio DC-DC converter.

The world is moving towards the utilization of hydrogen vehicle technology because its advantages are uniformity in power production, more efficiency, and high durability when compared to fossil fuels. So, in this work, the Proton Exchange Membrane Fuel Stack (PEMFS) device is selected for producing the energy for the hydrogen vehicle. The merits of this fuel technology are the possibility of operating less source temperature, and more suitability for stationery and transportation applications.

405 nm violet-blue light inactivates hepatitis C cell culture virus (HCVcc) in ex vivo human platelet concentrates and plasma.

Added safety measures coupled with the development and use of pathogen reduction technologies (PRT) significantly reduces the risk of transfusion-transmitted infections (TTIs) from blood products. Current approved PRTs utilize chemical and/or UV-light based inactivation methods. While the effectiveness of these PRTs in reducing pathogens are well documented, these can cause tolerable yet unintended consequences on the quality and efficacy of the transfusion products.

Genome-wide association mapping in safflower (Carthamus tinctorius L.) for genetic dissection of drought tolerance using DArTseq markers.

Understanding the genetic basis of drought tolerance in safflower (Carthamus tinctorius L.) is essential for developing resilient varieties. In this study, we performed a genome-wide association study (GWAS) using DArTseq markers to identify marker-trait associations (MTAs) linked to drought tolerance across 90 globally diverse safflower genotypes.

Predictive nomogram of ultrasound indicators for the termination outcome of caesarean scar pregnancy.

To develop and validate a nomogram for predicting the risk of adverse events (intraoperative massive haemorrhage or retained products of conception) associated with the termination of Caesarean scar pregnancy (CSP). Data were retrospectively collected from patients diagnosed with CSP who underwent Dilation and Curettage (D&C) at two hospitals. This data was divided into internal and external cohorts for analysis.

Comparative study of third harmonic generation in carbon and silicene nanotubes under magnetic fields.

This study investigates the optical properties of carbon nanotubes (CNTs) and silicene nanotubes (SiNTs) under the influence of external magnetic fields, focusing on their linear and nonlinear optical responses. A tight-binding model is employed to analyze the effects of magnetic fields on the electronic band structure, dipole matrix elements, and various optical susceptibilities of zigzag CNTs and SiNTs. The results reveal significant magnetic field-induced modifications in both linear and nonlinear optical spectra.

Altered neurovascular coupling and structure-function coupling in Moyamoya disease affect postoperative collateral formation.

Chronic ischemia in moyamoya disease (MMD) impaired white matter microstructure and neural functional network. However, the coupling between cerebral blood flow (CBF) and functional connectivity and the association between structural and functional network are largely unknown. 38 MMD patients and 20 sex/age-matched healthy controls (HC) were included for T1-weighted imaging, arterial spin labeling imaging, resting-state functional MRI and diffusion tensor imaging.

An improvised one-step OptiPrep cushion ultracentrifugation method for outer membrane vesicles isolation of Klebsiella pneumoniae.

Background: Extracellular vesicles (EVs) play a crucial role in intraspecies and interspecies communication, significantly influencing physiological and pathological processes. Outer membrane vesicles (OMVs) secreted by Gram-negative bacteria are rich in components from the parent cells and are important for bacterial communication, immune evasion, and pathogenic mechanisms. However, the extraction and purification of OMVs face numerous challenges due to their small size and heterogeneity.

Immunostimulatory effects of Heyndrickxia coagulans SANK70258.

Here, we examined the immunomodulating effects of Heyndrickxia coagulans SANK70258 (SANK70258). Mouse splenocytes treated with γ-ray-irradiated SANK70258 produced higher levels of IFN-γ than those with 7 types of lactic acid bacteria. IFN-γ was mainly produced by NK cells, involving IL-12/IL-23, dendritic cells (DCs), and NFκB signaling.

Dentin remineralization induced by experimental composites containing calcium orthophosphate particles.

Objectives: This study aimed to verify if composites containing dicalcium phosphate dihydrate particles (DCPD) are able to induce dentin remineralization in vitro. Additionally, the mechanical properties of the materials were tested.

Methods: Four composites with 50 vol% inorganic content and 1 BisGMA: 1 TEGDMA (mols) were prepared, with different DCPD:glass ratios (50:0, 40:10, 30:20 and 0:50).

Highly Sensitive LC-MS/MS Method for Determination of Dexamethasone in Rat Plasma and Brain Tissue: An Application to Pharmacokinetic Study in Rats.

A highly sensitive and rapid LC-MS/MS method was developed and validated for the quantification of dexamethasone in rat plasma and brain tissue. Protein precipitation method was used for sample preparation. The separation of dexamethasone and the IS (labetalol) was achieved on an Atlantis dC column using an isocratic mobile phase (10 mM ammonium formate and acetonitrile, 25/75, v/v) delivered at 0.

Age-related impact of phenobarbital in suppressing prenatal alcohol exposure-related seizures in developing rats.

Prenatal alcohol exposure (PAE) during pregnancy can increase the prevalence of N-methyl-D-aspartate (NMDA)-induced generalized tonic-clonic seizures (GTCSs) in developing rats. However, it is unclear whether phenobarbital (PB) can suppress these PAE-related seizures. To explore this knowledge gap, we investigated the effects of acute PB treatment on NMDA-induced seizures in postpartum rats, prenatally exposed to alcohol on gestational day 18 (GD18), at two developmental stages: day 7 (P7), the equivalent of pre-term neonates, and day 15 (P15), the equivalent of full-term neonates.