Macrophage and osteosarcoma cell crosstalk is dependent on oxygen tension and 3D culture.

Osteosarcoma (OS), the most common form of primary bone cancer in young adults, has had no improvements in clinical outcomes in 50 years. This highlights a critical need to advance mechanistic understanding of OS to further therapeutic discovery, which will only be possible with accurate models of the disease. Compared to traditional monolayer studies and preclinical models, in vitro models that better replicate the three-dimensional (3D) bone marrow microenvironment will facilitate methodical investigations of the events and factors that drive OS progression.

A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR.

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug.

Synbiotic supplementation may globally improve non-motor symptoms in patients with stable Parkinson's disease: results from an open label single-arm study.

Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson's Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms.

A spectroscopic analysis code for spatially resolved x-ray absorption data from the COAX platform.

Sophisticated tools such as computer vision techniques in combination with 1D lineout type analyses have been used in automating the analysis of spectral data for high energy density (HED) plasmas. Standardized automation can solve the problems posed by the complexity of HED spectra and the quantity of data. We present a spectroscopic code written for automated and streamlined analysis of spatially resolved x-ray absorption data from the COAX platform on Omega-60.

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer.

Unlabelled: Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion.

Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase.

Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels.

Multifunctional leather finishing vs. applications, through the addition of well-dispersed flower-like nanoparticles.

In the present paper, multifunctional flower-like nanoparticles were synthesized to be used in the leather finishing. They are capable of conferring simultaneously and synergistic antimicrobial, self-cleaning, light resistance, hydrophobic, mechanical, thermal, and fluorescent properties due to the presence of Ag, TiO, and SiO NPs. These nanoparticles form a "flower-like" structure in which the "pistil" is made up of TiO and the "petals" that surround it of silver nanoparticles and silica nanoparticles, whose dimensions are of the order of ten nanometers.

Silencing of Amylomyces rouxii aspartic II protease by siRNA to increase tyrosinase activity.

Amylomyces rouxii is a zygomycete that produces extracellular protease and tyrosinase. The tyrosinase activity is negatively regulated by the proteases and, which attempts to purify the tyrosinase (tyr) enzyme that has been hampered by the presence of a protease that co-purified with it. In this work we identified genes encoding aspartic protease II (aspII) and VI of A.

Cardiac human bitter taste receptors contain naturally occurring variants that alter function.

Bitter taste receptors (T2R) are a subfamily of G protein-coupled receptors that enable humans to detect aversive and toxic substances. The ability to discern bitter compounds varies between individuals and is attributed mainly to naturally occurring T2R polymorphisms. T2Rs are also expressed in numerous non-gustatory tissues, including the heart, indicating potential contributions to cardiovascular physiology.

An immune deficient mouse model for mucopolysaccharidosis IIIA (Sanfilippo syndrome).

Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA.

Reducing Sialylation Enhances Electrotaxis of Corneal Epithelial Cells.

Corneal wound healing is a complex biological process that integrates a host of different signals to coordinate cell behavior. Upon wounding, there is the generation of an endogenous wound electric field that serves as a powerful cue to guide cell migration. Concurrently, the corneal epithelium reduces sialylated glycoforms, suggesting that sialylation plays an important role during electrotaxis.

Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands.

The human GPCR family comprises circa 800 members, activated by hundreds of thousands of compounds. Bitter taste receptors, TAS2Rs, constitute a large and distinct subfamily, expressed orally and extra-orally and involved in physiological and pathological conditions. TAS2R14 is the most promiscuous member, with over 150 agonists and 3 antagonists known prior to this study.

Discovery of 2-Aminopyrimidines as Potent Agonists for the Bitter Taste Receptor TAS2R14.

The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenamic acid, a nonsteroidal anti-inflammatory drug, led us to 2-aminopyridines showing considerable efficacy and potency in an IPaccumulation assay.

Taste GPCRs and their ligands.

Taste GPCRs are expressed in taste buds on the tongue and play a key role in food choice and consumption. They are also expressed extra-orally, with various physiological roles that are currently under study. Unraveling the roles of these receptors relies on the knowledge of their ligands.

Midazolam premedication in ileocolic intussusception: a retrospective multicenter study.

Unlabelled: Ileocolic intussusception is a common cause of bowel obstruction. When spontaneous reduction does not occur, non-operative management through enema reduction is necessary. Despite the evidence indicating that sedatives favor success in the reduction, their use is still not a common practice.

bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum.

Background: Reactive oxygen species (ROS) trigger different morphogenic processes in filamentous fungi and have been shown to play a role in the regulation of the biosynthesis of some secondary metabolites. Some bZIP transcription factors, such as Yap1, AtfA and AtfB, mediate resistance to oxidative stress and have a role in secondary metabolism regulation. In this work we aimed to get insight into the molecular basis of this regulation in the industrially important fungus Penicillium chrysogenum through the characterization of the role played by two effectors that mediate the oxidative stress response in development and secondary metabolism.

, a Vintage Model with a Cutting-Edge Profile in Biotechnology.

The discovery of penicillin entailed a decisive breakthrough in medicine. No other medical advance has ever had the same impact in the clinical practise. The fungus (reclassified as ) has been used for industrial production of penicillin ever since the forties of the past century; industrial biotechnology developed hand in hand with it, and currently is a thoroughly studied model for secondary metabolite production and regulation.

An Cell-Based Delivery Platform for Zinc Finger Artificial Transcription Factors in Pre-clinical Animal Models.

Zinc finger (ZF), transcription activator-like effectors (TALE), and CRISPR/Cas9 therapies to regulate gene expression are becoming viable strategies to treat genetic disorders, although effective delivery systems for these proteins remain a major translational hurdle. We describe the use of a mesenchymal stem/stromal cell (MSC)-based delivery system for the secretion of a ZF protein (ZF-MSC) in transgenic mouse models and young rhesus monkeys. Secreted ZF protein from mouse ZF-MSC was detectable within the hippocampus 1 week following intracranial or cisterna magna (CM) injection.

Combination product of dermal matrix, preconditioned human mesenchymal stem cells and timolol promotes wound healing in the porcine wound model.

A combination product of human mesenchymal stem/stromal cells (MSCs) embedded in an extracellular matrix scaffold and preconditioned with hypoxia and the beta-adrenergic receptor antagonist, timolol, combined with sustained timolol application post implantation, has shown promising results for improving wound healing in a diabetic mouse model. In the present study, we extend those findings to the more translatable large animal porcine wound model and show that the combined treatment promotes wound reepithelialization in these excisional wounds by 40.2% and increases the CD31 immunostaining marker of angiogenesis compared with the matrix control, while maintaining an accumulated timolol plasma concentration below the clinically safe level of 0.

Flight system morphology and minimum flight temperature in North American cicadas (Insecta: Hemiptera: Cicadidae).

Thermal responses in cicadas have been studied for many years. The minimum flight temperature (MFT) does not show the same relationship to habitat and behavior as other thermal responses. We measured live mass, wing length, wingspan, wing area and wing loading in an attempt to correlate these morphological parameters to the MFT.

Mesenchymal Stromal Cells Regulate Sialylations of N-Glycans, Affecting Cell Migration and Survival.

N-Glycosylations are an important post-translational modification of proteins that can significantly impact cell function. Terminal sialic acid in hybrid or complex N-glycans has been shown to be relevant in various types of cancer, but its role in non-malignant cells remains poorly understood. We have previously shown that the motility of human bone marrow derived mesenchymal stromal cells (MSCs) can be modified by altering N-glycoforms.

High-Efficiency Electroporation for Genetic Improvement of Fungal Strains.

Electroporation is a method for the introduction of molecules (usually nucleic acids) into a cell, consisting of submitting the cells to high-voltage and short electric pulses in the presence of the exogenous DNA/molecule. It is a versatile method, adaptable to different types of cells, from bacteria to cultured cells to higher eukaryotes, and thus has applications in many diverse fields, such as environmental biology, biotechnology, genetic engineering, and medicine. Electroporation has some advantages over other genetic transformation strategies, including the simplicity of the method, a wide range of adjustable parameters (possibility of optimization), high reproducibility and avoidance of the use of chemicals toxic to cells.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity.

Lowered sensitivity of bitter taste receptors to β-glucosides in bamboo lemurs: an instance of parallel and adaptive functional decline in TAS2R16?

Bitter taste facilitates the detection of potentially harmful substances and is perceived via bitter taste receptors (TAS2Rs) expressed on the tongue and oral cavity in vertebrates. In primates, TAS2R16 specifically recognizes β-glucosides, which are important in cyanogenic plants' use of cyanide as a feeding deterrent. In this study, we performed cell-based functional assays for investigating the sensitivity of TAS2R16 to β-glucosides in three species of bamboo lemurs ( and ), which primarily consume high-cyanide bamboo.

Hypoxia up-regulates VEGF ligand and downregulates VEGF soluble receptor mRNA expression in bovine granulosa cells in vitro.

Oxygen concentration (0) in antral ovarian follicles is below that found in most tissues, which is important for adequate granulosa cell function. The VEGF system is linked to angiogenesis and responds to changing 0 by stimulating neovascularization when levels are low. However, in the avascular granulosa cell layer of the follicle, VEGF action is directed to stimulating cell viability and steroidogenesis.