Agonists of prostaglandin E2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies.

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.

Experiences and perceived outcomes of a grocery gift card programme for households at risk of food insecurity.

OBJECTIVE: This study explored programme recipients' and deliverers' experiences and perceived outcomes of accessing or facilitating a grocery gift card (GGC) programme from I Can for Kids (iCAN), a community-based programme that provides GGC to low-income families with children. DESIGN: This qualitative descriptive study used Freedman et al's framework of nutritious food access to guide data generation and analysis. Semi-structured interviews were conducted between August and November 2020. Data were analysed using directed content analysis with a deductive-inductive approach. PARTICIPANTS: Fifty-four participants were purposively recruited, including thirty-seven programme recipients who accessed iCAN's GGC programme and seventeen programme deliverers who facilitated it. SETTING: Calgary, Alberta, Canada. RESULTS: Three themes were generated from the data. First, iCAN's GGC programme promoted a sense of autonomy and dignity among programme recipients as they appreciated receiving financial support, the flexibility and convenience of using GGC, and the freedom to select foods they desired. Recipients perceived these benefits improved their social and emotional well-being. Second, recipients reported that the use of GGC improved their households' dietary patterns and food skills. Third, both participant groups identified programmatic strengths and limitations. CONCLUSION: Programme recipients reported that iCAN's GGC programme provided them with dignified access to nutritious food and improved their households' finances, dietary patterns, and social and emotional well-being. Increasing the number of GGC provided to households on each occasion, establishing clear and consistent criteria for distributing GGC to recipients, and increasing potential donors' awareness of iCAN's GGC programme may augment the amount of support iCAN could provide to households.

'My coupons are like gold': experiences and perceived outcomes of low-income adults participating in the British Columbia Farmers' Market Nutrition Coupon Program.

OBJECTIVE: The British Columbia Farmers' Market Nutrition Coupon Program (FMNCP) provides low-income households with coupons valued at $21/week for 16 weeks to purchase healthy foods in farmers' markets. Our objective was to explore FMNCP participants' experiences of accessing nutritious foods, and perceived programme outcomes. DESIGN: The current study used qualitative description methodology. Semi-structured interviews were conducted with FMNCP participants during the 2019 farmers' market season. Directed content analysis was used to analyse the data, whereby the five domains of Freedman et al.'s framework of nutritious food access provided the basis for an initial coding scheme. Data that did not fit within the framework's domains were coded inductively. SETTING: One urban and two rural communities in British Columbia, Canada. PARTICIPANTS: Twenty-eight adults who were participating in the FMNCP. RESULTS: Three themes emerged: autonomy and dignity, social connections and community building, and environmental and programmatic constraints. Firstly, the programme promoted a sense of autonomy and dignity through financial support, increased access to high-quality produce, food-related education and skill development and mitigating stigma and shame. Secondly, shopping in farmers' markets increased social connections and fostered a sense of community. Finally, participants experienced limited food variety in rural farmers' markets, lack of transportation and challenges with redeeming coupons. CONCLUSIONS: Participation in the FMNCP facilitated access to nutritious foods and enhanced participants' diet quality, well-being and health. Strategies such as increasing the amount and duration of subsidies and expanding programmes may help improve participants' experiences and outcomes of farmers' market food subsidy programmes.

Quantification of missing prescriptions in commercial claims databases: results of a cohort study.

PURPOSE: This study aims to quantify the magnitude of missed dispensings in commercial claims databases. METHODS: A retrospective cohort study has been used linking PharMetrics, a commercial claims database, to a prescription database (LRx) that captures pharmacy dispensings independently of payment method, including cash transactions. We included adults with dispensings for opioids, diuretics, antiplatelet medications, or anticoagulants. To determine the degree of capture of dispensings, we calculated the number of subjects with the following: (1) same number of dispensings in both databases; (2) at least one dispensing, but not all dispensings, missed in PharMetrics; and (3) all dispensings missing in PharMetrics. Similar analyses were conducted using dispensings as the unit of analysis. To assess whether a dispensing in LRx was in PharMetrics, the dispensing in PharMetrics had to be for the same medication class and within ±7 days in LRx. RESULTS: A total of 1 426 498 subjects were included. Overall, 68% of subjects had the same number of dispensings in both databases. In 13% of subjects, PharMetrics identified ≥1 dispensing but also missed ≥1 dispensing. In 19% of the subjects, PharMetrics missed all the dispensings. Taking dispensings as the unit of analysis, 25% of the dispensings present in LRx were not captured in PharMetrics. These patterns were similar across all four classes of medications. Of the dispensings missing in PharMetrics, 48% involved a subject who had >1 health insurance plan. CONCLUSIONS: Commercial claims databases provide an incomplete picture of all prescriptions dispensed to patients. The lack of capture goes beyond cash transactions and potentially introduces substantial misclassification bias. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

The British Columbia Farmers' Market Nutrition Coupon Program Reduces Short-Term Household Food Insecurity Among Adults With Low Incomes: A Pragmatic Randomized Controlled Trial.

BACKGROUND: The British Columbia Farmers' Market Nutrition Coupon Program (BC FMNCP) provides households with low incomes with coupons to purchase healthy foods from farmers' markets. OBJECTIVE: To examine the impact of the BC FMNCP on the short-term household food insecurity, malnutrition risk, mental well-being, sense of community (secondary outcomes), and subjective social status (exploratory outcome) of adults with low incomes post-intervention and 16 weeks post-intervention. DESIGN: Secondary analyses from a pragmatic randomized controlled trial conducted in 2019 that collected data at baseline, post-intervention, and 16 weeks post-intervention. PARTICIPANTS/SETTING: Adults ≥18 years with low incomes were randomized to an FMNCP group (n = 143) or a no-intervention control group (n = 142). INTERVENTION: Participants in the FMNCP group received 16 coupon sheets valued at $21 Canadian dollars (CAD)/sheet over 10 to 15 weeks to purchase healthy foods from farmers' markets and were eligible to participate in nutrition skill-building activities. MAIN OUTCOME MEASURES: Outcomes included short-term household food insecurity (modified version of Health Canada's 18-item Household Food Security Survey Module), malnutrition risk (Malnutrition Universal Screening Tool), mental well-being (Warwick-Edinburgh Mental Well-Being Scale), sense of community (Brief Sense of Community Scale), and subjective social status (MacArthur Scale of Subjective Social Status community scale). STATISTICAL ANALYSIS: Mixed-effects linear regression and multinomial logistic regression examined between-group differences in outcomes post-intervention and 16 weeks post-intervention. RESULTS: The risk of marginal and severe short-term household food insecurity was lower among those in the FMNCP group compared with those in the control group (relative risk ratio [RRR] 0.15, P = 0.01 and RRR 0.16, P = 0.02) post-intervention, with sustained reductions in severe household food insecurity 16 weeks post-intervention (RRR 0.11, P = 0.01). No statistically significant differences were observed in malnutrition risk, mental well-being, sense of community, or subjective social status post-intervention or 16 weeks post-intervention. CONCLUSIONS: The BC FMNCP reduced short-term household food insecurity but was not found to improve malnutrition risk or psychosocial well-being among adults with low incomes compared with a no-intervention control group.

The Impact of Providing Material Benefits to Improve Access to Food on Clinical Parameters, Dietary Intake, and Household Food Insecurity in People with Diabetes: A Systematic Review with Narrative Synthesis.

The high cost of healthy foods makes maintaining a healthy dietary pattern challenging, particularly among people with diabetes who are experiencing food insecurity. The objectives of this study were to: 1) review evidence on the impact of providing material benefits (e.g., food coupons/vouchers, free food, or financial subsidies/incentives) to improve access to food on clinical parameters, dietary intake, and household food insecurity in people with diabetes, and 2) review relevant economic evidence. Six databases were searched from inception to March 2023 for longitudinal studies with quantitative outcomes. Twenty-one studies were included in the primary review and 2 in the economic analysis. Risk of bias was high in 20 studies and moderate in 1 study. The number of randomized controlled trials and nonrandomized studies reporting statistically significant improvement, alongside Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty of the evidence was: HbA1c: 1/6 and 4/12 (very low), systolic blood pressure: 0/3 and 1/8 (very low), diastolic blood pressure: 0/3 and 1/7 (very low), BMI: 0/5 and 2/8 (very low), body weight: 0/0 and 1/3 (very low), hypoglycemia: 1/2 and 1/2 (very low), daily intake of fruits and vegetables: 1/1 and 1/3 (very low), daily intake of whole grains: 0/0 and 0/2 (very low), overall diet quality: 2/2 and 1/1 (low), and household food insecurity: 2/3 and 0/0 (very low). The 2 studies included in the economic analysis showed no difference in Medicare spending from Supplemental Nutrition Assistance Program participation and cost-savings from medically tailored meals in an economic simulation. Overall, providing material benefits to improve access to food for people with diabetes may improve household food insecurity, fruit and vegetable intake, and overall diet quality, but effects on clinical parameters and whole grain intake are unclear. The certainty of evidence was very low to low by GRADE. PROSPERO (CRD42021212951).

Impact of a farmers' market healthy food subsidy on the diet quality of adults with low incomes in British Columbia, Canada: a pragmatic randomized controlled trial.

BACKGROUND: Adults with low incomes have lower diet quality than their higher income counterparts. In Canada, the British Columbia Farmers' Market Nutrition Coupon Program (FMNCP) provides coupons to low-income households to purchase healthy foods in farmers' markets. OBJECTIVE: The objective of this study was to examine the impact of the FMNCP on the diet quality of adults with low incomes. METHOD: In a pragmatic randomized controlled trial conducted in 2019, adults with low incomes (≥18 y) were randomly assigned either to an FMNCP intervention (n = 143) or a no-intervention control group (n = 142). The FMNCP group received 16 coupon sheets valued at $21 per sheet over 10-15 wk to purchase healthy foods from farmers' markets. Participants completed a questionnaire and 2 24-h dietary recalls at baseline (0 wk), immediately post-intervention (10-15 wk), and 16-wk post-intervention (26-31 wk). Diet quality was calculated using the Healthy Eating Index-2015 (HEI-2015). Linear mixed-effects regression assessed differences in HEI-2015 total (primary outcome) and component scores (secondary outcomes) between the FMNCP and control groups at post-intervention and 16-wk post-intervention. Subgroup analyses examined program impacts by sex and age group (18-59 y, ≥60 y). RESULTS: There were no significant differences in HEI-2015 total scores between the FMNCP and control groups at post-intervention (-0.07; 95% CI: -4.07, 3.93) or 16-wk post-intervention (1.22; 95% CI: -3.00, 5.44) overall or between subgroups. There were no significant between-group differences in HEI-2015 component scores at post-intervention, although there were significant differences in component scores for dairy and fatty acids at 16-wk post-intervention. CONCLUSION: The FMNCP did not significantly improve diet quality among adults with low incomes over the study period. Further research is needed to explore whether higher subsidy amounts or a longer intervention period is needed to meaningfully improve diet quality among adults with low incomes. This trial was registered at [clinicaltrials.gov] as [NCT03952338].

Machine learning using longitudinal prescription and medical claims for the detection of non-alcoholic steatohepatitis (NASH).

OBJECTIVES: To develop and evaluate machine learning models to detect patients with suspected undiagnosed non-alcoholic steatohepatitis (NASH) for diagnostic screening and clinical management. METHODS: In this retrospective observational non-interventional study using administrative medical claims data from 1 463 089 patients, gradient-boosted decision trees were trained to detect patients with likely NASH from an at-risk patient population with a history of obesity, type 2 diabetes mellitus, metabolic disorder or non-alcoholic fatty liver (NAFL). Models were trained to detect likely NASH in all at-risk patients or in the subset without a prior NAFL diagnosis (at-risk non-NAFL patients). Models were trained and validated using retrospective medical claims data and assessed using area under precision recall curves and receiver operating characteristic curves (AUPRCs and AUROCs). RESULTS: The 6-month incidences of NASH in claims data were 1 per 1437 at-risk patients and 1 per 2127 at-risk non-NAFL patients . The model trained to detect NASH in all at-risk patients had an AUPRC of 0.0107 (95% CI 0.0104 to 0.0110) and an AUROC of 0.84. At 10% recall, model precision was 4.3%, which is 60× above NASH incidence. The model trained to detect NASH in the non-NAFL cohort had an AUPRC of 0.0030 (95% CI 0.0029 to 0.0031) and an AUROC of 0.78. At 10% recall, model precision was 1%, which is 20× above NASH incidence. CONCLUSION: The low incidence of NASH in medical claims data corroborates the pattern of NASH underdiagnosis in clinical practice. Claims-based machine learning could facilitate the detection of patients with probable NASH for diagnostic testing and disease management.

Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.

CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

Experiences and Perceived Outcomes of Low-Income Adults During and After Participating in the British Columbia Farmers' Market Nutrition Coupon Program: A Longitudinal Qualitative Study.

BACKGROUND: The British Columbia Farmers' Market Nutrition Coupon Program (FMNCP) is a farmers' market food subsidy program that provides low-income households with coupons valued at $21/wk for 16 weeks to purchase healthy foods at participating BC Association of Farmers' Markets members' markets. OBJECTIVE: This study aimed to explore changes, differences, and similarities in participants' experiences and perceived short-term outcomes during and after participating in the FMNCP. DESIGN: A longitudinal qualitative research approach was used to conduct a recurrent cross-sectional analysis. Data generation and analysis were guided by Freedman et al's theoretical framework of nutritious food access. Data generation occurred during 2019 FMNCP program (time 1) and 4 to 7 weeks after (time 2) the program year ended. Data at each time point were analyzed separately using directed content analysis, followed by a comparative analysis to identify changes, differences, and similarities between time points. PARTICIPANTS: Twenty-eight adult participants were interviewed during the program; 24 were re-interviewed post program. SETTING: Three communities in British Columbia, Canada. RESULTS: Three themes were generated: temporary relief and engagement; lasting experiences and outcomes; enhancing participant experiences and outcomes. The first theme related to how participants' experiences and perceived outcomes, such as increased financial support and improved diet quality and health, were temporary. The second theme reflected positive lasting experiences and outcomes from participating in the FMNCP, including increased food and nutrition knowledge and enhanced social ties. The third theme focused on enhancing participants' program experiences and outcomes, including increasing the duration of food subsidies. CONCLUSION: The FMNCP temporarily enhanced access to nutritious foods and had lasting positive effects on participants' nutrition-related knowledge and social outcomes. Nevertheless, participants struggled to maintain healthy eating practices post program due to financial constraints. Expanding farmers' market subsidy programs may improve access to nutritious foods; maintain positive dietary, social, and health outcomes for participants; and reach more low-income households.

Reducing HIV-related stigma among young people attending school in Northern Uganda: study protocol for a participatory arts-based population health intervention and stepped-wedge cluster-randomized trial.

BACKGROUND: HIV-related stigma negatively impacts HIV prevention, treatment, and care, particularly among children and adolescents in sub-Saharan Africa. Interventions that are culturally grounded and relevant for addressing root causes may reduce the stigma experienced by HIV-positive and HIV-affected young people. This study, to be conducted in a post-conflict, rural setting in Omoro District, Uganda, will develop and evaluate a transformative  arts-based HIV-related stigma intervention rooted in local cultural knowledge to reduce stigma and improve HIV prevention and care for young people living with HIV. The intervention will be delivered to young people attending school by community Elders, with the support of teachers, through the transfer of local cultural knowledge and practices with the aim of re-establishing the important cultural and social role of Elders within a community that has suffered the loss of intergenerational transfer of cultural knowledge throughout a 25-year civil war. METHODS: A formative research phase consisting of interviews with students, teachers, and Elders will inform the intervention and provide data for study objectives. Workshops will be delivered to Elders and teachers in participating schools to build capacity for arts-based, educational workshops to be conducted with students in the classroom. The intervention will be evaluated using a stepped-wedge cluster-randomized trial. Government-funded schools in Omoro District will be randomized into three blocks, each comprised of two primary and two secondary schools (n=1800 students). Schools will be randomly assigned to a crossover sequence from control to intervention condition in 8-week intervals. A process evaluation will be implemented throughout the study to evaluate pathways between intervention development, implementation, and effects. DISCUSSION: This study will generate comprehensive, in-depth participatory research and evaluation data to inform an effective and sustainable protocol for implementing arts-based HIV stigma interventions for young people in school settings. Findings will have widespread implications in post-conflict settings for HIV prevention, treatment, and care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04946071 . Registered on 30 June 2021.

Contribution of temporal preparation and processing speed to simple reaction time in persons with Alzheimer's disease and mild cognitive impairment.

Temporal preparation was assessed in 15 Alzheimer's disease (AD) patients, 20 persons with mild cognitive impairment (MCI) and 28 healthy older adults. Participants completed a simple reaction time task in which the preparatory interval duration varied randomly within two blocks (short versus long temporal window). Results indicated that AD and MCI patients had difficulty preparing for the shortest preparatory interval of the short temporal window. AD and MCI patients also had difficulty maintaining an optimal level of preparation up to 5 s within the short temporal window. These results suggest that AD and MCI patients might show difficulty preparing for rapidly occurring events and maintaining preparation over time. This phenomenon should be considered when using reaction time measures with such patients.

Impact of a farmers' market nutrition coupon programme on diet quality and psychosocial well-being among low-income adults: protocol for a randomised controlled trial and a longitudinal qualitative investigation.

INTRODUCTION: Low-income populations have poorer diet quality and lower psychosocial well-being than their higher-income counterparts. These inequities increase the burden of chronic disease in low-income populations. Farmers' market subsidies may improve diet quality and psychosocial well-being among low-income populations. In Canada, the British Columbia (BC) Farmers' Market Nutrition Coupon Programme (FMNCP) aims to improve dietary patterns and health among low-income participants by providing coupons to purchase healthy foods from farmers' markets. This study will assess the impact of the BC FMNCP on the diet quality and psychosocial well-being of low-income adults and explore mechanisms of programme impacts. METHODS AND ANALYSIS: In a parallel group randomised controlled trial, low-income adults will be randomised to an FMNCP intervention (n=132) or a no-intervention control group (n=132). The FMNCP group will receive 16 coupon sheets valued at CAD$21/sheet over 10-15 weeks to purchase fruits, vegetables, dairy, meat/poultry/fish, eggs, nuts and herbs at farmers' markets and will be invited to participate in nutrition skill-building activities. Overall diet quality (primary outcome), diet quality subscores, mental well-being, sense of community, food insecurity and malnutrition risk (secondary outcomes) will be assessed at baseline, immediately post-intervention and 16 weeks post-intervention. Dietary intake will be assessed using the Automated Self-Administered 24-hour Dietary Recall. Diet quality will be calculated using the Healthy Eating Index-2015. Repeated measures mixed-effect regression will assess differences in outcomes between groups from baseline to 16 weeks post-intervention. Furthermore, 25-30 participants will partake in semi-structured interviews during and 5 weeks after programme completion to explore participants' experiences with and perceived outcomes from the programme. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Calgary Conjoint Health Research Ethics Board, Rutgers University Ethics and Compliance, and University of Waterloo Office of Research Ethics. Findings will be disseminated through policy briefs, conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03952338.

Stereoselective synthesis of (+)-euphococcinine and (-)-adaline.

We describe the syntheses of (+)-euphococcinine and (-)-adaline, two naturally occurring alkaloids containing a quaternary carbon bearing a nitrogen atom. Key features of the syntheses are a 3,3-sigmatropic rearrangement to give an all-carbon quaternary center, a ring-closing alkene metathesis to give an 8-membered ring, and the use of a single enantiomer of p-menthane-3-carboxaldehyde to make two natural alkaloids of opposite configuration.

Characterizing the memory changes in persons with mild cognitive impairment.

Persons with mild cognitive impairment (MCI) do not meet criteria for Alzheimer's disease (AD) but are at high risk for developing the disease. Presence of a memory deficit is a key component in the characterization of MCI. This chapter presents empirical studies that attempt to describe and understand the nature of the memory deficit in MCI with a focus on episodic memory and working memory. Cross-sectional studies report prominent deficits of episodic memory characterized by impaired encoding of the contextual information that makes up complex events. This results in reduced free and cued recall, impaired recognition, and impaired associative learning. Although semantic encoding is found to be impaired in conditions that rely on explicit and intentional retrieval, preserved semantic processing is found with automatic conditions of testing. Studies indicate the presence of a partial deficit of working memory with the ability to divide attention being most severely impaired. However, there appears to be heterogeneity as to the extent of the working memory impairment. The presence of vascular anomalies on MRI, as well as being in a more advanced stage in the continuum from MCI to AD, are associated with more severe and more pervasive working memory deficits. Finally, longitudinal studies indicate that the combination of episodic and working memory deficits represents a strong predictor of progression from MCI to AD.

Stereocontrolled formation of amino acids and N-heterocycles bearing a quaternary chiral carbon.

Stereocontrolled formation of tertiary or quaternary chiral carbons bearing nitrogen was achieved using the [3,3]-sigmatropic rearrangement of cyanate to isocyanate as a key element. A short and highly selective sequence of reactions, starting from p-menthane-3-carboxaldehyde, was developed leading to alpha,alpha-dialkylated alpha-amino acids or N-heterocycles, depending on the method of cleavage of the auxiliary.

The DNA methyltransferase DNMT3C protects male germ cells from transposon activity.

DNA methylation is prevalent in mammalian genomes and plays a central role in the epigenetic control of development. The mammalian DNA methylation machinery is thought to be composed of three DNA methyltransferase enzymes (DNMT1, DNMT3A, and DNMT3B) and one cofactor (DNMT3L). Here, we describe the discovery of Dnmt3C, a de novo DNA methyltransferase gene that evolved via a duplication of Dnmt3B in rodent genomes and was previously annotated as a pseudogene. We show that DNMT3C is the enzyme responsible for methylating the promoters of evolutionarily young retrotransposons in the male germ line and that this specialized activity is required for mouse fertility. DNMT3C reveals the plasticity of the mammalian DNA methylation system and expands the scope of the mechanisms involved in the epigenetic control of retrotransposons.

Unprecedented catalytic asymmetric reduction of N-H imines.

[Reaction: see text] Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones 1a-j affords (E)-N-TMS-ketimines 2a-j that are reduced in situ to afford racemic perfluoromethylated amine hydrochloride salts 3a-j in 54-97% yields. Solvolysis of the N-Si bond in MeOH leads to formation of bench-stable, isolable N-H imine Z/E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures provides the first catalytic asymmetric synthesis of trifluoromethylated amines in 72-95% yields and 75-98% ee.

Interindividual differences in attentional control profiles among younger and older adults.

This study aimed at characterizing the individual variability in three attentional control functions (shifting, inhibition, and updating), among 75 older and 75 younger adults. It also examined the intellectual and health variables associated with different cognitive profiles. Cluster analyses identified three separate attentional control profiles for both age groups, but the patterns of variability were strikingly different. Younger adults' profiles were characterized by homogeneous performance across domains and differed only in their overall level of performance. In contrast, older adults' profiles were characterized by uneven levels of performance across domains and inhibition stood out as critical in distinguishing between profiles. One subgroup of older adults had poor inhibition and more adverse lifestyle characteristics and appeared more cognitively vulnerable. In conclusion, subgroups of younger and older adults with different attentional control profiles can be identified, but the expression of variability changes with age as older adults' profiles become more heterogeneous.