At risk of being risky: The relationship between "brain age" under emotional states and risk preference.

Developmental differences regarding decision making are often reported in the absence of emotional stimuli and without context, failing to explain why some individuals are more likely to have a greater inclination toward risk. The current study (N=212; 10-25y) examined the influence of emotional context on underlying functional brain connectivity over development and its impact on risk preference. Using functional imaging data in a neutral brain-state we first identify the "brain age" of a given individual then validate it with an independent measure of cortical thickness. We then show, on average, that "brain age" across the group during the teen years has the propensity to look younger in emotional contexts. Further, we show this phenotype (i.e. a younger brain age in emotional contexts) relates to a group mean difference in risk perception - a pattern exemplified greatest in young-adults (ages 18-21). The results are suggestive of a specified functional brain phenotype that relates to being at "risk to be risky.

De novo design of bioactive protein switches.

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix 'cage' with a single interface that can interact either intramolecularly with a terminal 'latch' helix or intermolecularly with a peptide 'key'. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cage-key systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering

Additive technology for pollutant control and efficient coal combustion

High efficiency and low emissions from pf coal power stations has been the drive behind the development of present and future efficient coal combustion technologies. Upgrading coal, capturing CO2, reducing emission of NOx, SO2 and particulate matter, mitigating slagging, fouling and corrosion are the key initiatives behind these efficient coal technologies. This study focuses on a newly developed fuel additive (Silanite™) based efficient coal combustion technology, which addresses most of the aforementioned key points. Silanite™ a finely milled multi-oxide additive when mixed with the coal without the need to change the boiler installation has proven to increase the boiler efficiency, flame temperature with reduction in corrosion, NOx and particulate matter (dust) emissions. The process has been developed through bench, pilot (100kW) and full scale (233 MWth). The process has been found to have a number of beneficial effects that add up to a viable retrofit to existing power plant as demonstrated on the 233MWth boiler tests (under BS EN 12952-15:2003 standard

The Next Generation Virgo Cluster Survey - Infrared (NGVS-IR): I. A new Near-UV/Optical/Near-IR Globular Cluster selection tool

The NGVS-IR project (Next Generation Virgo Survey - Infrared) is a contiguous near-infrared imaging survey of the Virgo cluster of galaxies. It complements the optical wide-field survey of Virgo (NGVS). The current state of NGVS-IR consists of Ks-band imaging of 4 deg^2 centered on M87, and J and Ks-band imaging of 16 deg^2 covering the region between M49 and M87. In this paper, we present the observations of the central 4 deg^2 centered on Virgo's core region. The data were acquired with WIRCam on the Canada-France-Hawaii Telescope and the total integration time was 41 hours distributed in 34 contiguous tiles. A survey-specific strategy was designed to account for extended galaxies while still measuring accurate sky brightness within the survey area. The average 5\sigma limiting magnitude is Ks=24.4 AB mag and the 50% completeness limit is Ks=23.75 AB mag for point source detections, when using only images with better than 0.7" seeing (median seeing 0.54"). Star clusters are marginally resolved in these image stacks, and Virgo galaxies with \mu_Ks=24.4 AB mag arcsec^-2 are detected. Combining the Ks data with optical and ultraviolet data, we build the uiK color-color diagram which allows a very clean color-based selection of globular clusters in Virgo. This diagnostic plot will provide reliable globular cluster candidates for spectroscopic follow-up campaigns needed to continue the exploration of Virgo's photometric and kinematic sub-structures, and will help the design of future searches for globular clusters in extragalactic systems. Equipped with this powerful new tool, future NGVS-IR investigations based on the uiK diagram will address the mapping and analysis of extended structures and compact stellar systems in and around Virgo galaxies.Comment: 23 pages, 18 figures. Accepted for publication in ApJ

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology

SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia

Although small molecule inhibitors of B-cell receptor-associated kinases have revolutionized therapy in chronic lymphocytic leukemia (CLL), responses are incomplete. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B cells resident in the protective lymphoid niches. B-cell activating factor (BAFF) is critical to the survival of both healthy and neoplastic B cells. However, the pro-survival pathways triggered by BAFF have not been fully characterized. Here we show that BAFF elicited resistance to spontaneous and drug-induced apoptosis in stromal co-cultures, induced activation of both canonical and non-canonical NFκB signaling pathways, and triggered B-cell receptor signaling in CLL cells, independently of IGHV mutational status. SYK, a proximal kinase in the B-cell receptor signaling cascade, acted via STAT3 to bolster transcription of the anti-apoptotic protein Mcl-1, thereby contributing to apoptosis resistance in BAFF-stimulated cells. SYK inhibitor entospletinib downregulated Mcl-1, abrogating BAFF-mediated cell survival. BAFF-B-cell receptor crosstalk in neoplastic B cells was mediated by SYK interaction with TRAF2/TRAF3 complex. Thus, SYK inhibition is a promising therapeutic strategy uniquely poised to antagonize crosstalk between BAFF and B-cell receptor, thereby disrupting the pro-survival microenvironment signaling in chronic lymphocytic leukemia

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

‘Buying a path’: rethinking resistance in Rwanda

In this essay, I tell the story of Jean-Baptiste, the president of a motorcycle taxi drivers’ co-operative, and his struggle against the machinations of certain high officials in Kigali City Council. Crucial to this story is the way in which Jean-Baptiste’s attempts to retain his position in the face of powerful opposition pit certain agencies of Rwanda’s party state against others. I use this ethnographic narrative to question the way in which much scholarship on popular resistance in Rwanda, drawing on Scott’s simplified opposition between the powerful and the powerless, opposes ‘ordinary Rwandans’ to ‘the state’ as monolithic entities with opposed interests. Theorising Jean-Baptiste’s story in terms of Rwandan idioms of relative power and influence, I suggest that such a Manichean view of power and resistance in Rwanda oversimplifies social realities. I propose instead a model of power and resistance that sees the state as a field of capacities and possible relationships that it presents for certain people, where ‘paths’ to influence and security may by ‘bought’ – especially, but not exclusively, by those who are ‘strong’ and ‘high’

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis