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Lipids orchestrate biological processes by acting remotely as signaling molecules or locally as membrane components that modulate protein function. Detailed insight into lipid function requires knowledge of the subcellular localization of individual lipids. We report an analysis of the subcellular lipidome of the mammalian macrophage, a cell type that plays key roles in inflammation, immune responses, and phagocytosis. Nuclei, mitochondria, endoplasmic reticulum (ER), plasmalemma, and cytoplasm were isolated from RAW 264.7 macrophages in basal and activated states. Subsequent lipidomic analyses of major membrane lipid categories identified 229 individual/isobaric species, including 163 glycerophospholipids, 48 sphingolipids, 13 sterols, and 5 prenols. Major subcellular compartments exhibited substantially divergent glycerophospholipid profiles. Activation of macrophages by the Toll-like receptor 4-specific lipopolysaccharide Kdo(2)-lipid A caused significant remodeling of the subcellular lipidome. Some changes in lipid composition occurred in all compartments (e.g., increases in the levels of ceramides and the cholesterol precursors desmosterol and lanosterol). Other changes were manifest in specific organelles. For example, oxidized sterols increased and unsaturated cardiolipins decreased in mitochondria, whereas unsaturated ether-linked phosphatidylethanolamines decreased in the ER. We speculate that these changes may reflect mitochondrial oxidative stress and the release of arachidonic acid from the ER in response to cell activation.

Latino students are increasingly represented in higher education within the United States, but remain one of the groups least likely to graduate from a four-year institution. Stress and sleep are factors that have been implicated in students' academic success. This study examined concurrent and longitudinal interactive effects of stress and sleep on academic cognitions in a sample of 196 Latino students (Mage = 18.95; 64.4% female) in their second and third semester of college. Stress and actigraphy-measured sleep (duration, efficiency, midpoint, midpoint-variability) were measured in the second semester and academic cognitions (engagement, motivation, self-efficacy) were measured in the second and third semesters. Structural equation modeling revealed that higher stress was concurrently related to lower academic cognitions for students with consistently delayed sleep timings (e.g., later average midpoints) and longitudinally related to reduced academic functioning for students with lower sleep efficiency. These findings can inform programs that target stress-reduction and sleep hygiene among incoming college students. [ABSTRACT FROM AUTHOR]

Background: With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA) under way, we need markers that confirm the impact of genetic variants in patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement. Objective: To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI). Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PDGBA patients compared to PDGBA_wildtype patients. Results: Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype. (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype. (3) CSF levels of total α‐synuclein were lower in PDGBA compared to PDGBA_wildtype. All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PDGBA_severe. Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PDGBA_severe. Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood–brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B‐epoxide (CBE), an irreversible inhibitor of acid beta‐glucosidase (GCase), the enzyme defective in nGD, with or without co‐injection with Genz‐667161, a prototype for SRT which crosses the BBB. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co‐injection with Genz‐667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that Genz‐667161 largely reversed the changes in genes and pathways that were differentially expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain. [ABSTRACT FROM AUTHOR]

Culturally linked family influences during adolescence are important predictors of health and well-being for Latino youth, yet few studies have examined whether these familial influences are associated with indicators of typical physiological stress processes. Following a cultural neurobiology framework, we examined the role of family in the everyday lives of Latino adolescents (N = 209; M age = 18.10; 85.1% Mexican descent; 64.4% female) by investigating familism values and perceptions of parent support as well as daily family assistance behaviors in relation to hypothalamic–pituitary–adrenal axis diurnal patterns, indexed by salivary cortisol five times a day for 3 weekdays. Three-level growth curve analyses revealed that perceptions of parental support were associated with greater cortisol awakening responses, whereas familism values were not associated with diurnal cortisol patterns. In day-to-day analyses, assisting family during the day (compared to not assisting family) was associated with lower waking cortisol levels and flatter diurnal slopes the next day. Our findings highlight the dynamic associations and multiple time courses between cultural values and behaviors, daily experiences, and physiological stress processes for Latino adolescents. Further, we identified important cultural risk and promotive factors associated with physiological regulation in daily life and potential pathways toward health outcomes in adulthood. [ABSTRACT FROM AUTHOR]