Identification of the agg1 mutation responsible for negative phototaxis in a “wild-type” strain of Chlamydomonas reinhardtii

AbstractThe unicellular green alga Chlamydomonas reinhardtii is a model organism for various studies in biology. CC-124 is a laboratory strain widely used as a wild type. However, this strain is known to carry agg1 mutation, which causes cells to swim away from the light source (negative phototaxis), in contrast to the cells of other wild-type strains, which swim toward the light source (positive phototaxis). Here we identified the causative gene of agg1 (AGG1) using AFLP-based gene mapping and whole genome next-generation sequencing. This gene encodes a 36-kDa protein containing a Fibronectin type III domain and a CHORD-Sgt1 (CS) domain. The gene product is localized to the cell body and not to flagella or basal body

Changes in body composition parameters with age

Health risks are associated with changes in body composition parameters with age. In the present study, body composition parameters （appendicular skeletal muscle mass ［ASMM］, fat mass ［FM］, and water content ［water］） using bioelectrical impedance analysis （BIA） and total skeletal MM （TSMM） measured by 24-h creatinine excretion （Cr） were obtained in 30 male and 38 female healthy subjects. BIA-ASMM in both sexes and Cr-TSMM in females were negatively correlated with aging, and BIA-FM was negatively correlated with BIA-water in both sexes. Of note, Cr-TSMM was a more sensitive marker of MM than BIA-ASMM. Thus, decreases in BIA-ASMM and Cr- TSMM were the most consistent markers of aging and sarcopenia. This study may help promote nursing care for healthy aging

Fibroblast Growth Factor–23 and Cardiac Structure and Function

Background: Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in klotho‐null mice, an established model of constitutively elevated FGF‐23. Methods and Results: Among 887 participants with coronary artery disease in the Heart and Soul Study, FGF‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in lnFGF‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5; CI, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1; CI, 0.9 to 1.3). FGF‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (eGFR <60 mL/min per 1.73 m2; odds ratio, 2.3; CI, 1.0 to 5.3; P‐interaction=0.28). Comparing klotho‐null with wild‐type mice, null mice did not have greater left ventricular mass (P=0.37) or a lower ejection fraction (P=0.94). Conclusions: Together, our results suggest that FGF‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor

Water balance in healthy and handicapped adults

The body’s water balance is changed by food and beverage intake, metabolism, and excretion. In this study, we performed a cross-sectional study that investigated the changes of water intake and water output in healthy Japanese young and elderly people and handicapped adults. Water balance was assessed by water intake from foods and beverages, metabolic water production, non-renal water losses (NRWL), and urine volume. Most of the parameters did not change with aging in healthy adults. Estimated total water intake (ml / kg / day) increased with aging. In the healthy men, healthy women, and handicapped adults, daily water intake (median [interquartile range]) accounted for 49.4 (41.4-59.9) ml / kg, 42.9 (38.7-51.8) ml / kg, and 50.9 (43.8-74.0) ml / kg, respectively. Water loss from the kidney accounted for 19.2 (16.2-29.2) ml / kg, 22.0 (16.2-26.6) ml / kg, and 27.5 (22.7- 47.2) ml / kg, respectively. NRWL accounted for 26.6 (18.5-35.2) ml / kg, 22.4 (16.2-28.8) ml / kg, and 23.5 (19.8-28.5) ml / kg, respectively. Our findings suggest that a daily total water intake of more than 50-55 ml / kg is required to prevent dehydration in healthy and handicapped adults

Vitamin D and serum 25-hydroxyvitamin D level

The changes in the serum 25-hydroxyvitamin D (25(OH)D) concentrations after daily 1000-IU vitamin D intake for 3 months (3-month-VD), 6 months (6-month-VD) and then 6-month cessation of vitamin D intake (6-month-VD cessation) were examined. The serum 25(OH)D levels in 11 male and 16 female subjects were 12.1 ± 3.5 ng / mL at baseline, increased to 27.1 ± 4.7 ng / mL at 3-month-VD, 28.5 ± 5.1 ng / mL at 6-month-VD and decreased to 16.4 ± 4.0 ng / mL at 6-month-VD cessation. The present study suggested that a vitamin D intake of 1000 IU / day is required to maintain the 25(OH) D concentration at 30 ng / mL or higher without vitamin D intoxication

Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics

SummaryActivation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell-fate decisions, although signals propagate through shared pathways. Using mathematical modeling and experimental approaches, we unravel how HRG and EGF generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands

Lack of impact of the ALDH2 rs671 variant on breast cancer development in Japanese BRCA1/2‐mutation carriers

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients

Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression

Lactation induces bone loss to provide sufficient calcium in the milk, a process that involves osteoclastic bone resorption but also osteocytes and perilacunar resorption. The exact mechanisms by which osteocytes contribute to bone loss remain elusive. Osteocytes express genes required in osteoclasts for bone resorption, including cathepsin K (Ctsk), and lactation elevates their expression. We show that Ctsk deletion in osteocytes prevented the increase in osteocyte lacunar area seen during lactation, as well as the effects of lactation to increase osteoclast numbers and decrease trabecular bone volume, cortical thickness, and mechanical properties. In addition, we show that Ctsk deletion in osteocytes increased bone parathyroid hormone-related peptide (PTHrP) and prevented the decrease in serum parathyroid hormone (PTH) induced by lactation, but amplified the increase in serum 1,25-dyhydroxyvitamin D [1,25(OH)(2)D]. The net result of these changes is to maintain serum and milk calcium levels in the normal range, ensuring normal offspring skeletal development. Our studies confirm the fundamental role of osteocytic perilacunar remodeling in physiological states of lactation and provide genetic evidence that osteocyte-derived Ctsk contributes not only to osteocyte perilacunar remodeling, but also to the regulation of PTH, PTHrP, 1,25(OH)(2)D, osteoclastogenesis, and bone loss in response to the high calcium demand associated with lactation