Understanding and exploiting molecular mechanisms in biology is central to chemical biology. Chemical biology studies of biological macromolecules are now in a perfect continuum with molecular level ...and nanomolecular level mechanistic studies involving whole organisms. The potential opportunity presented by such studies is the design and creation of genuine precision active pharmaceutical ingredients (APIs; including DNA, siRNA, smaller-molecule bioactives) that demonstrate exceptional levels of disease target specificity and selectivity. This article covers the best of my personal and collaborative academic research work using an organic chemistry and chemical biology approach towards understanding biological molecular recognition processes, work that appears to be leading to the generation of novel precision APIs with genuine potential for the treatments of major chronic diseases that afflict globally.
The overall goal of my career as an academic chemist has always been the design and creation of advanced therapeutics and diagnostics that address unmet medical need in the management of chronic ...diseases. Realising this goal has been an immensely difficult process involving multidisciplinary problem-driven research at the chemistry-biology-medicine interfaces. With success in the laboratory, I started seriously to question the value of remaining an academic whose career is spent in the pursuit of knowledge and understanding alone without making any significant effort to translate knowledge and understanding gained into products of genuine utility for public benefit. Therefore, I elected by choice to become an academic entrepreneur, seeking opportunities wherever possible for the translation of the best of my personal and collaborative academic research work into potentially valuable and useful products. This choice has brought with it many unexpected difficulties and challenges. Nevertheless, progress bas been made and sufficient learnt to suggest that this would be an appropriate moment to take stock and provide some personal reflections on what it takes to design and create advanced therapeutics and diagnostics in the laboratory then seek to develop, innovate and translate the best towards market.
Nanofibre-based mucoadhesive films were invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines. The mucoadhesive film consists of an electrospun nanofibrous ...reservoir layer, a mucoadhesive film layer and a protective backing layer. The mucoadhesive layer is responsible for tight adhesion of the whole system to the oral mucosa after application. The electrospun nanofibrous reservoir layer is intended to act as a reservoir for polymeric and lipid-based nanoparticles, liposomes, virosomes, virus-like particles, dendrimers and the like, plus macromolecular drugs, antigens and/or allergens. The extremely large surface area of nanofibrous reservoir layers allows high levels of nanoparticle loading. Nanoparticles can either be reversibly adsorbed to the surface of nanofibres or they can be deposited in the pores between the nanofibres. After mucosal application, nanofibrous reservoir layers are intended to promote prolonged release of nanoparticles into the submucosal tissue. Reversible adsorption of model nanoparticles as well as sufficient mucoadhesive properties were demonstrated. This novel system appears appropriate for the use in oral mucosa, especially for sublingual and buccal tissues. To prove this concept, trans-/intramucosal and lymph-node delivery of PLGA-PEG nanoparticles was demonstrated in a porcine model. This system can mainly be used for sublingual immunization and the development of “printed vaccine technology”.
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Raging against the Mass-Schooling Machine is a compelling autoethnographic account of one beginning teacher's struggle to transform his future teaching identity by unpacking the bruising encounters ...that shaped him as a student. This is a must-read book for all teachers wishing to 'teach against the grain.'.
Egg Activation at Fertilization Machaty, Zoltan; Miller, Andrew R; Zhang, Lu
Advances in experimental medicine and biology,
01/2017, Letnik:
953
Journal Article
Recenzirano
Fertilization is the union of gametes to initiate development of a new individual. The female gamete is formed during oogenesis. The process begins when, in the early embryo, primordial germ cells ...arise and subsequently colonize the genital ridges. They differentiate into oogonia, start meiosis, and become primary oocytes. The cell cycle of the primary oocytes then becomes arrested in mid-meiosis for an extended period of time. Prior to ovulation the oocytes undergo a growth phase and their sizes increase significantly. A hormonal cue then triggers oocyte maturation that involves the resumption of meiosis, the completion of the first meiotic division, and, as a result, the reduction in the diploid chromosome number. The cell cycle then stops again; in vertebrates this arrest occurs at the metaphase stage of the second meiotic division. Meiosis resumes at fertilization, when the sperm activates the egg, i.e., it causes a series of changes that are required for the initiation of embryo development. This is achieved by triggering an elevation in the egg's intracellular free calcium concentration. In response, the fertilized egg completes meiosis and enters the first embryonic cell cycle.
There is a recognised need for targeted community-wide mental health strategies and interventions aimed specifically at prevention and early intervention in promoting mental health. Young males are a ...high need group who hold particularly negative attitudes towards mental health services, and these views are detrimental for early intervention and help-seeking. Organised sports provide a promising context to deliver community-wide mental health strategies and interventions to adolescent males. The aim of the Ahead of the Game program is to test the effectiveness of a multi-component, community-sport based program targeting prevention, promotion and early intervention for mental health among adolescent males.
The Ahead of the Game program will be implemented within a sample drawn from community sporting clubs and evaluated using a sample drawn from a matched control community. Four programs are proposed, including two targeting adolescents, one for parents, and one for sports coaches. One adolescent program aims to increase mental health literacy, intentions to seek and/or provide help for mental health, and to decrease stigmatising attitudes. The second adolescent program aims to increase resilience. The goal of the parent program is to increase parental mental health literacy and confidence to provide help. The coach program is intended to increase coaches' supportive behaviours (e.g., autonomy supportive behaviours), and in turn facilitate high-quality motivation and wellbeing among adolescents. Programs will be complemented by a messaging campaign aimed at adolescents to enhance mental health literacy. The effects of the program on adolescent males' psychological distress and wellbeing will also be explored.
Organised sports represent a potentially engaging avenue to promote mental health and prevent the onset of mental health problems among adolescent males. The community-based design, with samples drawn from an intervention and a matched control community, enables evaluation of adolescent males' incremental mental health literacy, help-seeking intentions, stigmatising attitudes, motivation, and resilience impacts from the multi-level, multi-component Ahead of the Game program. Notable risks to the study include self-selection bias, the non-randomised design, and the translational nature of the program. However, strengths include extensive community input, as well as the multi-level and multi-component design.
Australian New Zealand Clinical Trials Registry ACTRN12617000709347 . Date registered 17 May 2017. Retrospectively registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Zika virus (ZIKV) infection is associated with microcephaly in neonates and Guillain-Barré syndrome in adults. ZIKV produces a class of nonstructural (NS) regulatory proteins that play a critical ...role in viral transcription and replication, including NS5, which possesses RNA-dependent RNA polymerase (RdRp) activity. Here we demonstrate that rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection, inhibits the enzymatic activity of NS5 and suppresses ZIKV infection and replication in primary human astrocytes. Similarly, other members of the NNRTI family, including etravirine and efavirenz, showed inhibitory effects on viral infection of brain cells. Site-directed mutagenesis identified 14 amino acid residues within the NS5 RdRp domain (AA265-903), which are important for the RPV interaction and the inhibition of NS5 polymerase activity. Administration of RPV to ZIKV-infected interferon-alpha/beta receptor (IFN-A/R) knockout mice improved the clinical outcome and prevented ZIKV-induced mortality. Histopathological examination of the brains from infected animals revealed that RPV reduced ZIKV RNA levels in the hippocampus, frontal cortex, thalamus, and cerebellum. Repurposing of NNRTIs, such as RPV, for the inhibition of ZIKV replication offers a possible therapeutic strategy for the prevention and treatment of ZIKV-associated disease.
Sariyer et al. report that rilpivirine (RPV), used in the treatment of HIV-1 infection, inhibits ZIKV infection in vitro and in vivo. Repurposing of NNRTIs, such as RPV, for the inhibition of ZIKV replication offers a possible therapeutic strategy for the prevention and treatment of ZIKV-associated disease.
Calcium ion concentration (Ca2+) in the systemic extracellular fluid, ECF-Ca2+, is maintained around a genetically predetermined set-point, which combines the operational level of the kidney and ...bone/ECF interfaces. The ECF-Ca2+ is maintained within a narrow oscillation range by the regulatory action of Parathyroid Hormone (PTH), Calcitonin, FGF-23, and 1,25(OH)2D3. This model implies two correction mechanisms, i.e. tubular Ca2+ reabsorption and osteoclast Ca2+ resorption. Although their alterations have an effect on the ECF-Ca2+ maintenance, they cannot fully account for rapid correction of the continuing perturbations of plasma Ca2+, which occur daily in life. The existence of Ca2+ fluxes at quiescent bone surfaces fulfills the role of a short-term error correction mechanism in Ca2+ homeostasis.
To explore the hypothesis that PTH regulates the cell system responsible for the fast Ca2+ fluxes at the bone/ECF interface, we have performed direct real-time measurements of Ca2+ fluxes at the surface of ex-vivo metatarsal bones maintained in physiological conditions mimicking ECF, and exposed to PTH. To further characterize whether the PTH receptor on osteocytes is a critical component of the minute-to-minute ECF-Ca2+ regulation, metatarsal bones from mice lacking the PTH receptor in these cells were tested ex vivo for rapid Ca2+ exchange. We performed direct real-time measurements of Ca2+ fluxes and concentration gradients by a scanning ion-selective electrode technique (SIET). To validate ex vivo measurements, we also evaluated acute calcemic response to PTH in vivo in mice lacking PTH receptors in osteocytes vs littermate controls.
Our data demonstrated that Ca2+ fluxes at the bone-ECF interface in excised bones as well as acute calcemic response in the short-term were unaffected by PTH exposure and its signaling through its receptor in osteocytes. Rapid minute-to-minute regulation of the ECF-Ca2+ was found to be independent of PTH actions on osteocytes. Similarly, mice lacking PTH receptor in osteocytes, responded to PTH challenge with similar calcemic increases.
•PTH has no effect on rapid calcium flux at the bone/plasma interface.•Osteocyte PTH receptor is not required for rapid calcium flux at this interface.•Mice lacking osteocyte PTH receptor have fast calcemic response to PTH as controls.•Bone mineral composition of PPR osteocyte KO mice differs from controls.
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