Proliferation versus Differentiation: Redefining Retinoic Acids Role.

Retinoic acid is commonly used in culture to differentiate stem cells into neurons and has established neural differentiation functions in vivo in developing and adult organisms. In this issue of Stem Cell Reports, Mishra et al. (2018) broaden its role in stem cell functions, showing that retinoic acid is necessary for stem and progenitor cell proliferation in the adult brain

Proliferation versus Differentiation: Redefining Retinoic Acids Role.

Retinoic acid is commonly used in culture to differentiate stem cells into neurons and has established neural differentiation functions in vivo in developing and adult organisms. In this issue of Stem Cell Reports, Mishra et al. (2018) broaden its role in stem cell functions, showing that retinoic acid is necessary for stem and progenitor cell proliferation in the adult brain

Recapitulating complex biological signaling environments using a multiplexed, DNA-patterning approach.

Elucidating how the spatial organization of extrinsic signals modulates cell behavior and drives biological processes remains largely unexplored because of challenges in controlling spatial patterning of multiple microenvironmental cues in vitro. Here, we describe a high-throughput method that directs simultaneous assembly of multiple cell types and solid-phase ligands across length scales within minutes. Our method involves lithographically defining hierarchical patterns of unique DNA oligonucleotides to which complementary strands, attached to cells and ligands-of-interest, hybridize. Highlighting our method's power, we investigated how the spatial presentation of self-renewal ligand fibroblast growth factor-2 (FGF-2) and differentiation signal ephrin-B2 instruct single adult neural stem cell (NSC) fate. We found that NSCs have a strong spatial bias toward FGF-2 and identified an unexpected subpopulation exhibiting high neuronal differentiation despite spatially occupying patterned FGF-2 regions. Overall, our broadly applicable, DNA-directed approach enables mechanistic insight into how tissues encode regulatory information through the spatial presentation of heterogeneous signals

Preclinical Assessment of Young Blood Plasma for Alzheimer Disease

Importance: Alzheimer disease (AD) pathology starts long before clinical symptoms manifest, and there is no therapy to treat, delay, or prevent the disease. A shared blood circulation between 2 mice (aka parabiosis) or repeated injections of young blood plasma (plasma from 2- to 3-month-old mice) into old mice has revealed benefits of young plasma on synaptic function and behavior. However, to our knowledge, the potential benefit of young blood has not been tested in preclinical models of neurodegeneration or AD. Objectives: To determine whether young blood plasma ameliorates pathology and cognition in a mouse model for AD and could be a possible future treatment for the disease. Design, Setting, and Participants: In this preclinical study, mice that harbor a human mutant APP gene, which causes familial AD, were aged to develop AD-like disease including accumulation of amyloid plaques, loss of synaptic and neuronal proteins, and behavioral deficits. The initial parabiosis studies were done in 2010, and the final studies were conducted in 2014. Alzheimer disease model mice were then treated either by surgically connecting them with a young healthy mouse, thus providing a shared blood circulation through parabiosis, or through repeated injections of plasma from young mice. Main Outcomes and Measures: Neuropathological parameters and changes in hippocampal gene expression in response to the treatment were assessed. In addition, cognition was tested in AD model mice intravenously injected with young blood plasma. Results: Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14). Amyloid plaques were not affected, but the beneficial effects in neurons in the hippocampus were accompanied by a reversal of abnormal extracellular receptor kinase signaling (P = .05), a kinase implicated in AD. Moreover, young plasma administration was associated with improved working memory (P = .01) and associative memory (P = .02) in amyloid precursor protein mice. Conclusions and Relevance: Factors in young blood have the potential to ameliorate disease in a model of AD

Microglial Beclin 1 Regulates Retromer Trafficking and Phagocytosis and Is Impaired in Alzheimer's Disease

SummaryPhagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer’s disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD

Women's preferences for contraceptive counseling and decision making

BACKGROUND: Little is known about what women value in their interactions with family planning providers and in decision making about contraception. STUDY DESIGN: We conducted semistructured interviews with 42 black, white and Latina patients. Transcripts were coded using modified grounded theory. RESULTS: While women wanted control over the ultimate selection of a method, most also wanted their provider to participate in the decision-making process in a way that emphasized the women’s values and preferences. Women desired an intimate, friend-like relationship with their providers and also wanted to receive comprehensive information about options, particularly about side effects. More black and Spanish-speaking Latinas, as compared to whites and English-speaking Latinas, felt that providers should only share their opinion if it is elicited by a patient or if they make their rationale clear to the patient. CONCLUSION: While, in the absence of medical contraindications, decision making about contraception has often been conceptualized as a woman’s autonomous decision, our data indicate that providers of contraceptive counseling can participate in the decision-making process within limits. Differences in preferences seen by race/ethnicity illustrate one example of the importance of individualizing counseling to match women’s preferences

Bringing Patients' Social Context into the Examination Room: An Investigation of the Discussion of Social Influence During Contraceptive Counseling

BackgroundAlthough social networks are an increasingly recognized influence on contraceptive use, little is known about if and how social influences are discussed during women's contraceptive counseling visits.MethodsWe performed a mixed-methods analysis of audio recordings of contraceptive counseling visits. We examined predictors of discussion of social influence arising in a contraceptive counseling visit and analyzed the content and process of social influence discussions.ResultsSocial influences were mentioned in 42% of the 342 visits included in the sample, with these discussions most commonly initiated by patients. Younger patients were more likely to have social influence mentioned than older patients. The content of social influence focused on side effects and adverse events, with the sources of influence being predominantly patients' friends and the media, with little input from partners. Providers were more likely to engage around the content of the social influence than the social influence itself.ConclusionThe frequency with which social influence was mentioned in these visits supports the importance of women's social context on their contraceptive decision making. However, the fact that patients initiated the discussion in the majority of cases suggests that providers may not recognize the relevance of these influences or may not be comfortable engaging with them. Increasing providers' ability to elicit and engage patients about their social context with regard to contraception could enhance providers' ability to understand women's contraceptive preferences and provide appropriate counseling to address their specific concerns or questions