Very large G protein-coupled receptor 1 regulates myelin-associated glycoprotein via Gαs/Gαq-mediated protein kinases A/C.

VLGR1 (very large G protein-coupled receptor 1), also known as MASS1 (monogenic audiogenic seizure susceptible 1), is an orphan G protein-coupled receptor that contains a large extracellular N terminus with 35 calcium-binding domains. A truncating mutation in the Mass1 gene causes autosomal recessive, sound-induced seizures in the Frings mouse. However, the function of MASS1 and the mechanism underlying Frings mouse epilepsy are not known. Here, we found that MASS1 protein is enriched in the myelinated regions of the superior and inferior colliculi, critical areas for the initiation and propagation of audiogenic seizures. Using a panel of myelin antibodies, we discovered that myelin-associated glycoprotein (MAG) expression is dramatically decreased in Frings mice. MASS1 inhibits the ubiquitylation of MAG, thus enhancing the stability of this protein, and the calcium-binding domains of MASS1 are essential for this regulation. Furthermore, MASS1 interacts with Gαs/Gαq and activates PKA and PKC in response to extracellular calcium. Suppression of signaling by MASS1 RNAi or a specific inhibitor abrogates MAG up-regulation. We postulate that MASS1 senses extracellular calcium and activates cytosolic PKA/PKC pathways to regulate myelination by means of MAG protein stability in myelin-forming cells of the auditory pathway. Further work is required to determine whether MAG dysregulation is a cause or consequence of audiogenic epilepsy and whether there are other pathways regulated by MASS1

MicroRNA-23a promotes myelination in the central nervous system.

Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR-23a-overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23a targets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a-dependent manner. The data presented here imply a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin

Paper-based tuberculosis diagnostic devices with colorimetric gold nanoparticles

A colorimetric sensing strategy employing gold nanoparticles and a paper assay platform has been developed for tuberculosis diagnosis. Unmodified gold nanoparticles and single-stranded detection oligonucleotides are used to achieve rapid diagnosis without complicated and time-consuming thiolated or other surface-modified probe preparation processes. To eliminate the use of sophisticated equipment for data analysis, the color variance for multiple detection results was simultaneously collected and concentrated on cellulose paper with the data readout transmitted for cloud computing via a smartphone. The results show that the 2.6 nM tuberculosis mycobacterium target sequences extracted from patients can easily be detected, and the turnaround time after the human DNA is extracted from clinical samples was approximately 1 h

Electrochemical-driven water reduction catalyzed by a water soluble cobalt(III) complex with Schiff base ligand

A B S T R A C T A new molecular catalyst based on cobalt complex [LCoCl] (1) is formed by the reaction of N, N-dimethylethylenediamino-N,N-bis(2,4-dimethyl) phenol (H 2 L) with CoCl 2 Á6H 2 O for electrolytic water reduction. To our knowledge 1 is by far the most active electrocatalyst for hydrogen generation from water with a turnover frequency (TOF) of 2744 mol of hydrogen per mole of catalyst per hour at an overpotential of À638 mV (pH 7.0). This is attributed to the ionic ligand, L 2À , that coordinates strongly through two nitrogen atoms and two oxygen atoms to the cobalt center, leaving one Cl À ion in axial position and making the Cl À ion ionize in water

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait.

In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes

“I can’t see an end in sight.” How the COVID-19 pandemic may influence suicide risk: a qualitative study

<jats:p> Zusammenfassung: Theoretischer Hintergrund: Das Ziel der vorliegenden Studie war es, eine deutschsprachige Adaptation der Bergen Study Addiction Scale (BStAS), einer Skala zur Erfassung von exzessivem Studierverhalten, zu entwickeln und zu validieren. Methode: Die Daten von 615 Studierenden wurden analysiert. Die Dimensionalität der BStAS wurde mittels konfirmatorischer Faktorenanalyse überprüft. Außerdem wurden Korrelations- und hierarchische Regressionsanalysen durchgeführt, um Zusammenhänge von exzessivem Studierverhalten mit Persönlichkeit und Gesundheit zu untersuchen. Ergebnisse: Der Vergleich mit Dynamic Fit Index Cutoffs deutete auf eine moderate Missspezifikation des einfaktoriellen Modells hin. Wie erwartet war exzessives Studierverhalten positiv mit wöchentlichen Lernstunden, Neurotizismus, wahrgenommenem Stress, psychosomatischen Beschwerden und Schlafproblemen assoziiert und hing negativ mit Lebenszufriedenheit zusammen. Schlussfolgerung: Es ist fraglich, ob alle Items der BStAS Aspekte einer Verhaltenssucht erfassen. Die Ergebnisse legen dennoch nahe, dass die BStAS ein Studierverhalten misst, das in Bezug auf physische und psychische Gesundheit von Relevanz ist. </jats:p&gt

Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells.

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic shock in Fadd-/-Ripk3-/- mice, implying distinct death processes in other cell types. Cathepsin-B contributes to IETD-mediated inflammasome activation, as its inhibition or down-regulation limited IETD-elicited IL-1β production. Therefore, the autophagy and cathepsin-B axis represents one of the pathways leading to atypical inflammasome activation when apoptosis and necroptosis are suppressed and capase-8 is inhibited in myeloid cells

Effect of total flavones of buckwheat flowers and leaves on protein tyrosine phosphatase 1B expression in type 2 diabetic rats

The total flavone content was obtained from flowers and leaf of buckwheat (Fagopyrum esculentum Moench) by heating reflux method. The effects of the total flavone extract on the protein tyrosine phosphatase 1B (PTP1B) expression in type 2 diabetic rats were evaluated by immunofluorescence, western blotting and real-time quantitative PCR. The results suggested that the total flavone fraction from buckwheat flowers and leaves can significantly decrease the PTP1B expression in liver.Colegio de Farmacéuticos de la Provincia de Buenos Aire