Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.

Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with at least six cognate G protein-coupled receptors. Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease.

How much of the paediatric core curriculum do medical students remember?

Few educational studies have investigated how well information learned by medical students is retained over time. The primary aim of this study was to investigate how much of the paediatric core curriculum undergraduates remembered a year after originally passing their paediatrics examination. In addition, we looked at whether students' repeat performance is related to their approach to learning. Medical students were presented with 8 out of a possible 46 core curriculum short answer questions (Mark 1). A year later these same students were re-tested, without prior warning, on the same 8 questions (Mark 2) and a further 8 questions (Mark 3) from the bank of 46. The participants also completed the Revised two-factor Study Process Questionnaire to characterise their approach to learning. After a year, students scores had diminished by 51.2 % (95 % CI 48.2-54.2 %, p < 0.0001) from a Mark 1 average of 89.1 % (standard deviation, SD = 9.2 %) to a Mark 2 average of 37.9 % (SD 6.1 %). Students who reported a superficial approach to learning achieved higher scores for mark 1 (4.1 % increase (95 % CI 0.9-7.4 %) per one standard deviation unit increase in Surface Approach score (p = 0.01)). Neither deep nor surface approach to learning significantly predicted performance a year later (Marks 2 and 3). Students had forgotten more than half of the paediatric core curricular content that they had previously proven that they knew for their summative assessment. Adopting either a deep or superficial approach to learning did not predict ability to retain this information a year later.

Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.

Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.

4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

Continuous electronic fetal monitoring during prolonged labor may be a risk factor for having a child diagnosed with autism spectrum disorder.

In just 50 years the prevalence of autism spectrum disorder has vaulted from extremely rare to common in every community. During this time, a large body of scientific literature has been amassed regarding what environmental, genetic, maternal, or obstetric factors may be at work. The hypothesis presented here identifies two developments in today's childbirth experience that, in combination, may provide the key: 1) a significant increase in the mean duration of labor and 2) the adoption of continuous electronic fetal monitoring utilizing Doppler ultrasound as the standard of care even in low-risk pregnancies. Together, these two factors have created an unprecedented fetal environment that has the potential to affect neuronal migration and cause non-inherited genetic disruptions. This paper will briefly describe the nature and history of contributing factors, why there may be a link between evolving maternal characteristics, obstetric trends and the increase in autism, as well as the means by which the hypothesis can be tested.

Low-dose X-ray imaging may increase the risk of neurodegenerative diseases.

The hypothesis presented here explores the possibility that X-ray imaging commonly used in dental practices may be a shared risk factor for sporadic dementias and motor-neuron diseases. As the evidence will suggest, the brain is ill-equipped to manage the intrusion of low-dose ionizing radiation (IR) beyond that which is naturally occurring. When the brain's antioxidant defenses are overwhelmed by IR, it produces an abundance of reactive oxygen species (ROS) that can lead to oxidative stress, mitochondrial dysfunction, loss of synaptic plasticity, altered neuronal structure and microvascular impairment that have been identified as early signs of neurodegeneration in Alzheimer's disease, Parkinson's, amyotrophic lateral sclerosis, vascular dementia and other diseases that progressively damage the brain and central nervous system. Although genes play a role in all outcomes, the focus here will be on the non-genetic processes at work. Common assumptions regarding the risks of low-dose IR will be addressed, such as: 1) comparing rapid, repeated bursts of man-made IR sent exclusively into the head to equivalent amounts of head-to-toe background IR over longer periods of time; 2) whether epidemiological studies that dismiss concerns regarding low-dose IR due to lack of evidence it causes cancer, heritable mutations or shortened life spans also apply to neurodegeneration; and 3) why even radiation-resistant neurons can be severely impacted by IR exposure, due to IR-induced injury to the processes they need to function. Also considered will be the difficulty of distinguishing the effects of dental X-ray exposure from similarly low amounts of background IR and where to find the evidence that they may, in fact, be responsible for neurodegeneration. Finally, the long-standing belief that whatever risks are inherent in dental radiography must be undertaken for the sake of oral health is challenged on two counts: 1) while dentists continue to drape their patients in lead-lined aprons, the most effective IR safety precautions are often ignored; and 2) there is an alternative dental imaging technology that does not use IR. While the thrust of this article will be on dental radiation and will touch on how age, gender, X-ray equipment and protocols may increase risk, chiropractic radiographs also will be considered because they focus exclusively on the central nervous system. If X-ray imaging is found to be associated with neurodegeneration, the risk-versus-benefit must be reevaluated, every means of reducing exposure implemented and imaging protocols revised.

Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.

Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.

Dental X-ray exposure and Alzheimer's disease: a hypothetical etiological association.

Despite the fact that Alzheimer's disease was identified more than 100 years ago, its cause remains elusive. Although the chance of developing Alzheimer's disease increases with age, it is not a natural consequence of aging. This article proposes that dental X-rays can damage microglia telomeres - the structures at the end of chromosomes that determine how many times cells divide before they die - causing them to age prematurely. Degenerated microglia lose their neuroprotective properties, resulting in the formation of neurofibrillary tau tangles and consequently, the neuronal death that causes Alzheimer's dementia. The hypothesis that Alzheimer's is caused specifically by microglia telomere damage would explain the delay of one decade or longer between the presence of Alzheimer's brain pathology and symptoms; telomere damage would not cause any change in microglial function, it would just reset the countdown clock so that senescence and apoptosis occurred earlier than they would have without the environmental insult. Once microglia telomere damage causes premature aging and death, the adjacent neurons are deprived of the physical support, maintenance and nourishment they require to survive. This sequence of events would explain why therapies and vaccines that eliminate amyloid plaques have been unsuccessful in stopping dementia. Regardless of whether clearing plaques is beneficial or harmful - which remains a subject of debate - it does not address the failing microglia population. If microglia telomere damage is causing Alzheimer's disease, self-donated bone marrow or dental pulp stem cell transplants could give rise to new microglia populations that would maintain neuronal health while the original resident microglia population died.

Designer laccases: a vogue for high-potential fungal enzymes?

Laccases are blue multicopper oxidases that catalyse the four-electron reduction of O(2) to water coupled with the oxidation of small organic substrates. Secreted basidiomycete white-rot fungal laccases orchestrate this with high thermodynamic efficiency, making these enzymes excellent candidates for exploitation as industrial oxidants. However, these fungi are less tractable genetically than the ascomycetes, which predominantly produce lower-potential laccases. We address the state-of-play regarding expression of high reduction potential laccases in heterologous hosts, and issues regarding enzyme glycosylation status. We describe the synergistic role of structural biology, particularly in unmasking structure-function relationships following genetic modification and their collective impact on laccase yields. Such recent research draws closer the prospect of industrial quantities of designer, fit-for-purpose laccases.

Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.

The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.