Complex expression dynamics and robustness in C. elegans insulin networks

Gene families expand by gene duplication and resulting paralogs diverge through mutation. Functional diversification can include neo-functionalization as well as sub-functionalization of ancestral functions. In addition, redundancy in which multiple genes fulfill overlapping functions is often maintained. Here, we use the family of 40 Caenorhabditis elegans insulins to gain insight into the balance between specificity and redundancy. The insulin/insulin-like growth factor (IIS) pathway comprises a single receptor, DAF-2. To date, no single insulin-like peptide recapitulates all DAF-2-associated phenotypes, likely due to redundancy between insulin-like genes. To provide a first-level annotation of potential patterns of redundancy, we comprehensively delineate the spatiotemporal and conditional expression of all 40 insulins in living animals. We observe extensive dynamics in expression that can explain the lack of simple patterns of pair-wise redundancy. We propose a model in which gene families evolve to attain differential alliances in different tissues and in response to a range of environmental stresses

The Evidence Does Not Speak for Itself: The Role of Research Evidence in Shaping Policy Change for the Implementation of Publicly Funded Syringe Exchange Programs in Three US Cities

BACKGROUND: A breadth of literature exists that explores the utilization of research evidence in policy change processes. From this work, a number of studies suggest research evidence is applied to change processes by policy change stakeholders primarily through instrumental, conceptual, and/or symbolic applications, or is not used at all. Despite the expansiveness of research on policy change processes, a deficit exists in understanding the role of research evidence during change processes related to the implementation of structural interventions for HIV prevention among injection drug users (IDU). This study examined the role of research evidence in policy change processes for the implementation of publicly funded syringe exchange services in three US cities: Baltimore, MD, Philadelphia, PA, and Washington, DC. METHODS: In-depth qualitative interviews were conducted with key stakeholders (n=29) from each of the study cities. Stakeholders were asked about the historical, social, political, and scientific contexts in their city during the policy change process. Interviews were transcribed and analyzed for common themes pertaining to applications of research evidence. RESULTS: In Baltimore and Philadelphia, the typological approaches (instrumental and symbolic/conceptual, respectively) to the applications of research evidence used by harm reduction proponents contributed to the momentum for securing policy change for the implementation of syringe exchange services. Applications of research evidence were less successful in DC because policymakers had differing ideas about the implications of syringe exchange program implementation and because opponents of policy change used evidence incorrectly or not at all in policy change discussions. CONCLUSION: Typological applications of research evidence are useful for understanding policy change processes, but their efficacy falls short when sociopolitical factors complicate legislative processes. Advocates for harm reduction may benefit from understanding how to effectively integrate research evidence into policy change processes in ways that confront the myriad of factors that influence policy change

Magnetic structure and low-temperature properties of geometrically frustrated SrNd2O4

We report the low-temperature properties of SrNd2O4, a geometrically frustrated magnet. Magnetization and heat capacity measurements performed on polycrystalline samples indicate the appearance of a magnetically ordered state at TN = 2.28(4)K. Powder neutron diffraction measurements reveal that an antiferromagnetic state with the propagation vector q = (0 1/2 1/2 ) is stabilized below this temperature. The magnetic order is incomplete, as only one of the two Nd3+ sites carries a significant magnetic moment while the other site remains largely disordered. The presence of a disordered magnetic component below TN is confirmed with polarized neutron diffraction measurements. In an applied magnetic field, the bulk property measurements indicate a phase transition at about 30 kOe. We construct a tentative H-T phase diagram of SrNd2O4 from these measurements

Magnetic structures of geometrically frustrated SrGd2O4 derived from powder and single-crystal neutron diffraction

We present the low-temperature magnetic structures of SrGd2O4 combining neutron diffraction methods on polycrystalline and single-crystal samples containing the 160Gd isotope. In contrast to other members of the SrLn2O4 family (Ln = lanthanide) this system reveals two long-range ordered magnetic phases, which our diffraction data unambiguously identify. Below TN1 = 2.73 K, a q1 = (0 0 0) magnetic structure is stabilized where ferromagnetic chains along the c axis (space group Pnam) are coupled antiferromagnetically with neighboring chains. On cooling below TN2 = 0.48 K, an additional incommensurate component modulated by q2 = (0 0 0.42) evolves and is aligned along either of the perpendicular axes for the two different Gd sites, resulting in a fanlike magnetic structure. The identification of the particular Gd sites with the magnetic order observed with neutron diffraction is facilitated by a detailed analysis of the crystal fields acting on the sites. The observed ordering phenomena underline the complex multiaxial anisotropy in this system

Corrigendum to "Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action [European Neuropsychopharmacology (2020) 36, 121-136]"

The authors regret that there was an error in the author list, this should appear as above. The authors apologise for any inconvenience caused

Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action

Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substantial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treatment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more specific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical interventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively

Association between solar insolation and a history of suicide attempts in bipolar I disorder

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p <0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.Peer reviewe

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p &lt; 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification