Synthesis of methyl 16-trideuteriohexadecanoate

Methyl 16-trideuteriohexadecanoate has been prepared in high isotopic purity and in 29% overall yield, from methyl 7-oxo-16-heptadecenoate. The oxo group was reduced with sodium cyanoborohydride and the CD₃ group was introduced by reduction with lithium aluminum deuteride, first of the ester group to the alcohol and then of the derived mesylate. The carboxyl group was formed by oxidative cleavage of the double bond.     

Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.     

Synthesis of [11-2H2], [8-2H2], [7-2H2], [6-2H2], [5-2H2], [4-2H2] and [3-2H2] cis-9-octadecenoates

Deuterated oleates have been synthesized by semihydrogenation of acetylenic intermediates. [11-²H₂]Oleate was prepared by two-carbon chain extension of the C₁₆ alcohol obtained from [1-²H₂]octyl bromide and 7-octyn-1-ol. [8-²H₂] and [7-²H₂]oleates were both prepared from dimethyl suberate, tetradeutero intermediate C₁₆ alcohols were synthesized from [1,8-²H₄] and [2,7-²H₄]octane diols by monobromination, conversion to deuterated 9-decyn-1-ols and reaction with octyl bromide. Oxidation gave [8-²H₂]-9-octadecynoate and [2,7-²H₂]-9-octadecynoate, after semihydrogenation of the latter, deuterons at C-2 were removed by exchange with aqueous alkali. [6-²H₂] and [5-²H₂]oleates were obtained from methyl 5-tetradecynoate, semihydrogenation, deuterium exchange at C-2 and two malonate extensions gave [6-²H₂]oleate; reduction with lithium aluminum deuteride, two malonate extensions and semihydrogenation gave the [5-²H₂] ester. [4-²H₂] and [3-²H₂]oleates were both obtained from methyl 7-cis-hexadecenoate, exchange of the α protons and chain extension gave the [4-²H₂] ester and reduction with lithium aluminum deuteride and chain extension gave the [3-²H₂] ester.     

Downsizing in plants—UV light induces pronounced morphological changes in the absence of stress

Ultraviolet (UV) light induces a stocky phenotype in many plant species. In this study, we investigate this effect with regard to specific UV wavebands (UV-A or UV-B) and the cause for this dwarfing. UV-A- or UV-B-enrichment of growth light both resulted in a smaller cucumber (Cucumis sativus L.) phenotype, exhibiting decreased stem and petiole lengths and leaf area (LA). Effects were larger in plants grown in UV-B- than in UV-A-enriched light. In plants grown in UV-A-enriched light, decreases in stem and petiole lengths were similar independent of tissue age. In the presence of UV-B radiation, stems and petioles were progressively shorter the younger the tissue. Also, plants grown under UV-A-enriched light significantly reallocated photosynthates from shoot to root and also had thicker leaves with decreased specific LA. Our data therefore imply different morphological plant regulatory mechanisms under UV-A and UV-B radiation. There was no evidence of stress in the UV-exposed plants, neither in photosynthetic parameters, total chlorophyll content, or in accumulation of damaged DNA (cyclobutane pyrimidine dimers). The abscisic acid content of the plants also was consistent with non-stress conditions. Parameters such as total leaf antioxidant activity, leaf adaxial epidermal flavonol content and foliar total UV-absorbing pigment levels revealed successful UV acclimation of the plants. Thus, the UV-induced dwarfing, which displayed different phenotypes depending on UV wavelengths, occurred in healthy cucumber plants, implying a regulatory adjustment as part of the UV acclimation processes involving UV-A and/or UV-B photoreceptors.

A stocky phenotype develops in healthy cucumber plants as a regulatory adjustment toward UV-A and UV-B-enriched light, revealing a strong interaction between UV acclimation and developmental processes.     

The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation

The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.     

4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17beta-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate

A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.     

Epicuticular wax of Juniperus scopulorum

Epicuticular wax from Juniperus scopulorum contains hydrocarbons (16%), esters (11%), free acids (1%), nonacosan-10-ol (27%), nonacosane-diols (7%) and estolides (16%). The major hydrocarbon is tritriacontane; the principal esters are C₃₄–C₄₆, mainly octyl and decyl esters of C₂₈-C₃₆ acids; and the diols consist of nonacosane-4,10-diol (57%),5,10-diol (28%), 7,10-diol (11%) and 10,13-diol (4%). Hydrolysis of the estolides gave a mixture of acids, ω-hydroxy acids, , ω-diols, alcohols and hydroxy acids. The hydroxy acids are a new class of C₂₈–C₃₆ acids with the OH attached to either the eighteenth or twentieth carbon from the terminal methyl end; the major component is 13-hydroxydotriacontanoic acid. Syntheses of this acid and of nonacosane-4,10-dione and nonacosane-4,10-diol are described.     

Predicting species distributions for conservation decisions

Species distribution models (SDMs) are increasingly proposed to support conservation decision making. However, evidence of SDMs supporting solutions for on‐ground conservation problems is still scarce in the scientific literature. Here, we show that successful examples exist but are still largely hidden in the grey literature, and thus less accessible for analysis and learning. Furthermore, the decision framework within which SDMs are used is rarely made explicit. Using case studies from biological invasions, identification of critical habitats, reserve selection and translocation of endangered species, we propose that SDMs may be tailored to suit a range of decision‐making contexts when used within a structured and transparent decision‐making process. To construct appropriate SDMs to more effectively guide conservation actions, modellers need to better understand the decision process, and decision makers need to provide feedback to modellers regarding the actual use of SDMs to support conservation decisions. This could be facilitated by individuals or institutions playing the role of ‘translators’ between modellers and decision makers. We encourage species distribution modellers to get involved in real decision‐making processes that will benefit from their technical input; this strategy has the potential to better bridge theory and practice, and contribute to improve both scientific knowledge and conservation outcomes.