Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells.

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu homeostasis in cancer cells are rarely explored because small molecule Cu chelators have poor binding affinity in comparison to the intracellular Cu chaperones, enzymes, or ligands.

Ion and Molecular Sieving With Ultrathin Polydopamine Nanomembranes.

In contrast to biological cell membranes, it is still a major challenge for synthetic membranes to efficiently separate ions and small molecules due to their similar sizes in the sub-nanometer range. Inspired by biological ion channels with their unique channel wall chemistry that facilitates ion sieving by ion-channel interactions, the first free-standing, ultrathin (10-17 nm) nanomembranes composed entirely of polydopamine (PDA) are reported here as ion and molecular sieves. These nanomembranes are obtained via an easily scalable electropolymerization strategy and provide nanochannels with various amine and phenolic hydroxyl groups that offer a favorable chemical environment for ion-channel electrostatic and hydrogen bond interactions.

Supramolecular Assembly in Live Cells Mapped by Real-Time Phasor-Fluorescence Lifetime Imaging.

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters.

Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren's Disease and Systemic Lupus Erythematosus.

SjD (Sjögren's Disease) and SLE (Systemic Lupus Erythematosus) are similar diseases. There is extensive overlap between the two in terms of both clinical features and pathobiologic mechanisms. Shared genetic risk is a potential explanation of this overlap.

Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with complex causes involving genetic and environmental factors. While genome-wide association studies (GWASs) have identified genetic loci associated with SLE, the functional genomic elements responsible for disease development remain largely unknown. Mendelian Randomization (MR) is an instrumental variable approach to causal inference based on data from observational studies, where genetic variants are employed as instrumental variables (IVs).

An Outer Membrane-Inspired Polymer Coating Protects and Endows Escherichia coli with Novel Functionalities.

A bio-inspired membrane made of Pluronic L-121 is produced around Escherichia coli thanks to the simple co-extrusion of bacteria and polymer vesicles. The block copolymer-coated bacteria can withstand various harsh shocks, for example, temperature, pressure, osmolarity, and chemical agents. The polymer membrane also makes the bacteria resistant to enzymatic digestion and enables them to degrade toxic compounds, improving their performance as whole-cell biocatalysts.

Assembly of biomimetic microreactors using caged-coacervate droplets.

Complex coacervates are liquid-like droplets that can be used to create adaptive cell-like compartments. These compartments offer a versatile platform for the construction of bioreactors inspired by living cells. However, the lack of a membrane significantly reduces the colloidal stability of coacervates in terms of fusion and surface wetting, which limits their suitability as compartments.

Systematic modulation of the lipid composition enables the tuning of liposome cellular uptake.

As liposomes have been widely explored as drug delivery carriers over the past decades, they are one of the most promising platforms due to their biocompatibility and versatility for surface functionalization. However, to improve the specific design of liposomes for future biomedical applications such as nanovaccines, it is necessary to understand how these systems interact with cell membranes, as most of their potential applications require them to be internalized by cells. Even though several investigations on the cellular uptake of liposomes were conducted, the effect of the liposome membrane properties on internalization in different cell lines remains unclear.

Comparative analysis of the repertoire of insulin-reactive B cells in type 1 diabetes-prone and resistant mice.

Seropositivity for autoantibodies against multiple islet antigens is associated with development of autoimmune type 1 diabetes (T1D), suggesting a role for B cells in disease. The importance of B cells in T1D is indicated by the effectiveness of B cell-therapies in mouse models and patients. B cells contribute to T1D by presenting islet antigens, including insulin, to diabetogenic T cells that kill pancreatic beta cells.

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans.

Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool.

Membrane Manipulation of Giant Unilamellar Polymer Vesicles with a Temperature-Responsive Polymer.

Understanding the complex behavior and dynamics of cellular membranes is integral to gain insight into cellular division and fusion processes. Bottom-up synthetic cells are as a platform for replicating and probing cellular behavior. Giant polymer vesicles are more robust than liposomal counterparts, as well as having a broad range of chemical functionalities.

A bespoke target selection tool to guide biomarker discovery in tubo-ovarian cancer.

Introduction: Cancers presenting at advanced stages inherently have poor prognosis. High grade serous carcinoma (HGSC) is the most common and aggressive form of tubo-ovarian cancer. Clinical tests to accurately diagnose and monitor this condition are lacking.

SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.

Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter.

Liquid biopsy in ovarian cancer: Catching the silent killer before it strikes.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy in the western world. The majority of women presenting with the disease are asymptomatic and it has been dubbed the "silent killer". To date there is no effective minimally invasive method of stratifying those with the disease or screening for the disease in the general population.

Inhibitory Receptor Trap: A Platform for Discovery of Inhibitory Receptors That Utilize Inositol Lipid and Phosphotyrosine Phosphatase Effectors.

Among the areas of most impactful recent progress in immunology is the discovery of inhibitory receptors and the subsequent translation of this knowledge to the clinic. Although the original and canonical member of this family is FcγRIIB, more recent studies defined PD1 as an inhibitory receptor that constrains T cell immunity to tumors. These studies led to development of "checkpoint blockade" immunotherapies (CBT) for cancers in which PD1 interactions with its ligand are blocked.

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.

Background: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours.

Methods: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting.

Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.

Ninety percent of systemic lupus erythematosus (SLE) patients are women. X chromosome-dosage increases susceptibility to SLE and primary Sjögren's syndrome (pSS). Chromosome X open reading frame 21 escapes X-inactivation and is an SLE risk gene of previously unknown function.

Defining the molecular evolution of extrauterine high grade serous carcinoma.

Objective: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC).

GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition.

Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing .

and both contain risk alleles for systemic lupus erythematosus (SLE) and Sjögren's syndrome (pSS). The former escapes X inactivation. Our group predicts specific endolysosomal-dependent immune responses are driven by the protein products of these genes, which form a complex at the endolysosomal surface.