Controlling crystallization and its absence: Proteins, colloids and patchy models

The ability to control the crystallization behaviour (including its absence) of particles, be they biomolecules such as globular proteins, inorganic colloids, nanoparticles, or metal atoms in an alloy, is of both fundamental and technological importance. Much can be learnt from the exquisite control that biological systems exert over the behaviour of proteins, where protein crystallization and aggregation are generally suppressed, but where in particular instances complex crystalline assemblies can be formed that have a functional purpose. We also explore the insights that can be obtained from computational modelling, focussing on the subtle interplay between the interparticle interactions, the preferred local order and the resulting crystallization kinetics. In particular, we highlight the role played by ``frustration'', where there is an incompatibility between the preferred local order and the global crystalline order, using examples from atomic glass formers and model anisotropic particles.Comment: 11 pages, 7 figure

Genomic Regions Identified by Overlapping Clusters of Nominally-Positive SNPs from Genome-Wide Studies of Alcohol and Illegal Substance Dependence

Declaring “replication” from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one “nontemplate” approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans

Relationship Contexts as Sources of Socialization: An Exploration of Intimate Partner Violence Experiences of Economically Disadvantaged African American Adolescents

Intimate partner violence (IPV) among African Americans is a serious public health concern. Research suggest that African Americans adolescents, particularly those from economically disadvantaged communities, are at heightened risk for experiencing and perpetrating dating violence compared to youth from other racial and ethnic groups. In the present study, we examined different relationship contexts that are sources of IPV socialization. Semi-structured interviews were conducted with 22 economically disadvantaged African American adolescents. Content analysis yielded five relationship contexts through which the participants witnessed, experienced, and perpetrated IPV: (a) adolescents’ own dating relationships (64%), (b) siblings and extended family members (e.g., cousins, aunts, uncles) (59%), (c) parent-partners (27%), (d) friends (23%), and (e) neighbors (18%). Adolescents also frequently described IPV in their own dating relationships and in parent-partner relationships as mutual. Moreover, they appeared to minimize the experience of IPV in their own relationships. Efforts to reduce rates of IPV among economically disadvantaged African American adolescents should consider these relational contexts through which adolescents are socialized with regards to IPV and adolescents’ beliefs about mutual violence in relationships. Results highlight the importance of culturally relevant prevention and intervention programs that consider these relationship contexts

Rationality versus reality: the challenges of evidence-based decision making for health policy makers

<p>Abstract</p> <p>Background</p> <p>Current healthcare systems have extended the evidence-based medicine (EBM) approach to health policy and delivery decisions, such as access-to-care, healthcare funding and health program continuance, through attempts to integrate valid and reliable evidence into the decision making process. These policy decisions have major impacts on society and have high personal and financial costs associated with those decisions. Decision models such as these function under a shared assumption of rational choice and utility maximization in the decision-making process.</p> <p>Discussion</p> <p>We contend that health policy decision makers are generally unable to attain the basic goals of evidence-based decision making (EBDM) and evidence-based policy making (EBPM) because humans make decisions with their naturally limited, faulty, and biased decision-making processes. A cognitive information processing framework is presented to support this argument, and subtle cognitive processing mechanisms are introduced to support the focal thesis: health policy makers' decisions are influenced by the subjective manner in which they individually process decision-relevant information rather than on the objective merits of the evidence alone. As such, subsequent health policy decisions do not necessarily achieve the goals of evidence-based policy making, such as maximizing health outcomes for society based on valid and reliable research evidence.</p> <p>Summary</p> <p>In this era of increasing adoption of evidence-based healthcare models, the rational choice, utility maximizing assumptions in EBDM and EBPM, must be critically evaluated to ensure effective and high-quality health policy decisions. The cognitive information processing framework presented here will aid health policy decision makers by identifying how their decisions might be subtly influenced by non-rational factors. In this paper, we identify some of the biases and potential intervention points and provide some initial suggestions about how the EBDM/EBPM process can be improved.</p

Detecting parent of origin and dominant QTL in a two-generation commercial poultry pedigree using variance component methodology

<p>Abstract</p> <p>Introduction</p> <p>Variance component QTL methodology was used to analyse three candidate regions on chicken chromosomes 1, 4 and 5 for dominant and parent-of-origin QTL effects. Data were available for bodyweight and conformation score measured at 40 days from a two-generation commercial broiler dam line. One hundred dams were nested in 46 sires with phenotypes and genotypes on 2708 offspring. Linear models were constructed to simultaneously estimate fixed, polygenic and QTL effects. Different genetic models were compared using likelihood ratio test statistics derived from the comparison of full with reduced or null models. Empirical thresholds were derived by permutation analysis.</p> <p>Results</p> <p>Dominant QTL were found for bodyweight on chicken chromosome 4 and for bodyweight and conformation score on chicken chromosome 5. Suggestive evidence for a maternally expressed QTL for bodyweight and conformation score was found on chromosome 1 in a region corresponding to orthologous imprinted regions in the human and mouse.</p> <p>Conclusion</p> <p>Initial results suggest that variance component analysis can be applied within commercial populations for the direct detection of segregating dominant and parent of origin effects.</p

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder

Background: Manic-depression or bipolar disorder (BD) is a multi-faceted illness with an inevitably complex treatment. Methods: This article summarizes the current status of our knowledge and practice of its treatment. Results: It is widely accepted that lithium is moderately useful during all phases of bipolar illness and it might possess a specific effectiveness on suicidal prevention. Both first and second generation antipsychotics are widely used and the FDA has approved olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole for the treatment of acute mania. These could also be useful in the treatment of bipolar depression, but only limited data exists so far to support the use of quetiapine monotherapy or the olanzapine-fluoxetine combination. Some, but not all, anticonvulsants possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be effective in the treatment of depression but not mania. Antidepressant use is controversial. Guidelines suggest their cautious use in combination with an antimanic agent, because they are supposed to induce switching to mania or hypomania, mixed episodes and rapid cycling. Conclusion: The first-line psychosocial intervention in BD is psychoeducation, followed by cognitive-behavioral therapy. Other treatment options include Electroconvulsive therapy and transcranial magnetic stimulation. There is a gap between the evidence base, which comes mostly from monotherapy trials, and clinical practice, where complex treatment regimens are the rule