Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics.

Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization.

A gH/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge.

Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells.

Sensitive bispecific chimeric T cell receptors for cancer therapy.

The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes.

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect.

Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway.

IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model.

Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis.

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8 T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis.

Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity.

Background: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy.

Atomic-Scale Elucidation of Unusually Distorted Dimeric Complexes Confined in a Zr-Based Metal-Organic Framework.

Nanoconfinement in metal-organic framework (MOF) pores can lead to the isolation of unusual or reactive metal complexes. However, MOFs that support the stabilization and precise structural elucidation of metal complexes and small metal clusters are rare. Here, we report a thermally and chemically stable zirconium-based MOF (University of Adelaide Material-1001, UAM-1001) with a high density of free bis-pyrazolyl units that can confine mono- and dinuclear metal complexes.

Versatile Tissue-Injectable Hydrogels with Extended Hydrolytic Release of Bioactive Protein Therapeutics.

Hydrogels generally have broad utilization in healthcare due to their tunable structures, high water content, and inherent biocompatibility. FDA-approved applications of hydrogels include spinal cord regeneration, skin fillers, and local therapeutic delivery. Drawbacks exist in the clinical hydrogel space, largely pertaining to inconsistent therapeutic exposure, short-lived release windows, and difficulties inserting the polymer into tissue.

Identifying cancer-associated leukocyte profiles using high-resolution flow cytometry screening and machine learning.

Background: Machine learning (ML) is a valuable tool with the potential to aid clinical decision making. Adoption of ML to this end requires data that reliably correlates with the clinical outcome of interest; the advantage of ML is that it can model these correlations from complex multiparameter data sets that can be difficult to interpret conventionally. While currently available clinical data can be used in ML for this purpose, there exists the potential to discover new "biomarkers" that will enhance the effectiveness of ML in clinical decision making.

High-pressure single-crystal diffraction at the Australian Synchrotron.

A new high-pressure single-crystal diffraction setup has been designed and implemented at the Australian Synchrotron for collecting molecular and protein crystal structures. The setup incorporates a modified micro-Merrill-Bassett cell and holder designed specifically to fit onto the horizontal air-bearing goniometer, allowing high-pressure diffraction measurements to be collected with little to no modification of the beamline setup compared with ambient data collections. Compression data for the amino acid, L-threonine, and the protein, hen egg-white lysozyme, were collected, showcasing the capabilities of the setup.

Clostridium perfringens virulence factors are nonredundant activators of the NLRP3 inflammasome.

Inflammasome signaling is a central pillar of innate immunity triggering inflammation and cell death in response to microbes and danger signals. Here, we show that two virulence factors from the human bacterial pathogen Clostridium perfringens are nonredundant activators of the NLRP3 inflammasome in mice and humans. C.

: a high-throughput tool for the serial refinement and analysis of crystallographic data collected under varying conditions.

is a new open-source software project designed to greatly reduce the time required to analyse crystallographic data collected under varying conditions. Scripted in Python3, can automatically refine, finalize and analyse data collections with wide-ranging temperatures, pressures . This is achieved using a reference structure, allowing for quick identification of problems, phase changes and even model comparison.

Safety assessment scheme for menstrual cups and application for the evaluation of a menstrual cup comprised of medical grade silicone.

Background: Ensuring menstrual cup safety is paramount, yet a menstrual cup safety assessment scheme is lacking. This paper presents a quadripartite scheme, showing how it can be applied.

Methods: The Tampax Menstrual Cup was evaluated in the safety assessment scheme: (1) Biocompatibility and chemical safety of cup constituents.

Visible-Light-Responsive Self-Assembled Complexes: Improved Photoswitching Properties by Metal Ion Coordination.

A photoswitchable ligand based on azobenzene is self-assembled with palladium(II) ions to form a [Pd (E-L) ] cage. Irradiation with 470 nm light results in the near-quantitative switching to a monomeric species [Pd(Z-L) ] , which can be reversed by irradiation with 405 nm light, or heat. The photoswitching selectivity towards the metastable isomer is significantly improved upon self-assembly, and the thermal half-life is extended from 40 days to 850 days, a promising approach for tuning photoswitching properties.

Guest-Induced Multistep to Single-Step Spin-Crossover Switching in a 2-D Hofmann-Like Framework with an Amide-Appended Ligand.

A detailed study of the two-dimensional (2-D) Hofmann-like framework [Fe(furpy)Pd(CN)]·G (furpy: -(pyridin-4-yl)furan-2-carboxamide, G = HO,EtOH (·HO,Et), and HO (·HO)) is presented, including the structural and spin-crossover (SCO) implications of subtle guest modification. This 2-D framework is characterized by undulating Hofmann layers and an array of interlayer spacing environments─this is a strategic approach that we achieve by the inclusion of a ligand with multiple host-host and host-guest interaction sites. Variable-temperature magnetic susceptibility studies reveal an asymmetric multistep SCO for ·HO,Et and an abrupt single-step SCO for ·HO with an upshift in transition temperature of ∼75 K.

Immunization with a self-assembling nanoparticle vaccine displaying EBV gH/gL protects humanized mice against lethal viral challenge.

Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 165,000 deaths annually. EBV is also the etiological agent of infectious mononucleosis and is linked to multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine would have a significant global health impact.

Regulation of Multistep Spin Crossover Across Multiple Stimuli in a 2-D Framework Material.

We investigate the effects of a broad array of external stimuli on the structural, spin-crossover (SCO) properties and nature of the elastic interaction within the two-dimensional Hofmann framework material [Fe(cintrz)Pd(CN)]·guest (cintrz = -cinnamalidene 4-amino-1,2,4-triazole; ·guest; guest = 3HO, 2HO, and Ø). This framework exhibits a delicate balance between ferro- and antiferro-elastic interaction characters; we show that manipulation of the pore contents across guests = 3HO, 2HO, and Ø can be exploited to regulate this balance. In ·3HO, the dominant antiferroelastic interaction character between neighboring Fe sites sees the low-temperature persistence of the mixed spin-state species {HS-LS} for {Fe1-Fe2} (HS = high spin, LS = low spin).

Machine learning predicts cancer subtypes and progression from blood immune signatures.

Clinical adoption of immune checkpoint inhibitors in cancer management has highlighted the interconnection between carcinogenesis and the immune system. Immune cells are integral to the tumour microenvironment and can influence the outcome of therapies. Better understanding of an individual's immune landscape may play an important role in treatment personalisation.

The Nitrogen Stress Response Changes Radically in the Face of Concurrent Phosphate Stress.

Expression of hundreds of genes changed more than two-fold in response to either nitrogen or phosphate limitation. When these two stresses were applied together, stress responsive gene expression shifted dramatically. In particular, the nitrogen stress response in the presence of phosphate stress had only 30 of about 350 genes in common with the 280 genes that responded to nitrogen stress with adequate phosphate.

Templated synthesis of zirconium(IV)-based metal-organic layers (MOLs) with accessible chelating sites.

Metal-organic layers (MOLs) are of great interest in heterogeneous catalysis, particularly materials that can accommodate extraneous metal centres. Here, we demonstrate a two-step preorganisation/delamination synthetic strategy using CuI as a template to prepare Zr-based MOLs with accessible 'syn' bis-pyrazolyl chelating sites (named ) that are poised for quantitative post-synthetic metalation with late transition metals.

Guest-Dependent Isomer Convergence of a Permanently Fluxional Coordination Cage.

A fluxional bis-monodentate ligand, based on the archetypal shape-shifting molecule bullvalene, self-assembles with M (M=Pd or Pt ) to produce a highly complex ensemble of permanently fluxional coordination cages. Metal-mediated self-assembly selects for an M L architecture while maintaining shape-shifting ligand complexity. A second level of simplification is achieved with guest-exchange; the binding of halides within the M L cage mixture results in a convergence to a cage species with all four ligands present as the "B isomer".

Elastically flexible molecular crystals.

The discovery of molecular single crystals that display interesting elastic behaviour has generated excitement regarding their potential applications as it has upended the common perception of crystals as brittle objects. In order to design new functional materials based on molecular crystals, a comprehensive understanding of how these materials respond to deformation on a molecular-level is required. An introduction to the underlying mechanical theory and how it may be applied to single crystals is provided, along with a comprehensive discussion on how these mechanical properties can be characterised.