Distinct mechanisms of Drosophila CRYPTOCHROME-mediated light-evoked membrane depolarization and in vivo clock resetting.

Drosophila CRYPTOCHROME (dCRY) mediates electrophysiological depolarization and circadian clock resetting in response to blue or ultraviolet (UV) light. These light-evoked biological responses operate at different timescales and possibly through different mechanisms. Whether electron transfer down a conserved chain of tryptophan residues underlies biological responses following dCRY light activation has been controversial. To examine these issues in in vivo and in ex vivo whole-brain preparations, we generated transgenic flies expressing tryptophan mutant dCRYs in the conserved electron transfer chain and then measured neuronal electrophysiological phototransduction and behavioral responses to light. Electrophysiological-evoked potential analysis shows that dCRY mediates UV and blue-light-evoked depolarizations that are long lasting, persisting for nearly a minute. Surprisingly, dCRY appears to mediate red-light-evoked depolarization in wild-type flies, absent in both cry-null flies, and following acute treatment with the flavin-specific inhibitor diphenyleneiodonium in wild-type flies. This suggests a previously unsuspected functional signaling role for a neutral semiquinone flavin state (FADH•) for dCRY. The W420 tryptophan residue located closest to the FAD-dCRY interaction site is critical for blue- and UV-light-evoked electrophysiological responses, while other tryptophan residues within electron transfer distance to W420 do not appear to be required for light-evoked electrophysiological responses. Mutation of the dCRY tryptophan residue W342, more distant from the FAD interaction site, mimics the cry-null behavioral light response to constant light exposure. These data indicate that light-evoked dCRY electrical depolarization and clock resetting are mediated by distinct mechanisms

Distributed human computation framework for linked data co-reference resolution

Distributed Human Computation (DHC) is a technique used to solve computational problems by incorporating the collaborative effort of a large number of humans. It is also a solution to AI-complete problems such as natural language processing. The Semantic Web with its root in AI is envisioned to be a decentralised world-wide information space for sharing machine-readable data with minimal integration costs. There are many research problems in the Semantic Web that are considered as AI-complete problems. An example is co-reference resolution, which involves determining whether different URIs refer to the same entity. This is considered to be a significant hurdle to overcome in the realisation of large-scale Semantic Web applications. In this paper, we propose a framework for building a DHC system on top of the Linked Data Cloud to solve various computational problems. To demonstrate the concept, we are focusing on handling the co-reference resolution in the Semantic Web when integrating distributed datasets. The traditional way to solve this problem is to design machine-learning algorithms. However, they are often computationally expensive, error-prone and do not scale. We designed a DHC system named iamResearcher, which solves the scientific publication author identity co-reference problem when integrating distributed bibliographic datasets. In our system, we aggregated 6 million bibliographic data from various publication repositories. Users can sign up to the system to audit and align their own publications, thus solving the co-reference problem in a distributed manner. The aggregated results are published to the Linked Data Cloud

A Longitudinal Analysis of the Families First Screening Program in Manitoba, Canada: Cleaning, Validating and Linking via Health Registry Data

Introduction Manitoba Public Health Nurses (PHNs) attempt to visit all families with newborns shortly after discharge from birth hospitalizations. Since 2000, PHNs have completed the Families First Screen (FFS) at these visits, to identify families at risk for child maltreatment. The information captured in FFS is a valuable tool for research. Objectives and Approach Our objective was to clean and validate FFS data and link to health data in the Manitoba repository in order to determine the percent of births in Manitoba hospitals that had FFS. We identified all babies born in Manitoba hospitals 2000-2015 using ICD-9-CM /ICD-10-CA codes. Mothers were identified through the Health Registry (Mom_Baby Link File) using scrambled Personal Health Identification Numbers (sPHINs). FFS data were linked to births via baby’s sPHIN. Determining which FFS records linked to babies required several steps of cleaning and validating the data to account for differences in birthdates between files, missing sPHINs, and multiple records. Results For example, in 2014 there were 16,079 births and 14,002 FFS records; 13,524 FFS had mother and/or baby sPHIN. For those missing baby sPHIN (9,295), 99.8% were retrieved via the Mom_Baby Link File. Linking the FFS to the hospital births we found: 3,043 births didn’t have an FFS; 12,762 had a single FFS, and 274 births had multiple FFS (i.e., baby associated with more than one mother, FFS and/or form date). To ensure that the baby was only associated with one mother and one FFS the most current FFS was kept. We found that in 2014, 81.07% (13,036/16,079) of the births had an FFS. In the longitudinal analysis, the percent of births with an FFS ranged from 74.6% in 2000 to 81.1% in 2014. Conclusion/Implications We were able to achieve good linkage between FFS and health registry data, allowing this rich data source to be used for research on maternal and child health. Information on percent of births with FFS has been shared with policy-makers over the years and changes to screening practices implemented

The Overlap Between the Child Welfare and Youth Justice Systems in Manitoba, Canada

Introduction Manitoba has one of the highest rates of children taken into care of child welfare services (Child and Family Services; CFS) in the world, and also one of the highest youth incarceration rates in Canada. Policy-makers recognize there is overlap between these systems; the extent of that overlap is unknown. Objectives and Approach We linked CFS, Justice, and Population Health Registry data to quantify the overlap between having a history of CFS during childhood (0-17 years) and being charged with a crime as a youth (12-17 years). Using a cohort approach, we selected all individuals in Manitoba who were born in 1988 (N=28,178); those not in the province at any time from 12-17 years were excluded, leaving a final cohort of 18,182. The cohort was divided into 3 groups according to CFS involvement: CFS out-of-home care (1,148); CFS in-home services (3,395); no CFS (13,639). Criminal charges between 12-17 years were identified. Results 6.3% of our cohort had CFS out-of-home care, 18.7% received CFS in-home services, and 75% had no CFS involvement. 10.5% of the cohort were charged of a crime between 12-17 years. Almost half (46.6%) of youth who had CFS out-of-home care had criminal charges, compared to 19.4% of youth who had CFS in-home services, and 5.3% of youth with no CFS. Despite accounting for only 6.3% of the cohort, youth who had out-of-home care accounted for 28.0% of youth with criminal charges. Indigenous (First Nations (FN) and Metis) children/youth were over-represented in both systems; for example, 24.5% of FN youth had been in care compared to 3.1% of non-Indigenous; and 32.2% of FN youth were charged with a crime compared to 6.6% of non-Indigenous youth. Conclusion/Implications There is substantial overlap between the child welfare and youth justice systems, with overrepresentation of Indigenous youth in both systems. Culturally appropriate programs and policies aimed at supporting parents, families and communities to care for their own children will likely have long-term positive impacts on the youth justice system

Our Children, Our Future: The Health and Well-being of First Nations Children in Manitoba, Canada.

Objectives Given the impact of colonization and responding to Canada’s Truth and Reconciliation Commission, we aimed to provide baseline measures of First Nations children’s health and social outcomes in Manitoba, Canada. We also aimed to create a research process where Indigenous and non-Indigenous researchers work collaboratively and in culturally safe ways. Approach We formed a team consisting of members of First Nation organizations and academic researchers.  Knowledge Keepers from Anishinaabe, Cree, Anishininew, Dakota and Dene Nations guided the study, interpreted results and ensured meaningful knowledge translation.  This retrospective cohort study utilized population-based health, social services, education and justice administrative data that allowed de-identified individual-level linkages across all databases through a scrambled health number.  Adjusted rates and rate ratios were calculated using a generalized liner modeling approach to compare First Nations children (n=61,726) and all other Manitoba children (n=279,087) and comparing First Nations children living on and off-reserve. Results Large disparities between First Nations and other Manitoba children were found in birth outcomes, physical and mental health, health services, education, social services, justice system involvement and mortality. First Nations infants had higher rates of preterm births, large-for-gestational-age births, newborn readmissions to hospital and lower rates of breastfeeding initiation compared with other Manitoba infants. Suicide rates among First Nations adolescents were ten times higher than among other adolescents in Manitoba, yet we found few differences in diagnosis of mood and anxiety disorders between the groups. First Nations children were also seven times more likely to apprehended by child protection services and youth were ten times more likely to be criminally accused.  Knowledge Keepers offered their perspectives on these findings. Conclusion These findings demonstrate that an enormous amount of work is required in virtually every area – health, social, education and justice – to improve First Nations children’s lives. There is an urgent need for equitable access to services, and these services should be self-determined, planned and implemented by First Nations people

Is PAX-Good Behaviour Game (PAX) Associated with Better Mental Health and Educational Outcomes for First Nations Children?

Objectives PAX, a mental health promotion approach, has been shown to decrease negative mental health outcomes and improve academic achievement. These effects have yet to be shown among Indigenous children. We evaluated PAX for improving First Nations children’s outcomes following a research process wherein community members and researchers work more collaboratively. Approach Building on a long-term relationship with Swampy Cree Tribal Council, community members, First Nations leaders and researchers worked together through all phases of the project. This cluster randomized controlled trial used population-based health, social services, and education administrative data that allowed de-identified individual-level linkages across all databases through a scrambled health number.  Our cohort of 725 children from 20 First Nations schools were randomized to PAX (n=469, 11 schools) or wait-list control (n=256, 9 schools). We used propensity score weighting and multi-level modeling to estimate the differences over time (2011 up to 2020) between children exposed to PAX and those who were not. Results Differences in baseline characteristics were found between the two groups of children, despite the cluster randomization. After applying propensity score weights, children in the PAX group had significantly greater decreases in conduct problems (β:-1.08, standard error(se):0.2505, p<.0001), hyperactivity (β:-1.13, se:0.3617, p=.0018 ), and peer problems (β:-1.10, se:0.3043, p=.0003) and a greater increase in prosocial scores (β:2.68, se:0.4139, p<.0001) than control group children. The percentage of children in the PAX group who met academic expectations was higher than those in the control group, however, only grade 3 numeracy (odds ratio (OR):4.30, confidence interval (CI):1.34 – 13.77) and grade 8 reading and writing (OR:2.78, CI:1.01 – 7.67) met statistical significance.  We found no evidence that PAX was associated with less emotional problems, diagnosed mental disorders or better student engagement. Conclusion These findings suggest that PAX was effective in improving First Nations children’s mental health and academic outcomes in First Nations communities. Examining what works in Indigenous communities is crucial because approaches that are effective in some populations may not necessarily be culturally appropriate for remote Indigenous communities

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer.

We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance

Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009). From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27).Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.This work was supported by grants from the Congress Directed Medical Research Program (BC995364 and DAMD17-01-1-0241), Cure Cancer Australia Foundation, NHMRC Australia (projects 1047149, Fellowships 1058356, 481310, 1043400), the Australian Research Council Discovery Project (DP110102288), Princeton University, NIH grant 1R01GM110161-01 (AK), Sidney Kimmel Foundation for Cancer Research (AK), Burroughs Wellcome Foundation (AK), Banque Nationale de Paris-Paribas Australia and New Zealand, Mostyn Family Foundation, Cue Clothing Co., Estee Lauder Australia, RT Hall Trust and Fellowships (ECF-13-08 and ECF-16-022) from the National Breast Cancer Foundatio