The plasma metabolome of juvenile idiopathic arthritis varies according to subtype and underlying inflammatory status.

Background: Juvenile idiopathic arthritis (JIA) is challenging to classify and effectively monitor due to the lack of disease- and subtype-specific biomarkers. A robust molecular signature that tracks with specific JIA features over time is urgently required, and targeted plasma metabolomics may reveal such a signature. The primary aim of this study was to characterise the differences in the plasma metabolome between JIA patients and non-JIA controls and identify specific markers of JIA subtype.

Tranexamic acid in hip and spine surgery for children with cerebral palsy - a PRISMA-compliant scoping review.

Many children with cerebral palsy (CP) are frail and require major hip and/or spine surgeries associated with substantial blood loss. Tranexamic acid (TXA) is commonly used to reduce blood loss, but there is uncertainty around the optimal dose and timing of administration. There have been reviews in sub-populations and specific dosing regimens, but a broad overview of the available literature is lacking.

Protein shapeshifting in necroptotic cell death signaling.

Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors - Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL - can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux.

A pathway-based genetic score for inflammation: An indicator of vulnerability to phthalate-induced adverse neurodevelopment outcomes.

Introduction: Phthalates, chemical additives used to enhance plastic products' flexibility, are easily released into the environment, and can harm the brain development through various mechanisms including inflammation. Genetic variation influencing an individual's susceptibility to inflammation may play a role in the effects of phthalate exposure on neurodevelopment however there is no summary measure developed for genetic susceptibility to inflammation.

Methods: We developed a genetic pathway function score for inflammation (gPFS), based on the transcriptional activity of the inflammatory response pathway in the brain and other tissues.

Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries.

Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2.

pH-Responsive nanotubes from asymmetric cyclic peptide-polymer conjugates.

Self-assembling cyclic peptide nanotubes are fascinating supramolecular systems with promising potential for various applications, such as drug delivery, transmembrane ionic channels, and artificial light-harvesting systems. In this study, we present novel pH-responsive nanotubes based on asymmetric cyclic peptide-polymer conjugates. The pH response is introduced by a tertiary amine-based polymer, poly(dimethylamino ethyl methacrylate) (pDMAEMA) or poly(diethylamino ethyl methacrylate) (pDEAEMA) which is protonated at low pH.

Segmental MRI pituitary and hypothalamus volumes post Fontan: An analysis of the Australian and New Zealand Fontan registry.

Objective: Short stature, central hypothyroidism and infertility are common in those with a Fontan circulation. Given that the Fontan circulation often results in hepatic portal venous congestion, we hypothesize that the hypothalamic-pituitary portal circulation is also affected, contributing to subsequent hypothalamic-pituitary axis dysfunction.

Methods: MRI data from the Australian and New Zealand Fontan Registry (86 cases) was compared to 86 age- and sex-matched normal published controls.

A national Australian Congenital Heart Disease registry; methods and initial results.

Background: Although several National Data Registries for Congenital Heart Disease (CHD) exist, few are comprehensive and contemporary. A National Australian CHD Registry has been developed that aims to redress this by creating the first comprehensive data collection for CHD children and adults, initially across Australia.

Methods: We defined and collected a minimum dataset of demographics, diagnoses, and procedures from people with CHD presenting at participating quaternary CHD services Australia-wide.

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

Profiling the extracellular vesicles of two human placenta-derived mesenchymal stromal cell populations.

Increasing evidence shows extracellular vesicles (EVs) are primarily responsible for the beneficial effects of cell-based therapies. EVs derived from mesenchymal stromal cells (MSCs) show promise as a source of EVs for cell-free therapies. The human placental fetal-maternal interface is a rich and abundant source of MSCs from which EVs can be isolated.

Structural insights into the enzymatic breakdown of azomycin-derived antibiotics by 2-nitroimdazole hydrolase (NnhA).

The antibiotic 2-nitroimidazole (2NI) or azomycin, used for treating drug-resistant tuberculosis and imaging tumor hypoxia, requires activation by bacterial nitroreductases for its antibiotic and cytotoxic effect. Mycobacterium sp. JS330 produces 2-nitroimidazole nitrohydrolase (NnhA) that circumvents 2NI activation, conferring 2NI resistance by hydrolysing it to nitrite and imidazol-2-one (IM2O) instead.

Impact of nanoparticle properties on immune cell interactions in the lymph node.

The lymphatic system plays an important role in health and many diseases, such as cancer, autoimmune, cardiovascular, metabolic, hepatic, viral, and other infectious diseases. The lymphatic system is, therefore, an important treatment target site for a range of diseases. Lymph nodes (LNs), rich in T cells, B cells, dendritic cells, and macrophages, are also primary sites of action for vaccines and immunotherapies.

Hormone-responsive progenitors have a unique identity and exhibit high motility during mammary morphogenesis.

Hormone-receptor-positive (HR) luminal cells largely mediate the response to estrogen and progesterone during mammary gland morphogenesis. However, there remains a lack of consensus on the precise nature of the precursor cells that maintain this essential HR lineage. Here we refine the identification of HR progenitors and demonstrate their unique regenerative capacity compared to mature HR cells.

Electrochemical detection of extracellular vesicles for early diagnosis: a focus on disease biomarker analysis.

This review article presents a detailed examination of the integral role that electrochemical detection of extracellular vesicles (EVs) plays, particularly focusing on the potential application for early disease diagnostics through EVs biomarker analysis. Through an exploration of the benefits and challenges presented by electrochemical detection vetted for protein, lipid, and nucleic acid biomarker analysis, we underscore the significance of these techniques. Evidence from recent studies renders this detection modality imperative in identifying diverse biomarkers from EVs, leading to early diagnosis of diseases such as cancer and neurodegenerative disorders.

Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.

Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified.

Metabolic glycan labelling with bio-orthogonal targeting and its potential in drug delivery.

New modes of targeted drug delivery are emerging with promise of enhancing therapeutic efficacy while reducing side effects. This review examines the landscape of metabolic glycan labelling-a technique gaining traction for its potential in specific drug targeting. By exploiting the natural glycan synthetic pathway of monosaccharides, unnatural sugar analogues are incorporated into glycoproteins, allowing for the presentation of unique functional groups on cells.

Principles of CRISPR-Cas13 mismatch intolerance enable selective silencing of point-mutated oncogenic RNA with single-base precision.

Single-nucleotide variants (SNVs) are extremely prevalent in human cancers, although most of these remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target oncogenic RNAs. However, silencing oncogenic SNVs with single-base precision remains extremely challenging due to the intrinsic mismatch tolerance of Cas13.

Effect of bicalutamide on serum total testosterone concentration in transgender adults: a case series.

Background: There is interest in repurposing bicalutamide for gender-affirming hormone therapy, but little data regarding efficacy and safety in the transgender population.

Objectives: To determine the effect of bicalutamide on serum total testosterone concentrations and liver function. Given bicalutamide is a pure androgen receptor antagonist, we hypothesized that serum total testosterone concentrations would be higher than the cisgender female reference range and those recommended for transgender individuals in consensus guidelines.

mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting.

We investigated mRNA vaccines encoding a membrane-anchored receptor-binding domain (RBD), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail fragments of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In naive mice, RBD-TM mRNA vaccines against SARS-CoV-2 variants induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays revealed broad neutralizing activity against a range of variant RBDs.

Binaural Processing Deficits in a Child with Chiari Malformation (Type 1).

Chiari malformation is a condition involving caudal descent of the hindbrain which herniates the cerebellar tonsils through the foramen magnum. The purpose of this study was to quantify auditory deficits in an affected individual and to explore the hypothesis that cerebellar malformation specifically disrupts binaural processing. We present audiometric, electrophysiologic, imaging and auditory perceptual findings for a 17-year-old female with Chiari 1 malformation and for a cohort of 35 hearing- and age-matched controls.

Snap Diagnosis: Developing an Artificial Intelligence Algorithm for Penile Cancer Detection from Photographs.

: Penile cancer is aggressive and rapidly progressive. Early recognition is paramount for overall survival. However, many men delay presentation due to a lack of awareness and social stigma.

The Synthesis of Sulfonyl Fluoride Functionalized 2-Aminothiazoles Using a Diversity Oriented Clicking Strategy.

We present a Diversity Oriented Clicking approach to synthesize a library of novel clickable -substituted 2-aminothiazoles which serve as versatile hubs for SuFEx click chemistry diversification. Leveraging the spring-loaded reactivity of the 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) connectors, the transformation is simple to perform, tolerant of a wide range of functionality, and regioselective for a single product. Finally, we propose a detailed stepwise reaction mechanism that is supported by experimental and computational analysis.

The benefits of removing toxic chemicals from plastics.

More than 16,000 chemicals are incorporated into plastics to impart properties such as color, flexibility, and durability. These chemicals may leach from plastics, resulting in widespread human exposure during everyday use. Two plastic-associated chemicals-bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP)-and a class of chemicals-brominated flame retardants [polybrominated diphenyl ethers (PBDEs)]-are credibly linked to adverse health and cognitive impacts.