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ObjectiveThe gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. While human genetic variants near APOE and TOMM40 have been shown to be strongly associated with plasma lipid levels, a specific role for TOMM40 in lipid metabolism has not been established, and the present study was aimed at assessing this possibility.MethodsTOMM40 was knocked down by siRNA in human hepatoma HepG2 cells, and effects on mitochondrial function, lipid phenotypes, and crosstalk between mitochondria, ER, and lipid droplets were examined. Additionally, hepatic and plasma lipid levels were measured in mice following shRNA-induced knockdown of Tomm40 shRNA.ResultsIn HepG2 cells, TOMM40 knockdown upregulated expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content were increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining was significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content was reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice resulted in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis.ConclusionsThese findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

IntroductionUnhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub-Saharan Africa (SSA).MethodsAs part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills-based alcohol intervention among PWH with self-reported unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non-suppression, defined as either recent HIV viral non-suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3-month in-person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (200 ng/ml (RR 0.97, 95% CI: 0.92-1.02).ConclusionsIn a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non-suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV-associated co-morbidities.

IntroductionUnhealthy alcohol use is associated with a range of adverse outcomes among people with HIV (PWH). Testing the efficacy and promoting the availability of effective interventions to address unhealthy alcohol use among PWH is thus a priority. Alcohol use outcomes in intervention studies are often measured by self-report alone, which can lead to spurious results due to information biases (eg, social desirability). Measuring alcohol outcomes objectively through biomarkers, such as phosphatidylethanol (PEth), in addition to self-report has potential to improve the validity of intervention studies. This protocol outlines the methods for a systematic review and individual participant data meta-analysis that will estimate the efficacy of interventions to reduce alcohol use as measured by a combined categorical self-report/PEth variable among PWH and compare these estimates to those generated when alcohol is measured by self-report or PEth alone.Methods and analysisWe will include randomised controlled trials that: (A) tested an alcohol intervention (behavioural and/or pharmacological), (B) enrolled participants 15 years or older with HIV; (C) included both PEth and self-report measurements, (D) completed data collection by 31 August 2023. We will contact principal investigators of eligible studies to inquire about their willingness to contribute data. The primary outcome variable will be a combined self-report/PEth alcohol categorical variable. Secondary outcomes will include PEth alone, self-report alone and HIV viral suppression. We will use a two-step meta-analysis and random effects modelling to estimate pooled treatment effects; I2 will be calculated to evaluate heterogeneity. Secondary and sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots will be used to explore publication bias.Ethics and disseminationThe study will be conducted with deidentified data from completed randomised controlled trials and will be considered exempt from additional ethical approval. Results will be disseminated through peer-reviewed publications and international scientific meetings.Prospero registration numberCRD42022373640.

As students enter the upper elementary grades, word problems become a main component of mathematics instruction, increasing in complexity as students advance through the curriculum. For students identified as emergent bilinguals with mathematics difficulty (MD), the linguistic complexity inherent in word problems may serve as a barrier to word-problem proficiency. The current study investigated the potential relation between academic English proficiency and word-problem outcomes for emergent bilinguals with MD. After analyzing data from 241 third-grade students, results indicated students who participated in an evidence-based word-problem intervention outperformed students who did not receive the intervention. Moreover, students' academic English-language proficiency scores in the domains of reading and writing positively correlated with higher scores on a measure of word-problem solving.

Increasingly, students must demonstrate knowledge in mathematics through mathematics writing, yet research lags in understanding how students engage in mathematics-writing tasks. Most available research on mathematics writing focuses on typically achieving students without considering students with mathematics difficulty (MD). In this study, we explored how students with MD who participated in a word-problem intervention randomized-control trial performed on a mathematics-writing task. We sampled 144 third-grade students with MD and evaluated student performance on an explanatory mathematics-writing measure. Overall, students with MD, on a mathematics-writing rubric with five categories, scored between 1 and 2 points out of a possible 5 points for each category. For one of the five rubric categories, Mathematics Content, the students in the word-problem interventions marginally outperformed the students in the business-as-usual condition. On average, students wrote 33.3 words, numbers, and symbols in response to the mathematics-writing prompt with an average of 8.7 mathematics vocabulary words. Of the mathematics vocabulary words used, students most frequently used formal mathematics vocabulary and names for symbolic numbers, with symbolic symbols and general vocabulary used to a lesser extent. The trends in this study will support future research to enhance mathematics-writing instruction.

BACKGROUND: The use of biomarkers in behavioral HIV research can help to address limitations of self-reported data. The COVID-19 pandemic forced many researchers to transition from standard in-person data collection to remote data collection. We present data on the feasibility of remote self-collection of dried blood spots (DBS), hair, and nails for the objective assessment of alcohol use, antiretroviral therapy adherence, and stress in a sample of people with HIV (PWH) who are hazardous drinkers. METHODS: Standardized operating procedures for remote self-collection of DBS, hair, and nails were developed for an ongoing pilot study of a transdiagnostic alcohol intervention for PWH. Prior to each study appointment, participants were mailed a kit containing materials for self-collection, instructions, a video link demonstrating the collection process, and a prepaid envelope for returning samples. RESULTS: A total of 133 remote study visits were completed. For DBS and nail collection at baseline, 87.5% and 83.3% of samples, respectively, were received by the research laboratory, of which 100% of samples were processed. Although hair samples were intended to be analyzed, most of the samples (77.7%) were insufficient or the scalp end of the hair was not marked. We, therefore, decided that hair collection was not feasible in the framework of this study. CONCLUSION: An increase in remote self-collection of biospecimens may significantly advance the field of HIV-related research, permitting the collection of specimens without resource-intensive laboratory personnel and facilities. Further research is needed on the factors that impeded participants ability to complete remote biospecimen collection.

PURPOSE: To test the efficacy of two interventions to reduce alcohol use and increase viral suppression compared to a control in persons with HIV (PWH). METHODS: In a three-arm (1:1:1) randomized controlled trial (N = 269), we compared in-person counselling (45-70 minutes, two sessions over three months) with interim monthly booster phone calls (live call arm) or twice-weekly automated booster sessions (technology arm) to a brief advice control arm. We enrolled PWH self-reporting unhealthy alcohol use (Alcohol Use Disorders Identification Test - Consumption, prior three months, women ≥3, men ≥4). Primary outcomes were number of self-reported drinking days (NDD) in the prior 21 and biomarker phosphatidylethanol (PEth) at six and nine months and viral suppression (

Understanding rational numbers is critical for secondary mathematics achievement. However, students with mathematics difficulties (MD) struggle with rational number topics, including fractions, decimals, and percentages. The purpose of this systematic review was to describe the instructional foci of rational number interventions, determine the overall effect size, and explore potential moderators. Forty-three studies were included and 150 effect sizes were meta-analyzed using robust variance estimation. The majority of studies focused on teaching fraction magnitude and arithmetic. An overall effect size of g = 1.02 [0.80, 1.25] was found for rational number interventions favoring treatment conditions over business as usual control. Proximal measures contributed to higher effect sizes than distal measures. Limitations included a high number of fraction interventions contributing to the overall effect size and a large amount of heterogeneity among study effect sizes.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimers disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

Background: Brief alcohol reduction interventions for people living with HIV (PLWH) have resulted in mixed findings with some studies showing null or limited treatment effects. To better understand factors that may contribute to their success or failure, this qualitative study sought to explore participants experiences in a randomized trial (RCT) of a brief counseling-based alcohol reduction intervention, including challenges that may have impeded alcohol reduction. Methods: We conducted in-depth semi-structured interviews with 24 PLWH engaging in unhealthy alcohol use, who were enrolled in an RCT to reduce alcohol consumption conducted in southwestern Uganda in 2019-2020 (NCT03928418). We used a collaborative thematic approach to analyze data from transcribed and translated audio recordings. Results: Perceived benefits of the intervention included increased awareness of alcohol use and its impact on personal finances, the relationship between alcohol use and violence, and a commitment to drinking reduction. Participants experienced several barriers to decreasing their alcohol use, including: prevailing social norms about alcohol use, lack of social support, and economic and social consequences of the COVID-19 pandemic. Conclusion: Factors in the immediate contexts of PLWH in low-income settings, including social norms influencing alcohol consumption and lack of social support, may impede the impact of alcohol reduction interventions, especially during times of stress such as the COVID-19 pandemic.

Polarization-dependent photoemission electron microscopy (PD-PEEM) exploits spatial variation in the optical selection rules of materials to image domain formation and material organization on the nanoscale. In this Perspective, we discuss the mechanism of PD-PEEM that results in the observed image contrast in experiments and provide examples of a wide range of material domain structures that PD-PEEM has been able to elucidate, including molecular and polymer domains, local electronic structure and defect symmetry, (anti)ferroelectricity, and ferromagnetism. In the end, we discuss challenges and new directions that are possible with this tool for probing domain structure in materials, including investigating the formation of transient ordered states, multiferroics, and the influence of molecular and polymer order and disorder on excited state dynamics and charge transport. [ABSTRACT FROM AUTHOR]

An understanding of concepts related to geometric measurement is considered to be critical to the development of individuals' mathematics knowledge. Specifically, the National Mathematics Advisory Panel's 2008 report listed the skills of area and perimeter as foundational for algebra readiness. Yet, this content knowledge continues to be an underdeveloped skill area for many school-age children and especially those with learning disabilities. This article provides educators with the following four strategies that are grounded in research and can be implemented during instruction on area and perimeter: (1) instruction using manipulatives; (2) focusing on salient variables within problems; (3) utilizing visual-chunking representations; and (4) incorporating contextualized scenarios and experiences.

The integration of ideas, defined as the process by which students organize and connect new knowledge for deeper understanding, is essential for lifelong learning. (Government of Canda, Employment and Social Development Canada, 2017; Rateau, Kaufman, & Cletzer, 2015). Integration across sub-disciplines in biology requires an understanding of organizational scales (molecular to ecosystems) and time frames (physiological to evolutionary), and how they inter-relate. The challenge lies in allowing students opportunity to integrate knowledge, given that sub-disciplines are taught in relative isolation through individual courses. To promote integration, we designed a poster assignment in which ~700 students in three foundation courses worked together (130 groups) to investigate empirical research in multiple subdisciplines. While a major goal was to enrich understanding by integrating knowledge, we also sought to develop transferable skills (e.g. teamwork, information literacy). Hence, this cross-course assignment provides benefits that exceed that of equivalent assignments in individual courses; we believe that "the whole is greater than the sum of the parts." Assignment grades indicated that the majority (81%) of students successfully met or exceeded our expectations. This assignment lends support to the positive impact of learning communities, is easily adapted to other disciplines, and aligns with calls for educational reform advocating for curiosity-driven learning (American Association for the Advancement of Science, 2011; Bradforth et al., 2015).

BackgroundAlcohol consumption is a critical driver of the HIV epidemic worldwide, particularly in sub-Saharan Africa, where unhealthy alcohol use and HIV are prevalent. Brief alcohol interventions are effective in reducing alcohol use; however, they depend on effective screening for unhealthy alcohol use, which is often underreported. Thus, there is a need to develop methods to improve reporting of unhealthy alcohol use as an essential step toward referral to brief alcohol interventions. Self-administered digital health screeners may improve reporting.ObjectiveThis study aimed to develop and test a digital, easy-to-use self-administered health screener. The health screener was designed to be implemented in a busy, underresourced HIV treatment setting and used by patients with varying levels of literacy.MethodsWe conducted a qualitative study at the Immune Suppression Syndrome (ISS) Clinic of Mbarara Regional Referral Hospital in Uganda to develop and test a digital self-administered health screener. The health screener included a training module and assessed behaviors regarding general health, HIV care, and mental health as well as sensitive topics such as alcohol use and sexual health. We conducted focus group discussions with clinicians and patients with HIV of the Mbarara ISS Clinic who consumed alcohol to obtain input on the need for and content, format, and feasibility of the proposed screener. We iteratively revised a tablet-based screener with a subset of these participants, piloted the revised screener, and conducted individual semistructured in-depth interviews with 20 participants who had taken part in our previous studies on alcohol and HIV, including those who had previously underreported alcohol use and with low literacy.ResultsA total of 45 people (n=5, 11% clinicians and n=40, 89% Mbarara ISS Clinic patients) participated in the study. Of the patient participants, 65% (26/40) were male, 43% (17/40) had low literacy, and all (40/40, 100%) had self-reported alcohol use in previous studies. Clinicians and patients cited benefits such as time savings, easing of staff burden, mitigation of patient-provider tension around sensitive issues, and information communication, but also identified areas of training required, issues of security of the device, and confidentiality concerns. Patients also stated fear of forgetting how to use the tablet, making mistakes, and losing information as barriers to uptake. In pilot tests of the prototype, patients liked the feature of a recorded voice in the local language and found the screener easy to use, although many required additional help and training from the study staff to complete the screener.ConclusionsWe found a self-administered digital health screener to be appealing to patients and clinicians and usable in a busy HIV clinic setting, albeit with concerns about confidentiality and training. Such a screener may be useful in improving reporting of unhealthy alcohol use for referral to interventions.

Hazardous drinking by persons living with HIV (PLHIV) is a well-established determinant of sub-optimal HIV care and treatment outcomes. Despite this, to date, few interventions have sought to reduce hazardous drinking among PLHIV in sub-Saharan Africa (SSA). We describe an iterative cultural adaptation of an evidence-based multi-session alcohol reduction intervention for PLHIV in southwestern Uganda. The adaptation process included identifying core, theoretically informed, intervention elements, and conducting focus group discussions and cognitive interviews with community members, HIV clinic staff and patients to modify key intervention characteristics for cultural relevance and saliency. Adaptation of evidence-based alcohol reduction interventions can be strengthened by the inclusion of the target population and key stakeholders in shaping the content, while retaining fidelity to core intervention elements.

Objective: College students are among the age-group most affected by sexually transmitted infections, yet few evidence-based interventions have proved effective in increasing college student condom use. The goal of this study was to determine which combination of referent proximity and width of discrepancy between perceived and actual norms within a normative feedback intervention produced the greatest motivation to increase condom use among US college students. Design: A 2 (proximity) × 2 (width of discrepancy) × 2 (gender) randomised-factorial experiment was conducted. Setting: Sexually active college students (N = 212; 50.5% female; 70.4% White) were recruited via Amazon Mechanical Turk, an online labour market. Method: Participants were randomised, stratified by gender, to one of four sham feedback conditions--proximal referent wide discrepancy, proximal referent narrow discrepancy, distal referent wide discrepancy and distal referent narrow discrepancy. Following delivery of the feedback, participants completed measures assessing their willingness to change their condom use. Results: A three-way factorial analysis of covariance revealed a significant interaction between referent proximity and width of discrepancy (F = 7.88, p = 0.005, [partial eta squared] = 0.04), such that the effect of proximity on willingness to use condoms was greater in the narrow, compared with wide, discrepancy condition. Conclusion: Findings from this study indicate that it may be beneficial to assess students' perceptions of their peers' sexual behaviour before selecting the reference group to include within normative feedback. This is the first study to demonstrate that the importance of selecting referents within normative feedback may be dependent on the accuracy of students' perceptions.

BackgroundFoods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate.ObjectiveWe aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition.MethodsWe performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based 'Run-In' diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution.ResultsCompared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group.ConclusionsThese results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.