Surface modified cationic PLGA microparticles as long-acting injectable carriers for intra-articular small molecule drug delivery.

Controlled local delivery of therapeutics (small molecule drug crystals or biologics) for knee-associated diseases such as osteoarthritis necessitates patient compliance, ensuring that the injected depot does not trigger local tissue inflammation and immune responses. A local drug delivery strategy that releases drug at a controlled rate while ensuring minimal tolerability issues at the injection site would be an appealing paradigm in intra-articular (IA) therapies. Herein, we report the formulation development and characterization of surface modified PLGA microparticles (MPs) through the surface integration of a cationic lipid, DOTAP (1,2-Dioleoyl-3-trimethylammonium propane).

Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency.

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization.

Practical Application of the 3Rs in Rodent Transgenesis.

The principles of the 3Rs (replace, reduce, refine), as originally published by Russell and Burch, are internationally acclaimed guidelines for meeting ethical and welfare standards in animal experimentation. Genome manipulation is a standard technique in biomedical research and beyond. The goal of this chapter is to give practical advice on the implementation of the 3Rs in laboratories generating genetically modified rodents.

3R measures in facilities for the production of genetically modified rodents.

Sociocultural changes in the human-animal relationship have led to increasing demands for animal welfare in biomedical research. The 3R concept is the basis for bringing this demand into practice: Replace animal experiments with alternatives where possible, Reduce the number of animals used to a scientifically justified minimum and Refine the procedure to minimize animal harm. The generation of gene-modified sentient animals such as mice and rats involves many steps that include various forms of manipulation.

Toll-like Receptors in Viral Encephalitis.

Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear.

Complete loss of H3K9 methylation dissolves mouse heterochromatin organization.

Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp. We used mouse embryonic fibroblasts (MEFs) with a conditional mutation for Eset1 and introduced progressive deletions for the other SET domain genes by CRISPR/Cas9 technology.

Repeat to gene expression ratios in leukemic blast cells can stratify risk prediction in acute myeloid leukemia.

Background: Repeat elements constitute a large proportion of the human genome and recent evidence indicates that repeat element expression has functional roles in both physiological and pathological states. Specifically for cancer, transcription of endogenous retrotransposons is often suppressed to attenuate an anti-tumor immune response, whereas aberrant expression of heterochromatin-derived satellite RNA has been identified as a tumor driver. These insights demonstrate separate functions for the dysregulation of distinct repeat subclasses in either the attenuation or progression of human solid tumors.

New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence.

Progressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood.

Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia.

Acquired severe aplastic anaemia (SAA) has an immune pathogenesis, and immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine is effective therapy. Eltrombopag (EPAG) added to standard IST was associated with higher overall and complete response rates in patients with treatment-naïve SAA compared to a historical IST cohort. We performed a paediatric subgroup analysis of this trial including all patients aged <18 years who received EPAG plus standard IST (n = 40 patients) compared to a historical cohort (n = 87) who received IST alone.

An Activity-Based Probe Targeting Non-Catalytic, Highly Conserved Amino Acid Residues within Bromodomains.

Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl-lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule-based approach to covalently modify recombinant and endogenous bromodomain-containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops.

Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load.

Tendons are dense connective tissues that attach muscles to bone with an indispensable role in locomotion because of their intrinsic properties of storing and releasing muscle- generated elastic energy. Tenomodulin (Tnmd) is a well-accepted gene marker for the mature tendon/ligament lineage and its loss-of -function in mice leads to a phenotype with distinct signs of premature aging on tissue and stem/progenitor cell levels. Based on these findings, we hypothesized that Tnmd might be an important factor in the functional performance of tendons.

Zooming in on Transcription Preinitiation.

Class II gene transcription commences with the assembly of the Preinitiation Complex (PIC) from a plethora of proteins and protein assemblies in the nucleus, including the General Transcription Factors (GTFs), RNA polymerase II (RNA pol II), co-activators, co-repressors, and more. TFIID, a megadalton-sized multiprotein complex comprising 20 subunits, is among the first GTFs to bind the core promoter. TFIID assists in nucleating PIC formation, completed by binding of further factors in a highly regulated stepwise fashion.