The Burundi Heart Centre: From concept to design.

Burundi is one of the worlds poorest nations, which is also reflected in its relative lack of cardiac facilities, particularly those catering to young children and adults. The authors discuss current efforts to build The Burundi Heart Centre to help address this challenge. In particular, they highlight how the project can act as a case study for a sustainable architecture that involves local people and uses locally available materials in a contemporary and innovative way

Correction: Chemical proteomics approaches for identifying the cellular targets of natural products

Covering: 2010 up to 2016. Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied "in situ" - in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide-alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss 'competitive mode' approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed

A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML

Zero-bias anomaly and kondo-assisted quasiballistic 2D transport

Nonequilibrium transport measurements in mesoscopic quasiballistic 2D electron systems show an enhancement in the differential conductance around the Fermi energy. At very low temperatures, such a zero-bias anomaly splits, leading to a suppression of linear transport at low energies. We also observed a scaling of the nonequilibrium characteristics at low energies which resembles electron scattering by two-state systems, addressed in the framework of two-channel Kondo model. Detailed sample-to-sample reproducibility indicates an intrinsic phenomenon in unconfined 2D systems in the low electron-density regime

Chemical probes unravel an antimicrobial defense response triggered by binding of the human opioid dynorphin to a bacterial sensor kinase

Host-microbe communication via small molecule signals is important for both symbiotic and pathogenic relationships, but is often poorly understood at the molecular level. Under conditions of host stress, levels of the human opioid peptide dynorphin are elevated, triggering virulence in the opportunistic pathogenic bacterium Pseudomonas aeruginosa via an unknown pathway. Here we apply a multilayered chemical biology strategy to unravel the mode of action of this putative interkingdom signal. We designed and applied dynorphin-inspired photoaffinity probes to reveal the protein targets of the peptide in live bacteria via chemical proteomics. ParS, a largely uncharacterized membrane sensor of a two-component system, was identified as the most promising hit. Subsequent full proteome studies revealed that dynorphin(1-13) induces an antimicrobial peptide-like response in Pseudomonas, with specific upregulation of membrane defence mechanisms. No such response was observed in a parS mutant, which was more susceptible to dynorphin-induced toxicity. Thus, P. aeruginosa exploits the ParS sensing machinery to defend itself against the host in response to dynorphin as a signal. This study highlights interkingdom communication as a potential essential strategy not only for induction of P. aeruginosa virulence but also for maintaining viability in the hostile environment of the host

Infant cortex responds to other humans from shortly after birth

A significant feature of the adult human brain is its ability to selectively process information about conspecifics. Much debate has centred on whether this specialization is primarily a result of phylogenetic adaptation, or whether the brain acquires expertise in processing social stimuli as a result of its being born into an intensely social environment. Here we study the haemodynamic response in cortical areas of newborns (1–5 days old) while they passively viewed dynamic human or mechanical action videos. We observed activation selective to a dynamic face stimulus over bilateral posterior temporal cortex, but no activation in response to a moving human arm. This selective activation to the social stimulus correlated with age in hours over the first few days post partum. Thus, even very limited experience of face-to-face interaction with other humans may be sufficient to elicit social stimulus activation of relevant cortical regions

Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme

Thoracic arachnoiditis, arachnoid cyst and syrinx formation secondary to myelography with Myodil, 30 years previously

Spinal arachnoiditis can rarely occur following irritation from foreign body substances, including certain oil based contrast agents used for myelography. We describe a patient with thoracic arachnoiditis, arachnoid cyst and syringomyelia, 30 years following a myelogram with Myodil. A 62-year-old female presented with chronic thoraco-lumbar back pain, a spastic paraparesis and sphincter disturbance. She had undergone a myelogram with Myodil, 30 years previously for investigation of back pain. A MRI scan revealed evidence of arachnoiditis, thoracic syringomyelia (T6–T8) and an anteriorly placed, extramedullary, arachnoid cyst at T10–T12, compressing the cord. At surgery, T7–T10 thoracic laminectomies were carried out and syringo- and cysto-subarachnoid shunts were inserted. At 12 months follow-up, the sphincter disturbance, lower limb weakness and mobility problems had almost resolved. Although, the use of oil based contrast agents such as Myodil has been discontinued, the present case illustrates some of the rare sequelae of its use, manifesting decades later. Aggressive surgical intervention produced symptomatic benefit