RNA Methylation by the MIS Complex Regulates a Cell Fate Decision in Yeast

For the yeast Saccharomyces cerevisiae, nutrient limitation is a key developmental signal causing diploid cells to switch from yeast-form budding to either foraging pseudohyphal (PH) growth or meiosis and sporulation. Prolonged starvation leads to lineage restriction, such that cells exiting meiotic prophase are committed to complete sporulation even if nutrients are restored. Here, we have identified an earlier commitment point in the starvation program. After this point, cells, returned to nutrient-rich medium, entered a form of synchronous PH development that was morphologically and genetically indistinguishable from starvation-induced PH growth. We show that lineage restriction during this time was, in part, dependent on the mRNA methyltransferase activity of Ime4, which played separable roles in meiotic induction and suppression of the PH program. Normal levels of meiotic mRNA methylation required the catalytic domain of Ime4, as well as two meiotic proteins, Mum2 and Slz1, which interacted and co-immunoprecipitated with Ime4. This MIS complex (Mum2, Ime4, and Slz1) functioned in both starvation pathways. Together, our results support the notion that the yeast starvation response is an extended process that progressively restricts cell fate and reveal a broad role of post-transcriptional RNA methylation in these decisions

The new frontier: a case for whole exome sequencing with multiple fetal anomalies

Abstract Objectives Standard genetic testing can fail to identify an underlying genetic etiology in pregnancies affected by multiple fetal abnormalities. Recently, whole exome sequencing (WES) studies have shown promise in recognizing genetic diagnoses where standard genetic testing does not yield answers. Case presentation A 35-year-old G1P0 healthy female found at anatomy scan to have multiple fetal anomalies, including severe bilateral ventriculomegaly, renal pyelectasis, and short long bones. Karyotype and microarray were normal. Whole exome sequencing showed the fetus was compound heterozygous for likely pathogenic variants in the ROBO1 gene. Conclusions In the presence of multiple fetal anomalies with normal karyotype and microarray, whole exome sequencing should be considered to not only provide answers for the affected parents, but also aid in future pregnancy planning

Age-related changes of nuclear architecture in Caenorhabditis elegans

Mutations in lamins cause premature aging syndromes in humans, including the Hutchinson–Gilford Progeria Syndrome (HGPS) and Atypical Werner Syndrome. It has been shown that HGPS cells in culture undergo age-dependent progressive changes in nuclear architecture. However, it is unknown whether similar changes in nuclear architecture occur during the normal aging process. We have observed that major changes of nuclear architecture accompany Caenorhabditis elegans aging. We found that the nuclear architecture in most nonneuronal cell types undergoes progressive and stochastic age-dependent alterations, such as changes of nuclear shape and loss of peripheral heterochromatin. Furthermore, we show that the rate of these alterations is influenced by the insulin/IGF-1 like signaling pathway and that reducing the level of lamin and lamin-associated LEM domain proteins leads to shortening of lifespan. Our work not only provides evidence for changes of nuclear architecture during the normal aging process of a multicellular organism, but also suggests that HGPS is likely a result of acceleration of the normal aging process. Because the nucleus is vital for many cellular functions, our studies raise the possibility that the nucleus is a prominent focal point for regulating aging

is there any rationale for prescribing hormone replacement therapy (HTR) to prevent or to treat osteoarthritis?

Background: During the last two decades of the 20th century, hormone replacement therapy (HRT) has been considered as the sole pharmacological approach for counterbalancing or mitigating the effects of estrogens deprivation in post-menopausal women. Subsequently, HRT has been widely recommended for the management of chronic diseases occurring, in women during the second half of their life. The overall risk/benefit ratio of estrogens has been recently reassessed in the light of long-term prospective studies failing to demonstrate the expected benefit of HRT on cardiovascular diseases incidence. Osteoarthritis (OA) is one of the chronic conditions for which HRT has been suggested to provide beneficial outcomes. Results: The presence of estrogen receptors in human cartilage is no longer debated. However, cellular or animal models of OA do not provide an unequivocal pathway for the influence of gonadal steroids on cartilage. Similarly, studies attempting to correlate serum or urinary levels of sex steroids to the onset or progression of OA gave conflicting results. No randomized, prospective, controlled trial was designed to specifically assess the impact of hormone replacement therapy on symptomatic or structural progression of OA. Large-scale observational studies or trials designed to assess other potential benefits of estrogens suggest that HRT use does not provide symptomatic relief in OA but may interfere with its long-term structural progression, particularly in the lower limbs. Conclusion: Based on the recent results of the Women Health Initiative suggesting that HRT health risks may outweigh benefits, one can hardly recommend, with the current level of evidence, HRT as a first-line treatment against progression of OA. (C) 2003 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved