The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma

The inflammatory potential of diet is related to incident frailty and slow walking in older adults

Background: Certain foods and dietary patterns have been associated with both inflammation and frailty. As chronic inflammation may play a role in frailty and disability, we examined the association of the inflammatory potential of diet with these outcomes. Methods: Data were taken from 1948 community-dwelling individuals =60 years old from the Seniors-ENRICA cohort, who were recruited in 2008–2010 and followed-up through 2012. Baseline diet data, obtained with a validated diet history, was used to calculate Shivappa's Dietary Inflammatory Index (DII), an “a priori” pattern score which is based on known associations of foods and nutrients with inflammation, and Tabung's Empirical Dietary Inflammatory Index (EDII), an “a posteriori” pattern score which was statistically derived from an epidemiological study. At follow-up, incident frailty was assessed with Fried's criteria, and incident limitation in instrumental activities of daily living (IADL) with the Lawton-Brody index. Statistical analyses were performed with logistic regression, and adjusted for the main confounders. Results: Compared with individuals in the lowest tertile of DII, those in the highest tertile showed higher risk of frailty (odds ratio [OR] 2.48; 95% confidence interval [CI]: 1.42, 4.44, p-trend = 0.001) and IADL disability (OR: 1.96; 95% CI: 1.03, 3.86, p-trend = 0.035). By contrast, EDII did not show an association with these outcomes. The DII score was associated with slow gait speed, both as a low score in the Short Physical Performance Battery test (OR: 1.82; 95% CI: 1.27, 2.62, p-trend = 0.001) and as a positive Fried's criterion (OR: 1.64; 95% CI: 1.08, 2.51, p-trend = 0.021), which use different thresholds. Conclusions: DII predicted frailty and IADL while EDII did not. DII is able to measure diet healthiness in terms of physical decline in addition to avoidance of inflammation

The Southern European Atlantic Diet is associated with lower concentrations of markers of coronary risk

Objective: The Southern European Atlantic Diet (SEAD) is the traditional diet of Northern Portugal and Galicia, a region in northwest Spain. The SEAD has been associated with a lower risk of non-fatal acute myocardial infarction, but the mechanisms of this association have not yet been investigated. Thus, we examined the association between the SEAD and numerous biomarkers of coronary risk, blood pressure and anthropometrics. Methods: Cross-sectional study conducted in 2008–2010 among 10,231 individuals representative of the population aged 18 years and older in Spain. Diet was assessed with a validated computerized diet history. SEAD adherence was measured with an index including 9 food components (fresh fish, cod, red meat and pork products, dairy products, legumes and vegetables, vegetable soup, potatoes, whole-grain bread, and wine), which ranges from 0 (lowest adherence) to 9 (highest adherence). C-reactive protein, uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, glucose, glycated hemoglobin, insulin, leptin, fibrinogen, were determined in 12-h fasting blood samples, while creatinine and urine albumin were determined in urine. Results: Mean SEAD score was 2.9 points (inter-quartile range 2–4 points). Higher SEAD adherence was associated with a lower level of plasma C-reactive protein (adjusted difference in geometric means between the highest and lowest SEAD quartiles −0.2 mg/l; p for trend <0.001), plasma triglycerides (−3.4 mg/dl; p for trend 0.012), insulin (−0.5 mU/l; p for trend <0.001), HOMA-IR (−0.12; p for trend <0.001), urine albumin (−0.8 mg/l; p for trend <0.001), urine albumin-creatinine ratio (−0.3 mg/g creatinine; p for trend <0.034), and systolic blood pressure (−1.6 mm Hg; p for trend <0.001). Conclusions: This study identifies possible mediators of the effect of SEAD on myocardial infarction, because SEAD is associated with a lower concentration of markers of inflammation and with reduced triglycerides, insulin, insulin resistance, and systolic blood pressure

Rationale of the association between Mediterranean diet and the risk of frailty in older adults and systematic review and meta-analysis

Frailty is a geriatric syndrome whose frequency is increasing in parallel with population aging and is of great interest due to its dire consequences: increased disability, hospitalizations, falls and fractures, institutionalization, and mortality. Frailty is multifactorial but nutritional factors, which are modifiable, play a crucial role in its pathogenesis. Epidemiologic evidence supports that high-quality dietary patterns can prevent, delay or even reverse the occurrence of frailty. In order to add new knowledge bridging the gap as the main purpose of the present article we performed a comprehensive review of the rationale behind the association of MedDiet with frailty and a systematic review and meta-analysis updating the latest ones published in 2018 specifically examining the relationship of Mediterranean diet (MedDiet) and incident frailty. Adding the updated information, our results confirmed a robust association of a higher adherence to MedDiet with reduced incident frailty. Key components of the MedDiet, i.e., abundant consumption of vegetables and fruit as well as the use of olive oil as the main source of fat, all of which have been associated with a lower incidence of frailty, may help explain the observed benefit. Future well-designed and sufficiently large intervention studies are needed to confirm the encouraging findings of the current observational evidence. Meanwhile, based on the existing evidence, the promotion of MedDiet, a high-quality dietary pattern, adapted to the conditions and traditions of each region, and considering lifelong and person-tailored strategies, is an open opportunity to reduced incident frailty. This could also help counteract the worrying trend towards the spread of unhealthy eating and lifestyle models such as those of Western diets that greatly contribute to the genesis of chronic non-communicable diseases and disability

The three-dimensional structure of Drosophila melanogaster (6-4) photolyase at room temperature

(6-4) photolyases are flavoproteins that belong to the photolyase/cryptochrome family. Their function is to repair DNA lesions using visible light. Here, crystal structures of Drosophila melanogaster (6-4) photolyase [Dm(6-4)photolyase] at room and cryogenic temperatures are reported. The room-temperature structure was solved to 2.27 angstrom resolution and was obtained by serial femtosecond crystallography (SFX) using an X-ray free-electron laser. The crystallization and preparation conditions are also reported. The cryogenic structure was solved to 1.79 angstrom resolution using conventional X-ray crystallography. The structures agree with each other, indicating that the structural information obtained from crystallography at cryogenic temperature also applies at room temperature. Furthermore, UV-Vis absorption spectroscopy confirms that Dm(6-4)photolyase is photoactive in the crystals, giving a green light to time-resolved SFX studies on the protein, which can reveal the structural mechanism of the photoactivated protein in DNA repair.Peer reviewe

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

A Novel Role for the GTPase-Activating Protein Bud2 in the Spindle Position Checkpoint

The spindle position checkpoint (SPC) ensures correct mitotic spindle position before allowing mitotic exit in the budding yeast Saccharomyces cerevisiae. In a candidate screen for checkpoint genes, we identified bud2Δ as deficient for the SPC. Bud2 is a GTPase activating protein (GAP), and the only known substrate of Bud2 was Rsr1/Bud1, a Ras-like GTPase and a central component of the bud-site-selection pathway. Mutants lacking Rsr1/Bud1 had no checkpoint defect, as did strains lacking and overexpressing Bud5, a guanine-nucleotide exchange factor (GEF) for Rsr1/Bud1. Thus, the checkpoint function of Bud2 is distinct from its role in bud site selection. The catalytic activity of the Bud2 GAP domain was required for the checkpoint, based on the failure of the known catalytic point mutant Bud2R682A to function in the checkpoint. Based on assays of heterozygous diploids, bud2R682A, was dominant for loss of checkpoint but recessive for bud-site-selection failure, further indicating a separation of function. Tem1 is a Ras-like protein and is the critical regulator of mitotic exit, sitting atop the mitotic exit network (MEN). Tem1 is a likely target for Bud2, supported by genetic analyses that exclude other Ras-like proteins

The spindle position checkpoint is coordinated by the Elm1 kinase

Localization and activation of Elm1 at the bud neck coordinates SPC activity with mother–daughter polarity during cell division

The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser

Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The data reveal a twist of the D-ring, which leads to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signaling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the observed collective changes are important for the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.Peer reviewe

The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

Large-scale human genetic data(1-3) have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)(4-6). VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization(6,7). We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele Cat rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. (8)). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.Peer reviewe