Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography.

Purpose: Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA).

Methods: Nude mice injected with U87MG tumor cells were longitudinally monitored for the development of orthotopic GBMs up to 15 days and observed for changes in sO upon administration of combretastatin A4 phosphate (CA4P, 30 mg/kg), an FDA approved VDA for treating solid tumors. We employed a newly-developed non-negative constrained approach for combined MSOT image reconstruction and unmixing in order to quantitatively map sO in whole mouse brains.

PRMT5-mediated regulation of developmental myelination.

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination.

Electrospun Pectin-Polyhydroxybutyrate Nanofibers for Retinal Tissue Engineering.

Natural polysaccharide pectin has for the first time been grafted with polyhydroxybutyrate (PHB) via ring-opening polymerization of β-butyrolactone. This copolymer, pectin-polyhydroxybutyrate (pec-PHB), was blended with PHB in various proportions and electrospun to produce nanofibers that exhibited uniform and bead-free nanostructures, suggesting the miscibility of PHB and pec-PHB. These nanofiber blends exhibited reduced fiber diameters from 499 to 336-426 nm and water contact angles from 123.

Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket.

Activating mutations within the epidermal growth factor receptor () kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance.

Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence: supporting the next generation of autophagy researchers and fostering international collaborations.

Recently, NIH has funded a center for autophagy research named the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center (UNM HSC), with aspirations to promote autophagy research locally, nationally, and internationally. The center has 3 major missions: (i) to support junior faculty in their endeavors to develop investigations in this area and obtain independent funding; (ii) to develop and provide technological platforms to advance autophagy research with emphasis on cellular approaches for high quality reproducible research; and (iii) to foster international collaborations through the formation of an International Council of Affiliate Members and through hosting national and international workshops and symposia. Scientifically, the AIM center is focused on autophagy and its intersections with other processes, with emphasis on both fundamental discoveries and applied translational research.

Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines.

Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics.

Effects of the differential expression of ZO-1 and ZO-2 on podocyte structure and function.

Glomerular podocytes in the kidney originate from columnar epithelial cells possessing tight junctions. During podocyte differentiation, tight junctions are replaced by slit diaphragms, which are formed between foot processes and function as a blood filtration barrier. Although the expression of most tight junction components is suppressed during podocyte differentiation, several components, including ZO-1 and ZO-2, are consistently expressed.

Biophysical studies and NMR structure of YAP2 WW domain - LATS1 PPxY motif complexes reveal the basis of their interaction.

YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively.

From Germline to Soma: Epigenetic Dynamics in the Mouse Preimplantation Embryo.

When reflecting about cell fate commitment we think of differentiation. Be it during embryonic development or in an adult stem cell niche, where cells of a higher potency specialize and cell fate decisions are taken. Under normal circumstances this process is definitive and irreversible.

Thermal proximity coaggregation for system-wide profiling of protein complex dynamics in cells.

Proteins differentially interact with each other across cellular states and conditions, but an efficient proteome-wide strategy to monitor them is lacking. We report the application of thermal proximity coaggregation (TPCA) for high-throughput intracellular monitoring of protein complex dynamics. Significant TPCA signatures observed among well-validated protein-protein interactions correlate positively with interaction stoichiometry and are statistically observable in more than 350 annotated human protein complexes.

Switch and Trace: Recombinase Genetics in Zebrafish.

Transgenic approaches are instrumental for labeling and manipulating cells and cellular machineries in vivo. Transgenes have traditionally been static entities that remained unaltered following genome integration, limiting their versatility. The development of DNA recombinase-based methods to modify, excise, or rearrange transgene cassettes has introduced versatile control of transgene activity and function.

Dual roles of TRF1 in tethering telomeres to the nuclear envelope and protecting them from fusion during meiosis.

Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages.

HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis.

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression.

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract.

PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression.

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function.

Noncoding RNAs: Master Regulators of Inflammatory Signaling.

Inflammatory signaling underlies many diseases, from arthritis to cancer. Our understanding of inflammation has thus far been limited to the world of proteins, because we are only just beginning to understand the role that noncoding RNAs (ncRNA) might play. It is now clear that ncRNA do not constitute transcriptional 'noise' but instead harbor physiological functions in controlling signaling pathways.

Chromatin dependencies in cancer and inflammation.

Multiple cell-signalling pathways converge on chromatin to induce gene expression programmes. The inducible transcriptional programmes that are established as a result of inflammatory or oncogenic signals are controlled by shared chromatin regulators. Therapeutic targeting of such chromatin dependencies has proved effective for controlling tumorigenesis and for preventing immunopathologies that are driven by overt inflammation.

Cavin-2 regulates the activity and stability of endothelial nitric-oxide synthase (eNOS) in angiogenesis.

Angiogenesis is a highly regulated process for formation of new blood vessels from pre-existing ones. Angiogenesis is dysregulated in various pathologies, including age-related macular degeneration, arthritis, and cancer. Inhibiting pathological angiogenesis therefore represents a promising therapeutic strategy for treating these disorders, highlighting the need to study angiogenesis in more detail.

The transcriptional program, functional heterogeneity, and clinical targeting of mast cells.

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions.

Cell size control - a mechanism for maintaining fitness and function.

The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on 'what regulates cell size', the question 'why cell size needs to be maintained' has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population.

Databases and Computational Tools for Evolutionary Analysis of Protein Phosphorylation.

Advancements in MS-based phospho-proteomics techniques have helped uncover hundred thousands of protein phosphorylation sites in human and various model organisms. The majority of these sites are uncharacterized. The sheer number of uncharacterized sites necessitates systematic approaches to prioritize sites for more in-depth annotation.

Emi2 Is Essential for Mouse Spermatogenesis.

The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2-in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions.