Biotic responses to volatile volcanism and environmental stresses over the Guadalupian-Lopingian (Permian) transition

Biotic extinction during the Guadalupian-Lopingian (G-L) transition is actively debated, with its timing, validity, and causality all questioned. Here, we show, based on detailed sedimentary, paleoecologic, and geochemical analyses of the Penglaitan section in South China, that this intra-Permian biotic crisis began with the demise of a metazoan reef system and extinction of corals and alatoconchid bivalves in the late Guadalupian. A second crisis, among nektonic organisms, occurred around the G-L boundary. Mercury concentration/total organic carbon (Hg/TOC) ratios show two anomalies. The first Hg/TOC peak broadly coincides with the reef collapse and a positive shift in Δ199Hg values during a lowstand interval, which was followed by microbial proliferation. A larger Hg/TOC peak is found just above the G-L boundary and speculatively represents a main eruption episode of the Emeishan large igneous province (ELIP). This volatile volcanism coincided with nektonic extinction, a negative δ13Ccarb excursion, anoxia, and sea-level rise. The temporal coincidence of these phenomena supports a cause-andeffect relationship and indicates that the eruption of the ELIP likely triggered the G-L crisis

Progressive environmental deterioration in northwestern Pangea leading to the latest Permian extinction

Stratigraphic records from northwestern Pangea provide unique insight into global processes that occurred during the latest Permian extinction (LPE). We examined a detailed geochemical record of the Festningen section, Spitsbergen. A stepwise extinction is noted as: starting with (1) loss of carbonate shelly macrofauna, followed by (2) loss of siliceous sponges in conjunction with an abrupt change in ichnofabrics as well as dramatic change in the terrestrial environment, and (3) final loss of all trace fossils. We interpret loss of carbonate producers as related to shoaling of the lysocline in higher latitudes, in relationship to building atmospheric CO2. The loss of siliceous sponges is coincident with the global LPE event and is related to onset of high loading rates of toxic metals (Hg, As, Co) that we suggest are derived from Siberian Trap eruptions. The final extinction stage is coincident with redox-sen- sitive trace metal and other proxy data that suggest onset of anoxia after the other extinction events. These results show a remarkable record of progressive environmental deterioration in northwestern Pangea during the extinction crises

Executive Functions and Prefrontal Cortex: A Matter of Persistence?

Executive function is thought to originates from the dynamics of frontal cortical networks. We examined the dynamic properties of the blood oxygen level dependent time-series measured with functional MRI (fMRI) within the prefrontal cortex (PFC) to test the hypothesis that temporally persistent neural activity underlies performance in three tasks of executive function. A numerical estimate of signal persistence, the Hurst exponent, postulated to represent the coherent firing of cortical networks, was determined and correlated with task performance. Increasing persistence in the lateral PFC was shown to correlate with improved performance during an n-back task. Conversely, we observed a correlation between persistence and increasing commission error – indicating a failure to inhibit a prepotent response – during a Go/No-Go task. We propose that persistence within the PFC reflects dynamic network formation and these findings underline the importance of frequency analysis of fMRI time-series in the study of executive functions

The evolutionary history of common genetic variants influencing human cortical surface area

Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Cellular Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the first crystal structure of inhibitor-bound hFEN1 and show a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein– substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the unpairing of substrate DNA necessary for reaction. Other compounds were more competitive with substrate. Cellular thermal shift data showed engagement of both inhibitor types with hFEN1 in cells with activation of the DNA damage response evident upon treatment. However, cellular EC50s were significantly higher than in vitro inhibition constants and the implications of this for exploitation of hFEN1 as a drug target are discussed