Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.

The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human-accelerated enhancers [6-14], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [15, 16]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [17-19]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt-HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain

Cooperation, collective action, and the archeology of large-scale societies

Archeologists investigating the emergence of large-scale societies in the past have renewed interest in examining the dynamics of cooperation as a means of understanding societal change and organizational variability within human groups over time. Unlike earlier approaches to these issues, which used models designated voluntaristic or managerial, contemporary research articulates more explicitly with frameworks for cooperation and collective action used in other fields, thereby facilitating empirical testing through better definition of the costs, benefits, and social mechanisms associated with success or failure in coordinated group action. Current scholarship is nevertheless bifurcated along lines of epistemology and scale, which is understandable but problematic for forging a broader, more transdisciplinary field of cooperation studies. Here, we point to some areas of potential overlap by reviewing archeological research that places the dynamics of social cooperation and competition in the foreground of the emergence of large-scale societies, which we define as those having larger populations, greater concentrations of political power, and higher degrees of social inequality. We focus on key issues involving the communal-resource management of subsistence and other economic goods, as well as the revenue flows that undergird political institutions. Drawing on archeological cases from across the globe, with greater detail from our area of expertise in Mesoamerica, we offer suggestions for strengthening analytical methods and generating more transdisciplinary research programs that address human societies across scalar and temporal spectra

PAH mineralization and bacterial organotolerance in surface sediments of the Charleston Harbor estuary

Semi-volatile organic compounds (SVOCs) in estuarine waters can adversely affect biota but watershed sources can be difficult to identify because these compounds are transient. Natural bacterial assemblages may respond to chronic, episodic exposure to SVOCs through selection of more organotolerant bacterial communities. We measured bacterial production, organotolerance and polycyclic aromatic hydrocarbon (PAH) mineralization in Charleston Harbor and compared surface sediment from stations near a known, permitted SVOC outfall (pulp mill effluent) to that from more pristine stations. Naphthalene additions inhibited an average of 77% of bacterial metabolism in sediments from the more pristine site (Wando River). Production in sediments nearest the outfall was only inhibited an average of 9% and in some cases, was actually stimulated. In general, the stations with the highest rates of bacterial production also were among those with the highest rates of PAH mineralization. This suggests that the capacity to mineralize PAH carbon is a common feature amongst the bacterial assemblage in these estuarine sediments and could account for an average of 5.6% of bacterial carbon demand (in terms of production) in the summer, 3.3% in the spring (April) and only 1.2% in winter (December)

The role of TcdB and TccC subunits in secretion of the photorhabdus Tcd toxin complex

The Toxin Complex (TC) is a large multi-subunit toxin encoded by a range of bacterial pathogens. The best-characterized examples are from the insect pathogens Photorhabdus, Xenorhabdus and Yersinia. They consist of three large protein subunits, designated A, B and C that assemble in a 5:1:1 stoichiometry. Oral toxicity to a range of insects means that some have the potential to be developed as pest control technology. The three subunit proteins do not encode any recognisable export sequences and as such little progress has been made in understanding their secretion. We have developed heterologous TC production and secretion models in E. coli and used them to ascribe functions to different domains of the crucial B+C sub-complex. We have determined that the B and C subunits use a secretion mechanism that is either encoded by the proteins themselves or employ an as yet undefined system common to laboratory strains of E. coli. We demonstrate that both the N-terminal domains of the B and C subunits are required for secretion of the whole complex. We propose a model whereby the N-terminus of the C-subunit toxin exports the B+C sub-complex across the inner membrane while that of the B-subunit allows passage across the outer membrane. We also demonstrate that even in the absence of the B-subunit, that the C-subunit can also facilitate secretion of the larger A-subunit. The recognition of this novel export system is likely to be of importance to future protein secretion studies. Finally, the identification of homologues of B and C subunits in diverse bacterial pathogens, including Burkholderia and Pseudomonas, suggests that these toxins are likely to be important in a range of different hosts, including man

Greatly increased occurrence of breast cancers in areas of mammographically dense tissue

INTRODUCTION: Mammographic density is a strong, independent risk factor for breast cancer. A critical unanswered question is whether cancers tend to arise in mammographically dense tissue (i.e. are densities directly related to risk or are they simply a marker of risk). This question cannot be addressed by studying invasive tumors because they manifest as densities and cannot be confidently differentiated from the densities representing fibrous and glandular tissue. We addressed this question by studying ductal carcinoma in situ (DCIS), as revealed by microcalcifications. METHOD: We studied the cranio-caudal and the mediolateral-oblique mammograms of 28 breasts with a solitary DCIS lesion. Two experienced radiologists independently judged whether the DCIS occurred in a mammographically dense area, and determined the density of different areas of the mammograms. RESULTS: It was not possible to determine whether the DCIS was or was not in a dense area for six of the tumors. Of the remaining 22 lesions, 21 occurred in dense tissue (test for difference from expected taken as the percentage of density of the 'mammographic quadrant' containing DCIS; P < 0.0001). A preponderance of DCIS (17 out of 28) occurred in the mammographic quadrant with the highest percentage density. CONCLUSION: DCIS occurs overwhelmingly in the mammographically dense areas of the breast, and pre-DCIS mammograms showed that this relationship was not brought about by the presence of the DCIS. This strongly suggests that some aspect of stromal tissue comprising the mammographically dense tissue directly influences the carcinogenic process in the local breast glandular tissue

Revisiting Synthesis Model of Sparse Audio Declipper

The state of the art in audio declipping has currently been achieved by SPADE (SParse Audio DEclipper) algorithm by Kiti\'c et al. Until now, the synthesis/sparse variant, S-SPADE, has been considered significantly slower than its analysis/cosparse counterpart, A-SPADE. It turns out that the opposite is true: by exploiting a recent projection lemma, individual iterations of both algorithms can be made equally computationally expensive, while S-SPADE tends to require considerably fewer iterations to converge. In this paper, the two algorithms are compared across a range of parameters such as the window length, window overlap and redundancy of the transform. The experiments show that although S-SPADE typically converges faster, the average performance in terms of restoration quality is not superior to A-SPADE

Benign breast disease, recent alcohol consumption, and risk of breast cancer: a nested case–control study

INTRODUCTION: Alcohol consumption is a well-established risk factor for breast cancer. Some studies have suggested that the risk of breast cancer associated with alcohol consumption is greater for women with a history of benign breast disease (BBD). We hypothesized that among women with biopsy-confirmed BBD, recent alcohol consumption would increase the risk of breast cancer in women with proliferative breast disease to a greater extent than in women with nonproliferative breast disease. METHODS: We conducted a nested case–control study in the Nurses' Health Study I and II. The cases (n = 282) were women diagnosed with incident breast cancer, with a prior biopsy-confirmed breast disease. The controls (n = 1,223) were participants with a previous BBD biopsy, but without a diagnosis of breast cancer. Pathologists reviewed benign breast biopsy slides in a blinded fashion and classified the BBD as nonproliferative, proliferative without atypia, or atypical hyperplasia, according to standard criteria. RESULTS: Women with nonproliferative breast disease consuming ≥ 15 g of alcohol per day had a nonsignificant 67% increased risk of breast cancer (odds ratio = 1.67; 95% confidence interval 0.65 to 4.34) compared with nondrinkers. There was no evidence that recent alcohol consumption increased the risk of breast cancer to a greater extent in women with proliferative BBD than among women with nonproliferative BBD (P for interactio n = 0.20). CONCLUSION: Contrary to our a priori hypothesis, there was no evidence that recent alcohol consumption increased the risk of breast cancer to a greater extent among women with proliferative BBD than among women with nonproliferative BBD

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Structural Insights into Triglyceride Storage Mediated by Fat Storage-Inducing Transmembrane (FIT) Protein 2

Fat storage-Inducing Transmembrane proteins 1 & 2 (FIT1/FITM1 and FIT2/FITM2) belong to a unique family of evolutionarily conserved proteins localized to the endoplasmic reticulum that are involved in triglyceride lipid droplet formation. FIT proteins have been shown to mediate the partitioning of cellular triglyceride into lipid droplets, but not triglyceride biosynthesis. FIT proteins do not share primary sequence homology with known proteins and no structural information is available to inform on the mechanism by which FIT proteins function. Here, we present the experimentally-solved topological models for FIT1 and FIT2 using N-glycosylation site mapping and indirect immunofluorescence techniques. These methods indicate that both proteins have six-transmembrane-domains with both N- and C-termini localized to the cytosol. Utilizing this model for structure-function analysis, we identified and characterized a gain-of-function mutant of FIT2 (FLL(157-9)AAA) in transmembrane domain 4 that markedly augmented the total number and mean size of lipid droplets. Using limited-trypsin proteolysis we determined that the FLL(157-9)AAA mutant has enhanced trypsin cleavage at K86 relative to wild-type FIT2, indicating a conformational change. Taken together, these studies indicate that FIT2 is a 6 transmembrane domain-containing protein whose conformation likely regulates its activity in mediating lipid droplet formation

The association of mammographic density with ductal carcinoma in situ of the breast: the Multiethnic Cohort

INTRODUCTION: It is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density. However, little research has been done on mammographic density and ductal carcinoma in situ (DCIS) of the breast, which is thought to be a precursor lesion to some invasive breast cancers. METHOD: We conducted a nested case-control study within the Multiethnic Cohort, and compared the mammographic densities of 482 patients with invasive breast cancer and 119 with breast DCIS cases versus those of 667 cancer-free control subjects. A reader blinded to disease status performed computer-assisted density assessment. For women with more than one mammogram, mean density values were computed. Polytomous logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for two measurements of mammographic density: percentage density and dense area. RESULTS: Mammographic density was associated with invasive breast cancer and breast DCIS. For the highest category of percentage breast density (≥50%) as compared with the lowest (<10%), the OR was 3.58 (95% CI 2.26–5.66) for invasive breast cancer and 2.86 (1.38–5.94) for breast DCIS. Similarly, for the highest category of dense area (≥45 cm(2)) as compared with the lowest (<15 cm(2)), the OR was 2.92 (95% CI 2.01–4.25) for invasive breast cancer and 2.59 (1.39–4.82) for breast DCIS. Trend tests were significant for invasive breast cancer (P for trend < 0.0001) and breast DCIS (P for trend < 0.001) for both percentage density and dense area. CONCLUSION: The similar strength of association for mammographic density with breast DCIS and invasive breast cancer supports the hypothesis that both diseases may have a common etiology