Tautomer Standardization in Chemical Databases: Deriving Business Rules from Quantum Chemistry.

Databases of small, potentially bioactive molecules are ubiquitous across the industry and academia. Designed such that each unique compound should appear only once, the multiplicity of ways in which many compounds can be represented means that these databases require methods for standardizing the representation of chemistry. This is commonly achieved through the use of "Chemistry Business Rules", sets of predefined rules that describe the "house style" of the database in question. At Syngenta, the historical approach to the design of chemistry business rules has been to focus on consistency of representation, with chemical relevance given secondary consideration. In this work, we overturn that convention. Through the use of quantum chemistry calculations, we define a set of chemistry business rules for tautomer standardization that reproduces gas-phase energetic preferences. We go on to show that, compared to our historic approach, this method yields tautomers that are in better agreement with those observed experimentally in condensed phases and that are better suited for use in predictive models.

Lack of decline in childhood malaria, Malawi, 2001-2010.

In some areas of Africa, health facility data have indicated declines in malaria that might have resulted from increasingly effective control programs. Most such reports have been from countries where malaria transmission is highly seasonal or of modest intensity. In Malawi, perennial malaria transmission is intense, and malaria control measures have been scaled up during the past decade. We examined health facility data for children seen as outpatients and parasitemia-positive children hospitalized with cerebral malaria in a large national hospital. The proportion of Plasmodium falciparum-positive slides among febrile children at the hospital declined early in the decade, but no further reductions were observed after 2005. The number of admissions for cerebral malaria did not differ significantly by year. Continued surveillance for malaria is needed to evaluate the effects of the increased malaria control efforts.

Universal Design in Architectural Education - Community Liaison on 'Live Projects'.

The infusion of Universal Design principles into existing courses in architecture should become evident in any project work undertaken. 'Live project' is a term used to describe projects that engage the academic world with real-world groups/organizations. CCAE sees such projects as valuable exercises in a student's education, particularly, the practical experience of interaction with 'user-experts.' In 2016 Cork County Council approached CCAE with a proposal to promote age-friendly housing as part of their age-friendly initiative. CCAE developed this into a 'live project' for Year 2 architecture students, continuing the integration of UD into the curriculum. This helps students to identify the negative disabling aspects of ageing and show UD principles can be seen as commonplace. For their part, the County Council were able to expand their own thinking, availing of the less constrained ideas that students brought to their schemes. An approach to achieving the adoption of UD is to consider the Vitruvian definition of architecture as having 'commodity, firmness and delight'. From this, the aesthetic integration of features to benefit users of limited ability can be achieved without stigmatising anyone as being old or disabled. Now in its second year the project is being run in West Cork. The chosen site in Bantry town centre, has interesting challenges for the students to incorporate UD principles. This paper will present imaginative but viable projects as examples of student' responses to the challenges of designing housing solutions and will report on their ability to integrate age-friendly features at different scales.

Good Intentions in Universal Design: A Global Challenge for Higher Education.

It is not often that a high-level edict requires higher education centres to promote universal design through their programmes; however the recent United Nations Beijing Declaration and Action Plan (UNESCAP 2017) expressly states that, "academic institutions should provide training programmes on universal design for policymakers, building inspectors and contractors, as well as integrating universal design and accessibility into curricula related to architecture, urban planning, transport, civil engineering and other relevant academic branches". This is particularly timely in the Asia-Pacific region, where economies continue to show massive expansion of their built environments. This imperative to future-proof any development therefore is vital, especially considering the growing percentile of older people with their needs for safe and accessible living. Achieving these ends clearly implies a need both to educate professionals and to enact appropriate codes and standards, which in turn require the training of personnel to carry them out. Anticipating this need, Goal 3 of the United Nations Incheon Strategy (UNESCAP 2012) optimistically calls for "civil society involvement in conducting accessibility audits, creating guidelines and advocacy work to promote universal design" and "to enhance mechanisms for tracking its progress". While such good intentions are admirable, they will require radical steps to be achieved. The paper describes examples, including those from the writers' own experiences, outlining a range of practical methods which academics and teachers involved in inculcating universal design principles in both European and Asian centres, through their teaching, training and technology transfer, can positively support continued cooperation towards a more inclusive World for everyone.

Bitis gabonica (Gaboon viper) snake venom gland: toward a catalog for the full-length transcripts (cDNA) and proteins.

The venom gland of the snake Bitis gabonica (Gaboon viper) was used for the first time to construct a unidirectional cDNA phage library followed by high-throughput sequencing and bioinformatic analysis. Hundreds of cDNAs were obtained and clustered into contigs. We found mostly novel full-length cDNA coding for metalloproteases (P-II and P-III classes), Lys49-phospholipase A2, serine proteases with essential mutations in the active site, Kunitz protease inhibitors, several C-type lectins, bradykinin-potentiating peptide, vascular endothelial growth factor, nucleotidases and nucleases, nerve growth factor, and L-amino acid oxidases. Two new members of the recently described short coding region family of disintegrin, displaying RGD and MLD motifs are reported. In addition, we have identified for the first time a cytokine-like molecule and a multi-Kunitz protease inhibitor in snake venoms. The CLUSTAL alignment and the unrooted cladograms for selected families of B. gabonica venom proteins are also presented. A significant number of sequences were devoid of database matches, suggesting that their biologic function remains to be identified. This paper also reports the N-terminus of the 15 most abundant venom proteins and the sequences matching their corresponding transcripts. The electronic version of this manuscript, available on request, contains spreadsheets with hyperlinks to FASTA-formatted files for each contig and the best match to the GenBank and Conserved Domain Databases, in addition to CLUSTAL alignments of each contig. We have thus generated a comprehensive catalog of the B. gabonica venom gland, containing for each secreted protein: (i) the predicted molecular weight, (ii) the predicted isoelectric point, (iii) the accession number, and (iv) the putative function. The role of these molecules is discussed in the context of the envenomation caused by the Gaboon viper.

The role of the periosteum in healing a large structural defect following sequestrectomy.

An eight-year-old boy had a sequestrum involving the entire femoral diaphysis removed before significant involucrum had formed. This procedure resulted in a large structural defect. Ten weeks later, the periosteum had completely repaired the effect, and no infection remained. The benefit in this case of early, radical sequestrectomy is discussed.

Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).

Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.

Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).

Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.

1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors.

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.