Angiotensin-converting enzyme and male fertility

The angiotensin-converting enzyme (ACE; EC 3.4.15.1) gene (Ace) encodes both a somatic isozyme found in blood and several other tissues, including the epididymis, and a testis-specific isozyme (testis ACE) found only in developing spermatids and mature sperm. We recently used gene targeting to disrupt the gene coding for both ACE isozymes in mice and reported that male homozygous mutants mate normally but have reduced fertility; the mutant females are fertile. Here we explore the male fertility defect. We demonstrate that ACE is important for achieving in vivo fertilization and that sperm from mice lacking both ACE isozymes show defects in transport within the oviducts and in binding to zonae pellucidae. Males generated by gene targeting that lack somatic ACE but retain testis ACE are normally fertile, establishing that somatic ACE in males is not essential for their fertility. Furthermore, male and female mice lacking angiotensinogen have normal fertility, indicating that angiotensin I is not a necessary substrate for testis ACE. Males heterozygous for the mutation inactivating both ACE isozymes sire wild-type and heterozygous offspring at an indistinguishable frequency, indicating no selection against sperm carrying the mutation

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

Preeclampsia (PE), high blood pressure and protein in the urine in the last third of pregnancy, complicates about 1 in 20 human pregnancies, and it is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in premature babies. Blood pressure-lowering drugs help, but results in preventing preterm delivery and correcting the fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that feeding high doses of nicotinamide, a vitamin, improves the maternal condition, prolongs pregnancies, and prevents FGR in mice having PE-like conditions due to two contrasting causes. Because nicotinamide benefits both mothers and pups, it merits evaluation for preventing or treating PE in humans

The Household Water Insecurity Experiences (HWISE) Scale: comparison scores from 27 sites in 22 countries

Abstract Household survey data from 27 sites in 22 countries were collected in 2017–2018 in order to construct and validate a cross-cultural household-level water insecurity scale. The resultant Household Water Insecurity Experiences (HWISE) scale presents a useful tool for monitoring and evaluating water interventions as a complement to traditional metrics used by the development community. It can also help track progress toward achievement of Sustainable Development Goal 6 ‘clean water and sanitation for all’. We present HWISE scale scores from 27 sites as comparative data for future studies using the HWISE scale in low- and middle-income contexts. Site-level mean scores for HWISE-12 (scored 0–36) ranged from 1.64 (SD 4.22) in Pune, India, to 20.90 (7.50) in Cartagena, Colombia, while site-level mean scores for HWISE-4 (scored 0–12) ranged from 0.51 (1.50) in Pune, India, to 8.21 (2.55) in Punjab, Pakistan. Scores tended to be higher in the dry season as expected. Data from this first implementation of the HWISE scale demonstrate the diversity of water insecurity within and across communities and can help to situate findings from future applications of this tool

Primary aldosteronism and impaired natriuresis in mice underexpressing TGF 1

To uncover the potential cardiovascular effects of human polymorphisms influencing transforming growth factor β1 (TGFβ1) expression, we generated mice with Tgfb1 mRNA expression graded in five steps from 10% to 300% normal. Adrenal expression of the genes for mineralocorticoid-producing enzymes ranged from 50% normal in the hypermorphs at age 12 wk to 400% normal in the hypomorphs accompanied with proportionate changes in plasma aldosterone levels, whereas plasma volumes ranged from 50% to 150% normal accompanied by marked compensatory changes in plasma angiotensin II and renin levels. The aldosterone/renin ratio ranged from 0.3 times normal in the 300% hypermorphs to six times in the 10% hypomorphs, which have elevated blood pressure. Urinary output of water and electrolytes are markedly decreased in the 10% hypomorphs without significant change in the glomerular filtration rate. Renal activities for the Na+, K+-ATPase, and epithelial sodium channel are markedly increased in the 10% hypomorphs. The hypertension in the 10% hypomorphs is corrected by spironolactone or amiloride at doses that do not change blood pressure in wild-type mice. Thus, changes in Tgfb1 expression cause marked progressive changes in multiple systems that regulate blood pressure and fluid homeostasis, with the major effects being mediated by changes in adrenocortical function

Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade

Congestive heart failure develops in human patients and experimental animals when the left ventricle becomes dilated. In the present study, mice were generated having graded genetic levels of endothelin-1 from 20% normal to 350% normal by modifying the 3′ untranslated region of the endothelin-1 gene. The 20% and 65% hypomorphs develop dilated cardiomyopathy, whereas the 350% hypermorph has a hypertrophic heart. Increases in superoxide levels and overexpression of matrix metalloproteinase 9 (MMP9) are involved in the development of the dilated cardiomyopathy in the 20% hypomorph. Our results show that endothelin-1 is critical for maintaining normal cardiac contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching

New CC0\pi\ GENIE Model Tune for MicroBooNE

A novel tune has been made for the MicroBooNE experiment. The fit uses 4 new parameters within the GENIE v3.0.6 Monte Carlo program. Charged current pionless data from the T2K experiment was used. New uncertainties were obtained. These results will be used in future MicroBooNE analyses.Comment: 24 pages, 14 figure