Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy.

Background & Aims: The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.

Methods: Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment.

Characterization of Human CD8αβ Interaction With Classical and Unconventional MHC Molecules.

The CD8 co-receptor exists as both an αα homodimer, expressed on subsets of specialized lymphoid cells, and as an αβ heterodimer, which is the canonical co-receptor on cytotoxic T-cells, tuning TCR thymic selection and antigen-reactivity in the periphery. However, the biophysical parameters governing human CD8αβ interactions with classical MHC class I (MHCI) and unconventional MHC-like molecules have not been determined. Using hetero-dimerized Fc-fusions to generate soluble human CD8αβ, we demonstrate similar weak binding affinity to multiple different MHCI alleles compared with CD8αα.

Metabolic dysfunction-associated steatotic liver disease - A new indication for sodium-glucose Co-transporter-2 inhibitors.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as a new name for the previous non-alcoholic fatty liver disease (NAFLD). There are some differences between MASLD and NAFLD, e.g.

The challenge of diagnosing and classifying eosinophilia and eosinophil disorders: A review.

Eosinophilia is a feature of multiple conditions, both hematologic and non-hematologic, and may be associated with organ damage. The pathogenesis of eosinophilia can follow two distinct pathways. Primary eosinophilia is caused by a cell-intrinsic mechanism originating from clonal expansion of eosinophils through acquisition of a somatic mutation, such as FIP1L1-PDGFRA.

Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine.

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles.

USP17 is required for clathrin mediated endocytosis of epidermal growth factor receptor.

Previously we have shown that expression of the deubiquitinating enzyme USP17 is required for cell proliferation and motility. More recently we reported that USP17 deubiquitinates RCE1 isoform 2 and thus regulates the processing of 'CaaX' motif proteins. Here we now show that USP17 expression is induced by epidermal growth factor and that USP17 expression is required for clathrin mediated endocytosis of epidermal growth factor receptor.

A novel RCE1 isoform is required for H-Ras plasma membrane localization and is regulated by USP17.

Processing of the 'CaaX' motif found on the C-termini of many proteins, including the proto-oncogene Ras, requires the ER (endoplasmic reticulum)-resident protease RCE1 (Ras-converting enzyme 1) and is necessary for the proper localization and function of many of these 'CaaX' proteins. In the present paper, we report that several mammalian species have a novel isoform (isoform 2) of RCE1 resulting from an alternate splice site and producing an N-terminally truncated protein. We demonstrate that both RCE1 isoform 1 and the newly identified isoform 2 are required to reinstate proper H-Ras processing and thus plasma membrane localization in RCE1-null cells.

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity.

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway.

Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization.

Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both.

The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.

Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis.

The high-adhesive properties of the FimH adhesin of Salmonella enterica serovar Enteritidis are determined by a single F118S substitution.

The binding properties of low- and high-adhesive forms of FimH adhesins from Salmonella enterica serovars Enteritidis and Typhimurium (S. Enteritidis and S. Typhimurium) were studied using chimeric proteins containing an additional peptide that represents an N-terminal extension of the FimF protein.

Phosphonoacetic acid utilization by fungal isolates: occurrence and properties of a phosphonoacetate hydrolase in some penicillia.

Among a collection of 18 fungal strains representing eight genera, only two strains (Penicillium oxalicum and P. minioluteum) were capable of growth on phosphonoacetic acid as sole phosphorous source. Enrichment liquid cultures in minimal medium with the compound as the only P-source selected four isolates, that were also identified as Penicillium spp.