Nkx2.1 regulates the proliferation and cell fate of telencephalic astrocytes during embryonic development

AbstractThe homeodomain transcription factor Nkx2.1 controls cell differentiation of telencephalic GABAergic interneurons and oligodendrocytes. Here, we show that Nkx2.1 additionally regulates astrogliogenesis of the telencephalon from embryonic day (E) 14.5 to E16.5. Our work aims to identify the different mechanisms by which Nkx2.1 controls telencephalic astrogliogenesis. InNkx2.1-/-, a drastic loss of astrocytes is observed which is not related to cell death.In vivoanalysis using BrdU incorporation reveals that Nkx2.1 affects the proliferation of ventral neural stem cells that generate early astrocytes.In vitroneurosphere assays show that Nkx2.1 additionally affects the differentiation step of Nkx2.1-derived astrocytes. Chromatin immunoprecipitation andin vitroco-transfection studies of a Nkx2.1-expressing plasmid indicate that Nkx2.1 binds to the promoter of astroglial differentiation gene GFAP, and regulates its expression. Hence, Nkx2.1 controls astroglial production spatiotemporally in embryos by regulating stem cell division and specification of the contributing Nkx2.1+precursors.</jats:p

Citizen advisory groups for the creation and improvement of decision aids: experience from two Swiss centers for primary care.

Guidelines for patient decision aids (DA) recommend target population involvement throughout the development process, but developers may struggle because of limited resources. We sought to develop a feasible means of getting repeated feedback from users. Between 2017 and 2020, two Swiss centers for primary care (Lausanne and Bern) created citizen advisory groups to contribute to multiple improvement cycles for colorectal, prostate and lung cancer screening DAs. Following Community Based Participatory Research principles, we collaborated with local organizations to recruit citizens aged 50 to 75 without previous cancer diagnoses. We remunerated incidental costs and participant time. One center supplemented in-person meetings by mailed paper questionnaires, while the other supplemented meetings using small-group workshops and analyses of meeting transcripts. In Lausanne, we received input from 49 participants for three DAs between 2017 and 2020. For each topic, participants gave feedback on the initial draft and 2 subsequent versions during in-person meetings with ~ 8 participants and one round of mailed questionnaires. In Bern, 10 participants were recruited among standardized patients from the university, all of whom attended in-person meetings every three months between 2017 and 2020. At both sites, numerous changes were made to the content, appearance, language, and tone of DAs and outreach materials. Participants reported high levels of satisfaction with the participative process. Citizen advisory groups are a feasible means of repeatedly incorporating end-user feedback during the creation of multiple DAs. Methodological differences between the two centers underline the need for a flexible model adapted to local needs

May direct-to-consumer genetic testing have an impact on general practitioners' daily practice? a cross-sectional study of patients' intentions towards this approach.

Direct-to-consumer genetic testing (DTCGT) offers individuals access to information on their probable risks of suffering from a wide range of chronic diseases. General practitioners (GPs) will probably play a major role in supporting its use, but patients' perception of DTCGT remain unclear. This study aimed to describe those attitudes and expectations and how they might affect GPs' daily practices. In 2018-2019, a study related to the use of DTCGT for preventive care in general medicine was conducted among patients in Switzerland's French-speaking areas. Data were collected in the waiting room using a self-administrated questionnaire about patients' interest in DTCGT and what their attitudes might be if testing revealed an elevated risk of diabetes, colorectal cancer, or Alzheimer's disease. About 40% of the 929 participating (participation rate about 80%) patients had heard about DTCGT and, once the test had been explained, 43% reported that they would be interested in being tested. If that testing suggested an elevated risk of disease, the majority of patients reported that they would change their lifestyle (65%-81%, depending on the disease), request more examinations (63%-77%), and expect changes in their GP's follow-up (48%-59%). Personal characteristics such as sex, age, urbanity, marital status, and perceived health were factors predictive of patients' attitudes. Findings indicated that the generalization of DTCGT might affect GPs' daily practices in terms of workload and knowledge about this approach. However, this result must be qualified by the fact that it is based on hypothetical situations

Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior.

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying a deficiency in hippocampal glucose metabolism as the underlying molecular/physiological origin of the markers, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point toward the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential

Effect of glycerol and dimethyl sulfoxide on the phase behavior of lysozyme: Theory and experiments

Salt, glycerol and dimethyl sulfoxide (DMSO) are used to modify the properties of protein solutions. We experimentally determined the effect of these additives on the phase behavior of lysozyme solutions. Upon the addition of glycerol and DMSO, the fluid-solid transition and the gas-liquid coexistence curve (binodal) shift to lower temperatures and the gap between them increases. The experimentally observed trends are consistent with our theoretical predictions based on the thermodynamic perturbation theory (TPT) and the Derjaguin-Landau-Verwey-Overbeek (DLVO) model for the lysozyme-lysozyme pair interactions. The values of the parameters describing the interactions, namely the refractive indices, dielectric constants, Hamaker constant and cut-off length, are extracted from literature or are experimentally determined by independent experiments, including static light scattering to determine the second virial coefficient. We observe that both, glycerol and DMSO, render the potential more repulsive, while sodium chloride reduces the repulsion.Comment: Manuscript accepted for publication in The Journal of Chemical Physic

Multiple glass transitions in star polymer mixtures: Insights from theory and simulations

The glass transition in binary mixtures of star polymers is studied by mode coupling theory and extensive molecular dynamics computer simulations. In particular, we have explored vitrification in the parameter space of size asymmetry $\delta$ and concentration $\rho_2$ of the small star polymers at fixed concentration of the large ones. Depending on the choice of parameters, three different glassy states are identified: a single glass of big polymers at low $\delta$ and low $\rho_2$, a double glass at high $\delta$ and low $\rho_2$, and a novel double glass at high $\rho_2$ and high $\delta$ which is characterized by a strong localization of the small particles. At low $\delta$ and high $\rho_2$ there is a competition between vitrification and phase separation. Centered in the $(\delta, \rho_2)$-plane, a liquid lake shows up revealing reentrant glass formation. We compare the behavior of the dynamical density correlators with the predictions of the theory and find remarkable agreement between the two.Comment: 15 figures, to be published in Macromolecule

A Passive Monitoring System in Assisted Living Facilities: 12-Month Comparative Study

The GE QuietCare® passive monitoring system uses advanced motion sensor technology that learns the daily living patterns of senior community residents and sends alerts when certain out-of-the-ordinary events occur. This study compared falls, hospitalizations, care level changes, and resident attrition between two similar assisted living facilities where one facility adopted the QuietCare® monitoring system and the other did not over a 12-month period. Average falls per week were significantly lower in the QuietCare® facility than the control facility. There was also a trend toward fewer weekly hospitalizations in the QuietCare® facility. There was higher resident retention at the QuietCare® facility. This study provides evidence of direct benefits to both the resident and the facility for the use of QuietCare®. There was a significant reduction in the number of falls, as well as a general facility performance improvement measured by care level consistency and higher resident retention rates

Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPβ

[Background] The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer-binding protein β is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein β and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells.[Methods] Adult male Wistar rats (8–12 weeks old) were used throughout the study. C/EBPβ+/+ and C/EBPβ–/– mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein β and C3.[Results] In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein β and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein β knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPβ in the hippocampus in vivo.[Conclusions] Altogether these results suggest that CCAAT/enhancer-binding protein β could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3.This work was supported by MINECO, Grant SAF2014-52940-R and partially financed with FEDER funds. CIBERNED is funded by the Instituto de Salud Carlos III. JAM-G was supported by CIBERNED. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe