A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine.

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007- 2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and AstraZeneca

Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors

We have previously highlighted the ability of testosterone to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy at 72hrs (after transfer to low serum media) via multiple population doublings (PD) vs. their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (Picropodophyllin/PPP, 150 nM) for 72 hrs and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-I, myoD and myogenin with increases in myostatin mRNA both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger increased in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. However, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, perhaps suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. Overall, this suggested that sufficient AR was important to enable normal gene expression of IGF-IR and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it appears that normal AR function in basal conditions is required for adequate IGF-IR gene expression and downstream Akt abundance

The influence of electromagnetic fields from two commercially available water-treatment devices on calcium carbonate precipitation

CaCO3 precipitation profiles, tracked by absorbance at 350 nm, showing accelerated precipitation upon exposure of the parent solutions to a pulsed electromagnetic field (PEMF) from a commercially available device.</p

L-glutamine improves skeletal muscle cell differentiation and prevents myotube atrophy after cytokine (TNF-α) stress via reduced p38 MAPK signal transduction

Tumour Necrosis Factor- Alpha (TNF-α) is chronically elevated in conditions where skeletal muscle loss occurs. As L-glutamine can dampen the effects of inflamed environments, we investigated the role of L-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-α (20 ng.ml−1) ± L-glutamine (20 mM).TNF-α reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I and Igfbp5. Furthermore, when administered to mature myotubes, TNF-α induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2 and glutamine synthetase and parallel increases in Fox03, Cfos, p53 and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-α. Importantly, 20 mM L-glutamine reduced p38 MAPK activity in TNF-α conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. L-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d and restored atrophic gene expression of Fox03 back to baseline in TNF-α conditions. In conclusion, L-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. L-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. This article is protected by copyright. All rights reserve

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease

Mathematical model of blood and interstitial flow and lymph production in the liver.

We present a mathematical model of blood and interstitial flow in the liver. The liver is treated as a lattice of hexagonal \u2018classic\u2019 lobules, which are assumed to be long enough that end effects may be neglected and a two-dimensional problem considered. Since sinusoids and lymphatic vessels are numerous and small compared to the lobule, we use a homogenized approach, describing the sinusoidal and interstitial spaces as porous media. We model plasma filtration from sinusoids to the interstitium, lymph uptake by lymphatic ducts, and lymph outflow from the liver surface. Our results show that the effect of the liver surface only penetrates a depth of a few lobules\u2019 thickness into the tissue. Thus, we separately consider a single lobule lying sufficiently far from all external boundaries that we may regard it as being in an infinite lattice, and also a model of the region near the liver surface. The model predicts that slightly more lymph is produced by interstitial fluid flowing through the liver surface than that taken up by the lymphatic vessels in the liver and that the on-peritonealized region of the surface of the liver results in the total lymph production (uptake by lymphatics plus fluid crossing surface) being about 5 % more than if the entire surface were covered by the Glisson\u2013peritoneal membrane. Estimates of lymph outflow through the surface of the liver are in good agreement with experimental data. We also study the effect of non-physiological values of the controlling parameters, particularly focusing on the conditions of portal hypertension and ascites. To our knowledge, this is the first attempt to model lymph production in the liver. The model provides clinically relevant information about lymph outflow pathways and predicts the systemic response to pathological variations

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis