The primary function of the placenta is to act as an interface between the dam and fetus. The anatomic structure of the chorioallantoic placenta in eutherian mammals varies between different animal species. The placental types in eutherian mammals are classified from various standpoints based on the gross shape, the histological structure of the materno-fetal interface, the type of materno-fetal interdigitation, etc. Particularly, the histological structure is generally considered one of the most useful and instructive classifications for functionally describing placental type. In this system, three main types are recognized according to the cell layers comprising the interhemal area: (1) epitheliochorial type (horses, pigs and ruminants), (2) endotheliochorial type (carnivores) and (3) hemochorial type (primates, rodents and rabbits). The number of cell layers in the interhemal area is considered to modify the transfer of nutrients between maternal and fetal blood and is one of the important factors with respect to the difference in placental permeability between animal species. Therefore, in reproductive and developmental toxicity studies, careful attention should be paid to the histological structure of the interhemal area when extrapolating information concerning placental transfer characteristics to different animal species.

Genes coding for the glutathione S-transferase M1 (GSTM1) and Theta 1 (GSTT1) proteins are polymorphic in humans and these genes are absent, or homozygous null, in 10-60% of different ethnic populations. These enzymes catalyze the conjugation of glutathione to numerous carcinogenic chemicals and previous epidemiologic studies have associated the null genotypes of these GST genes with higher risk of cancer. In this study the frequency of GSTM1 and GSTT1 null genotypes was determined in Japanese patients with gastric adenocarcinoma and colorectal adenocarcinoma and compared to frequencies determined in a community-based control group. The frequency of the null GSTM1 genotype in patients with gastric adenocarcinoma (56.8%) showed a statistically significant increase compared to the control group frequency (43.6%) (odds ratio (OR) = 1.70; 95% CI, 1.05-2.76). The frequency of GSTM1 null individuals was also higher among all colorectal adenocarcinoma cases, but this increase did not reach statistical significance. After grouping by tumor site, the GSTM1 null genotype was a risk factor among the subgroup with distal colorectal tumors (61.1%) (OR = 2.03; 95% CI, 1.06-3.90). No consistent difference was observed between smoking patients and corresponding controls for the frequency of the GSTM1 null genotype for either cancer, although a large risk (OR = 5.76; 95% CI 1.18-28.3) was associated with the GSTM1 null genotype in the low smoking group of gastric adenocarcinoma patients. On the other hand, no statistically significant differences were observed in the frequency of null GSTT1 genotypes in gastric (47.5%) or colorectal (48.5%) adenocarcinoma patients when compared with the control population (44.4%). These results suggest that the GSTM1 null genotype may be associated with susceptibility to gastric adenocarcinoma and distal colorectal adenocarcinoma in Japanese; however, the associations observed were relatively weak and additional studies will be needed to confirm these findings.

BackgroundDespite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic–environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient‐specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM.Methods and ResultsWe generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high‐speed video imaging. The differences between control and HCM iPSC‐derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease‐promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy‐promoting factors. Interestingly, endothelin‐1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC‐derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3‐targeted knock in mice. High‐speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC‐derived cardiomyocytes, which revealed that self‐beating HCM iPSC‐derived single cardiomyocytes stimulated by endothelin‐1 showed variable contractile directions.ConclusionsInteractions between the patient's genetic backgrounds and the environmental factor endothelin‐1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC‐derived cardiomyocytes.

Deconstructive functionalization involves C–C bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis 1 and olefin metathesis 2 , 3 have allowed each carbon in C–C double bonds to be viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of C–C double bonds, there are very few methods that achieve C( sp 3 )–C( sp 3 ) single bond cleavage/functionalization, especially in relatively unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, important moities in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C( sp 3 )–N/C( sp 3 )–C( sp 3 ) single bond cleavage followed by C( sp 3 )–halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.

Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp3)–C(sp3) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp3)–C(sp3) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late-stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks.

This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

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Studies of secondary metabolites (natural products) that cover their isolation, chemical synthesis and bioactivity investigation present myriad opportunities for discovery. For example, the isolation of novel secondary metabolites can inspire advances in chemical synthesis strategies to achieve their practical preparation for biological evaluation. In the process, chemical synthesis can also provide unambiguous structural characterization of the natural products. Although the isolation, chemical synthesis and bioactivity studies of natural products are mutually beneficial, they are often conducted independently. Here, we demonstrate the benefits of a collaborative study of the phomactins, diterpenoid fungal metabolites that serve as antagonists of the platelet activating factor receptor. Our isolation of novel phomactins has spurred the development of a bioinspired, unified approach that achieves the total syntheses of six congeners. We also demonstrate in vitro the beneficial effects of several phomactins in suppressing the rate of repopulation of tumour cells following gamma radiation therapy.