The principles underlying the use of powder diffraction data in solving pharmaceutical crystal structures

Solving pharmaceutical crystal structures from powder diffraction data is discussed in terms of the methodologies that have been applied and the complexity of the structures that have been solved. The principles underlying these methodologies are summarized and representative examples of polymorph, solvate, salt and cocrystal structure solutions are provided, together with examples of some particularly challenging structure determinations.

Detection of nitroaromatic vapours with diketopyrrolopyrrole thin films: exploring the role of structural order and morphology on thin film properties and fluorescence quenching efficiency

Sensitive optical detection of nitroaromatic vapours with diketo-pyrrolopyrrole thin films is reported for the first time and the impact of thin film crystal structure and morphology on fluorescence quenching behaviour demonstrated.

Asymmetric cyclopropanation of conjugated cyanosulfones using a novel cupreine organocatalyst: rapid access to d3-amino acids

An organocatalytic asymmetric synthesis of a novel, highly functionalised cyclopropane system furnished with versatile substituents and containing a quaternary centre is described. The process utilises a new bifunctional catalyst based on the cinchona alkaloid framework and the products made using this catalyst were obtained as single diastereoisomers, with very high enantioselectivities (up to 96% ee). We have also demonstrated that these resulting cyclopropanes are very useful synthetic intermediates to interesting products, such as the difficult to access d3-amino acids.

The effects of springtime mid-latitude storms on trace gas composition determined from the MACC reanalysis

The relationship between springtime air pollution transport of ozone (O3) and carbon monoxide (CO) and mid-latitude cyclones is explored for the first time using the Monitoring Atmospheric Composition and Climate (MACC) reanalysis for the period 2003–2012. In this study, the most intense spring storms (95th percentile) are selected for two regions, the North Pacific (NP) and the North Atlantic (NA). These storms (∼60 storms over each region) often track over the major emission sources of East Asia and eastern North America. By compositing the storms, the distributions of O3 and CO within a "typical" intense storm are examined. We compare the storm-centered composite to background composites of "average conditions" created by sampling the reanalysis data of the previous year to the storm locations. Mid-latitude storms are found to redistribute concentrations of O3 and CO horizontally and vertically throughout the storm. This is clearly shown to occur through two main mechanisms: (1) vertical lifting of CO-rich and O3-poor air isentropically, from near the surface to the mid- to upper-troposphere in the region of the warm conveyor belt; and (2) descent of O3-rich and CO-poor air isentropically in the vicinity of the dry intrusion, from the stratosphere toward the mid-troposphere. This can be seen in the composite storm's life cycle as the storm intensifies, with area-averaged O3 (CO) increasing (decreasing) between 200 and 500 hPa. The influence of the storm dynamics compared to the background environment on the composition within an area around the storm center at the time of maximum intensity is as follows. Area-averaged O3 at 300 hPa is enhanced by 50 and 36% and by 11 and 7.6% at 500 hPa for the NP and NA regions, respectively. In contrast, area-averaged CO at 300 hPa decreases by 12% for NP and 5.5% for NA, and area-averaged CO at 500 hPa decreases by 2.4% for NP while there is little change over the NA region. From the mid-troposphere, O3-rich air is clearly seen to be transported toward the surface, but the downward transport of CO-poor air is not discernible due to the high levels of CO in the lower troposphere. Area-averaged O3 is slightly higher at 1000 hPa (3.5 and 1.8% for the NP and NA regions, respectively). There is an increase of CO at 1000 hPa for the NP region (3.3%) relative to the background composite and a~slight decrease in area-averaged CO for the NA region at 1000 hPa (-2.7%).

Asymmetric organocatalytic synthesis of cyclopentane γ-nitroketones

This paper describes the use of bifunctional thiourea catalysts in the intramolecular reaction of a nitronate with conjugated ketones to generate the corresponding γ-nitroketones. In contrast to our previous studies in this area, we obtained the cis-functionalized systems as the major diastereoisomers in good yields and reasonable selectivities.

The synergies between goal sketching and enterprise architecture

This paper introduces a pragmatic and practical method for requirements modeling. The method is built using the concepts of our goal sketching technique together with techniques from an enterprise architecture modeling language. Our claim is that our method will help project managers who want to establish early control of their projects and will also give managers confidence in the scope of their project. In particular we propose the inclusion of assumptions as first class entities in the ArchiMate enterprise architecture modeling language and an extension of the ArchiMate Motivation Model principle to allow radical as well as normative analyses. We demonstrate the usefulness of this method using a simple university library system as an example.

A herald and his objects in exile: Roger Machado and his memorandum book, 1484-1485

A re-examination of the herald Roger Machado's extant memorandum book, which contains an inventory and mercantile accounts amongst its contents. It is argued that this little-studied source provides evidence for an otherwise undocumented period in Machado's life - when he fled into exile to join Henry Tudor.

Housing economics: a historical approach

This book develops a long-term economic perspective on macro and urban housing issues, from the Victorian era onwards. The historical perspective sheds light on modern problems, particularly concerning the key policy issues of housing supply, affordability, tenure, the distribution of migrant communities, mortgage markets and household mobility.

CDASH: a cloud-enabled program for structure solution from powder diffraction data

The simulated annealing approach to crystal structure determination from powder diffraction data, as implemented in the DASH program, is readily amenable to parallelization at the individual run level. Very large scale increases in speed of execution can be achieved by distributing individual DASH runs over a network of computers. The CDASH program delivers this by using scalable on-demand computing clusters built on the Amazon Elastic Compute Cloud service. By way of example, a 360 vCPU cluster returned the crystal structure of racemic ornidazole (Z0 = 3, 30 degrees of freedom) ca 40 times faster than a typical modern quad-core desktop CPU. Whilst used here specifically for DASH, this approach is of general applicability to other packages that are amenable to coarse-grained parallelism strategies.

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative "pain matrix" that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a "pain matrix" and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience.

Salt and ionic cocrystalline forms of amides: protonation of carbamazepine in aqueous media

The products of reactions of the pharmaceutical amide carbamazepine (CBZ) with strong acids under aqueous conditions were investigated by both powder and single crystal X-ray diffraction. Despite previous claims to the contrary, it was found that salt forms with CBZ protonated at the amide O atom could be isolated from reactions with both HCl and HBr. These forms include the newly identified hydrate phase [CBZ(H)][Cl]·H O. Reactions with other mineral acids (HI and HBF ) gave ionic cocrystalline (ICC) forms (CBZ· [acridinium][I ]·2.5I and CBZ·[H O ] [BF ] ·H O) as well as the salt form CBZ·[CBZ(H)][BF ]·0.5H O. Reaction 2 4 3 2 5 2 0.25 4 0.25 2 4 2 of CBZ with a series of sulfonic acids also gave salt forms, namely, [CBZ(H)][O SC H ], [CBZ(H)][O SC H (OH)]· 3 6 5 3 6 4 0.5H O, [CBZ(H)] [O SCH CH SO ], and [CBZ(H)][O SC H (OH) (COOH)]·H O. CBZ and protonated CBZ(H) 2 2 3 2 2 3 3 6 3 2 moieties can be differentiated in the solid state both by changes to molecular geometry and by differing packing preferences

Selective environmental stress caused by magmatic sulfur emissions from continental flood basalt eruptions

Several biotic crises during the past 300 million years have been linked to episodes of continental flood basalt volcanism, and in particular to the release of massive quantities of magmatic sulphur gas species. Flood basalt provinces were typically formed by numerous individual eruptions, each lasting years to decades. However, the environmental impact of these eruptions may have been limited by the occurrence of quiescent periods that lasted hundreds to thousands of years. Here we use a global aerosol model to quantify the sulphur-induced environmental effects of individual, decade-long flood basalt eruptions representative of the Columbia River Basalt Group, 16.5–14.5 million years ago, and the Deccan Traps, 65 million years ago. For a decade-long eruption of Deccan scale, we calculate a decadal-mean reduction in global surface temperature of 4.5 K, which would recover within 50 years after an eruption ceased unless climate feedbacks were very different in deep-time climates. Acid mists and fogs could have caused immediate damage to vegetation in some regions, but acid-sensitive land and marine ecosystems were well-buffered against volcanic sulphur deposition effects even during century-long eruptions. We conclude that magmatic sulphur from flood basalt eruptions would have caused a biotic crisis only if eruption frequencies and lava discharge rates had been high and sustained for several centuries at a time.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.