Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches.

The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize genetically defined progenitor subpopulations in live slices across key stages of mouse DG development, testing decades old static models of DG formation with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations, timings, dynamic cell-cell interactions, signaling activities, and routes underlie mosaic DG formation. Intermediate progenitors (IPs, Tbr2+) pioneered migrations, supporting and guiding later emigrating NSCs (Sox9+) through multiple transient zones prior to converging at the nascent outer adult niche in a dynamic settling process, generating all prenatal and postnatal granule neurons in defined spatiotemporal order. IPs (Dll1+) extensively targeted contacts to mitotic NSCs (Notch active), revealing a substrate for cell-cell contact support during migrations, a developmental feature maintained in adults. Mouse DG formation shares conserved features of human neocortical expansion

Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges

Exposure to toxic metals poses a serious human health hazard based on ubiquitous environmental presence, the extent of exposure, and the toxicity and disease states associated with exposure. This global health issue warrants accurate and reliable models derived from the risk assessment process to predict disease risk in populations. There has been considerable interest recently in the impact of environmental toxicants such as toxic metals on the epigenome. Epigenetic modifications are alterations to an individual's genome without a change in the DNA sequence, and include, but are not limited to, three commonly studied alterations: DNA methylation, histone modification, and non-coding RNA expression. Given the role of epigenetic alterations in regulating gene and thus protein expression, there is the potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. In the present review, epigenetic alterations induced by five high priority toxic metals/metalloids are prioritized for analysis and their possible inclusion into the risk assessment process is discussed

The development of emotion regulation: an fMRI study of cognitive reappraisal in children, adolescents and young adults

The ability to use cognitive reappraisal to regulate emotions is an adaptive skill in adulthood, but little is known about its development. Because reappraisal is thought to be supported by linearly developing prefrontal regions, one prediction is that reappraisal ability develops linearly. However, recent investigations into socio-emotional development suggest that there are non-linear patterns that uniquely affect adolescents. We compared older children (10–13), adolescents (14–17) and young adults (18–22) on a task that distinguishes negative emotional reactivity from reappraisal ability. Behaviorally, we observed no age differences in self-reported emotional reactivity, but linear and quadratic relationships between reappraisal ability and age. Neurally, we observed linear age-related increases in activation in the left ventrolateral prefrontal cortex, previously identified in adult reappraisal. We observed a quadratic pattern of activation with age in regions associated with social cognitive processes like mental state attribution (medial prefrontal cortex, posterior cingulate cortex, anterior temporal cortex). In these regions, we observed relatively lower reactivity-related activation in adolescents, but higher reappraisal-related activation. This suggests that (i) engagement of the cognitive control components of reappraisal increases linearly with age and (ii) adolescents may not normally recruit regions associated with mental state attribution, but (iii) this can be reversed with reappraisal instructions.National Science Foundation (U.S.) (Grant BCS-0224342

Toxicological responses of environmental mixtures: Environmental metal mixtures display synergistic induction of metal-responsive and oxidative stress genes in placental cells

Exposure to elevated levels of the toxic metals inorganic arsenic (iAs) and cadmium (Cd) represents a major global health problem. These metals often occur as mixtures in the environment, creating the potential for interactive or synergistic biological effects different from those observed in single exposure conditions. In the present study, environmental mixtures collected from two waste sites in China and comparable mixtures prepared in the laboratory were tested for toxicogenomic response in placental JEG-3 cells. These cells serve as a model for evaluating cellular responses to exposures during pregnancy. One of the mixtures was predominated by iAs and one by Cd. Six gene biomarkers were measured in order to evaluate the effects from the metals mixtures using dose and time-course experiments including: heme oxygenase 1 (HO-1) and metallothionein isoforms (MT1A, MT1F and MT1G) previously shown to be preferentially induced by exposure to either iAs or Cd, and metal transporter genes aquaporin-9 (AQP9) and ATPase, Cu2+ transporting, beta polypeptide (ATP7B). There was a significant increase in the mRNA expression levels of ATP7B, HO-1, MT1A, MT1F, and MT1G in mixture-treated cells compared to the iAs or Cd only-treated cells. Notably, the genomic responses were observed at concentrations significantly lower than levels found at the environmental collection sites. These data demonstrate that metal mixtures increase the expression of gene biomarkers in placental JEG-3 cells in a synergistic manner. Taken together, the data suggest that toxic metals that co-occur may induce detrimental health effects that are currently underestimated when analyzed as single metals

Effect of local environment and stellar mass on galaxy quenching and morphology at 0.5<z<2.00.5<z<2.0

We study galactic star-formation activity as a function of environment and stellar mass over 0.5<z<2.0 using the FourStar Galaxy Evolution (ZFOURGE) survey. We estimate the galaxy environment using a Bayesian-motivated measure of the distance to the third nearest neighbor for galaxies to the stellar mass completeness of our survey, $\log(M/M_\odot)>9 (9.5)$ at z=1.3 (2.0). This method, when applied to a mock catalog with the photometric-redshift precision ($\sigma_z / (1+z) \lesssim 0.02$), recovers galaxies in low- and high-density environments accurately. We quantify the environmental quenching efficiency, and show that at z> 0.5 it depends on galaxy stellar mass, demonstrating that the effects of quenching related to (stellar) mass and environment are not separable. In high-density environments, the mass and environmental quenching efficiencies are comparable for massive galaxies ($\log (M/M_\odot)\gtrsim$ 10.5) at all redshifts. For lower mass galaxies ($\log (M/M)_\odot) \lesssim$ 10), the environmental quenching efficiency is very low at $z\gtrsim$ 1.5, but increases rapidly with decreasing redshift. Environmental quenching can account for nearly all quiescent lower mass galaxies ($\log(M/M_\odot) \sim$ 9-10), which appear primarily at $z\lesssim$ 1.0. The morphologies of lower mass quiescent galaxies are inconsistent with those expected of recently quenched star-forming galaxies. Some environmental process must transform the morphologies on similar timescales as the environmental quenching itself. The evolution of the environmental quenching favors models that combine gas starvation (as galaxies become satellites) with gas exhaustion through star-formation and outflows ("overconsumption"), and additional processes such as galaxy interactions, tidal stripping and disk fading to account for the morphological differences between the quiescent and star-forming galaxy populations.Comment: 29 pages, 15 figure, accepted for publication in Ap

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption.

BACKGROUND: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. RESULTS: We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. CONCLUSION: A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat