Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.     

Mode of Action Studies on Nitrodiphenyl Ether Herbicides : II. The Role of Photosynthetic Electron Transport in Scenedesmus obliquus

The nitrodiphenyl ether herbicide 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroacetophenone oxime-o-(acetic acid, methyl ester) (DPEI) induces light- and O₂-dependent lipid peroxidation and chlorophyll (Chl) bleaching in the green alga Scenedesmus obliquus. Under conditions of O₂-limitation, these effects are diminished by prometyne and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), both inhibitors of photosynthetic electron transport. Mutants in which photosynthetic electron transport is blocked are also resistant to DPEI under conditions of O₂-limitation. Light- and O₂-dependent lipid peroxidation and Chl bleaching are also induced by 5-[2-chloro-4-(trifluoromethyl)phenoxy]-3-methoxyphthalide (DPEII), a diphenyl ether whose redox properties preclude reduction by photosystem I. However, these effects of DPEII are also inhibited by DCMU. Under conditions of high aeration, DCMU does not protect Scenedesmus cells from Chl bleaching induced by DPEI, but does protect against paraquat. DPEI, but not paraquat, induces tetrapyrrole formation in treated cells in the dark. This is also observed in a mutant lacking photosystem I but is suppressed under conditions likely to lead to O₂ limitation. Our results indicate that, in contrast to paraquat, the role of photosynthetic electron transport in diphenyl ether toxicity in Scenedesmus is not to reduce the herbicide to a radical species which initiates lipid peroxidation. Its role is probably to maintain a sufficiently high O₂ concentration, through water-splitting, in the algal suspension.     

Endoderm-secreted factor stimulates growth of embryonal carcinoma stem cells

Summary Stem cells of the embryonal carcinoma cell line called H6 can be induced to differnetiate to endoderm-like cells by retinoic acid (3×10⁻⁶ M). We have detected a diffusible and stable factor which is secreted by H6 endoderm-like cells and stimulates the growth of H6 stem cells. The stimulation by the endoderm-like cells is considereably greater than that by mouse fibroblasts or H6 stem cells themselves. No reciprocal stimulation of endoderm-like cells by stem cells occurs. Part but not all of the stimulation might be due to extracellular matrix proteins or to insulin-like growth factor type 2, each of which also stimulates the growth of H6 stem cells. Insulin causes no such stimulation. This work was supported by research rant no. CA-16754 from the National Cancer Institute to J. W. L. E. L. G. was supported by an American Heart Association Medical Student Research Award. Editor's Statement This paper presents a good example of cooperativity between undifferentiated teratoma stem cells and differentiated parietal endoderm-derived countrparts in terms of growth support. It raises the interesting question of the relationship between factors produced by paprietal and visceral endoderm cells. Gordon H. Sato     

Catalysis by heteropentalenes of electron transfer to oxygen from ferredoxin-NADP oxidoreductase reduced by NADPH

A range of heteropentalene and bipyridinium compounds have been tested as catalysts of electron transfer to oxygen from spinach ferredoxin-NADP⁺ oxidoreductase reduced by NADPH. For a particular class of compound, the rate of oxygen reduction increased with increasing midpoint potential of the compound under conditions in which reduction of the compound was rate-limiting. Compounds with similar midpoint potentials from different structural classes showed marked differences in rate, attributed to specificity in the interaction with ferredoxin-NADP⁺ oxidoreductase.     

Angiotensin I converting enzyme in human intestine and kidney. Ultrastructural immunohistochemical localization

The localization of immunoreactive angiotensin I-converting enzyme (ACE) has been investigated at the optical and ultrastructural level with anti-human ACE antibodies in the human kidney and small intestine. In both tissues ACE was found in blood vessels and in extravascular situation in the absorptive epithelial cells of intestinal mucosa and renal proximal tubules. Ultrastructural immunohistochemistry showed that in intestinal and renal proximal tubular cells ACE was prominent in microvilli and brush borders. In the kidney ACE was also present on the basolateral part of the plasmalemmal membrane, where it may contribute to the regulation of angiotensin II-dependent absorption processes. Intracellular positivities were also observed inside the renal vascular endothelial and proximal tubular cell in endoplasmic reticulum and nuclear envelope reflecting the synthesis and the cellular processing of ACE. The intestinal microvascular endothelium was strongly labeled suggesting that the mesenteric circulation is an important site for the production of angiotensin II. Vascular endothelial ACE was also detected in the peritubular but not glomerular capillaries of the kidney.     

Angiotensin I converting enzyme in human intestine and kidney

Summary The localization of immunoreactive angiotensin I-converting enzyme (ACE) has been investigated at the optical and ultrastructural level with anti-human ACE antibodies in the human kidney and small intestine. In both tissues ACE was found in blood vessels and in extravascular situation in the absorptive epithelial cells of intestinal mucosa and renal proximal tubules. Ultrastructural immunohistochemistry showed that in intestinal and renal proximal tubular cells ACE was prominent in microvilli and brush borders. In the kidney ACE was also present on the basolateral part of the plasmalemmal membrane, where it may contribute to the regulation of angiotensin II-dependant absorption processes. Intracellular positivities were also observed inside the renal vascular endothelial and proximal tubular cell in endoplasmic reticulum and nuclear envelope reflecting the synthesis and the cellular processing of ACE. The intestinal microvascular endothelium was strongly labeled suggesting that the mesenteric circulation is an important site for the production of angiotensin II. Vascular endothelial ACE was also detected in the peritubular but not glomerular capillaries of the kidney.     

A new species of Sicyos (Cucurbitaceae) from Chiapas,Mexico

Sicyos motozintlensis is described from the vicinity of Motozintla de Mendoza, Chiapas. It shows a strong similarity toS. chiriquensis Hammel & D’Arcy from Panama.