Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF

<p>Abstract</p> <p>Background</p> <p>Environmental enrichment (EE) is known to enhance BDNF levels and neurogenesis in the adult hippocampus. To examine the role of BDNF in modulating EE-mediated adult hippocampal neurogenesis, we conditionally ablated <it>BDNF </it>expression in the hippocampus (cKO mice) and have assessed proliferation, survival, differentiation and dendritic development of hippocampal progenitors.</p> <p>Results</p> <p>We show that while the extent of cell proliferation and neuronal fate differentiation in the hippocampus of cKO mice is not different from wild-type (WT) littermates maintained in either standard or enriched conditions, reduced BDNF levels significantly impaired the survival of newborn cells in both housing conditions. In addition, while highly active enriched WT mice exhibited a robust increase in progenitor cell proliferation, highly active cKO mice showed a modest increase in cell proliferation compared to standard housed or underactive cKO mice.</p> <p>Conclusions</p> <p>There results argue that while BDNF plays a role in exercise-induced cell proliferation, other factors must contribute to this phenomenon. We also show that dendritic development was impaired in cKO mice maintained in standard housing conditions, and that EE rescued this phenotype.</p

Emergence of robust 2D skyrmions in SrRuO3 ultrathin film without the capping layer

Magnetic skyrmions have fast evolved from a novelty, as a realization of topologically protected structure with particle-like character, into a promising platform for new types of magnetic storage. Significant engineering progress was achieved with the synthesis of compounds hosting room-temperature skyrmions in magnetic heterostructures, with the interfacial Dzyaloshinskii-Moriya interactions (DMI) conducive to the skyrmion formation. Here we report findings of ultrathin skyrmion formation in a few layers of SrRuO3 grown on SrTiO3 substrate without the heavy-metal capping layer. Measurement of the topological Hall effect (THE) reveals a robust stability of skyrmions in this platform, judging from the high value of the critical field 1.57 Tesla (T) at low temperature. THE survives as the field is tilted by as much as 85 degrees at 10 Kelvin, with the in-plane magnetic field reaching up to 6.5 T. Coherent Bragg Rod Analysis, or COBRA for short, on the same film proves the rumpling of the Ru-O plane to be the source of inversion symmetry breaking and DMI. First-principles calculations based on the structure obtained from COBRA find significant magnetic anisotropy in the SrRuO3 film to be the main source of skyrmion robustness. These features promise a few-layer SRO to be an important new platform for skyrmionics, without the necessity of introducing the capping layer to boost the spin-orbit coupling strength artificially.Comment: Supplementary Information available upon reques

Emergence of robust 2D skyrmions in SrRuO3 ultrathin film without the capping layer

Magnetic skyrmions have fast evolved from a novelty, as a realization of topologically protected structure with particle-like character, into a promising platform for new types of magnetic storage. Significant engineering progress was achieved with the synthesis of compounds hosting room-temperature skyrmions in magnetic heterostructures, with the interfacial Dzyaloshinskii-Moriya interactions (DMI) conducive to the skyrmion formation. Here we report findings of ultrathin skyrmion formation in a few layers of SrRuO3 grown on SrTiO3 substrate without the heavy-metal capping layer. Measurement of the topological Hall effect (THE) reveals a robust stability of skyrmions in this platform, judging from the high value of the critical field 1.57 Tesla (T) at low temperature. THE survives as the field is tilted by as much as 85 degrees at 10 Kelvin, with the in-plane magnetic field reaching up to 6.5 T. Coherent Bragg Rod Analysis, or COBRA for short, on the same film proves the rumpling of the Ru-O plane to be the source of inversion symmetry breaking and DMI. First-principles calculations based on the structure obtained from COBRA find significant magnetic anisotropy in the SrRuO3 film to be the main source of skyrmion robustness. These features promise a few-layer SRO to be an important new platform for skyrmionics, without the necessity of introducing the capping layer to boost the spin-orbit coupling strength artificially.Comment: Supplementary Information available upon reques

Plug-Based Microfluidics with Defined Surface Chemistry to Miniaturize and Control Aggregation of Amyloidogenic Peptides

Small with control: For miniaturization of protein aggregation experiments the interfacial chemistry must be controlled to avoid protein aggregation caused by interfacial adsorption. Plug-based microfluidics with defined surface chemistry (see schematic picture) can then be used to perform hundreds of aggregation experiments with volume-limited samples, such as cerebrospinal fluid from mice

Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice

<p>Abstract</p> <p>Background</p> <p>Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of <it>PSEN1 </it>and <it>PSEN2 </it>in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes.</p> <p>Results</p> <p>To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the <it>PSEN1/PSEN2 </it>double knock-out mice and littermate controls at five different ages ranging from 2–8 months. Our data suggest that combined deficiencies of <it>PSEN1 </it>and <it>PSEN2 </it>results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of <it>cathepsin </it>and <it>complement </it>system transcripts.</p> <p>Conclusion</p> <p>The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of <it>PSEN1 </it>and <it>PSEN2</it>. Furthermore, our results suggest that the evaluation of inhibitors of PS/γ-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.</p

Trophic diversity of chemosymbiont hosts in deep-sea hydrothermal vents using amino acid nitrogen isotopes

Chemosymbiotic species inhabiting deep-sea hydrothermal vents are known to rely on microbial symbionts for nutrition. However, the relative contributions of heterotrophic energy sources to their diets remain poorly understood. In this study, we investigate the trophic positions (TP) of symbiont-bearing taxa, including vent mussels, snails, and shrimps, and examine the contribution of copepods and detrital organic matter (OM) to the food chain. Amino acid nitrogen isotopic compositions (δ15NAA) were used to investigate the TP of vent mussels (Bathymodiolus septemdierum and Gigantidas vrijenhoeki), snails (Alviniconcha spp.), and shrimps (Alvinocaris sp. and Rimicaris kairei) from two different vent environments. δ15NAA values in copepods and OM were also measured. Microbial resynthesis index (ΣV) was calculated to predict the contribution of reworked OM as an energy source to the hydrothermal vent ecosystem. Variations in TP were observed among vent mussels and snails from different vent environments, with higher TP in species from diffusing vents than in those from black smoker vents. Shrimps dwelling in a single diffusing vent exhibited distinct TP, suggesting that microhabitat and phylogeny may influence their energy acquisition. Notably, copepods occupied higher TPs than expected, possibly owing to the consumption of detrital OM. Our findings provide new insights into the trophic diversity of chemosymbiotic species in deep-sea hydrothermal vents and demonstrate the utility of δ15NAA analysis as a tool for unraveling food web dynamics and ecosystem functioning in these unique environments

The usefulness of soluble transferrin receptor in the diagnosis and treatment of iron deficiency anemia in children

PurposeSoluble transferrin receptor (sTfR) is a truncated extracellular form of the membrane transferrin receptor produced by proteolysis. Concentrations of serum sTfR are related to iron status and erythropoiesis in the body. We investigated whether serum sTfR levels can aid in diagnosis and treatment of iron deficiency anemia (IDA) in children.MethodsNinety-eight patients with IDA were enrolled and were classified according to age at diagnosis. Group 1 comprised 78 children, aged 6-59 months, and group 2 comprised 20 adolescents, aged 12-16 years.ResultsIn group 1, patients' serum sTfR levels correlated negatively with mean corpuscular volume; hemoglobin (Hb), ferritin, and serum iron levels; and transferrin saturation and positively with total iron binding capacity (TIBC) and red cell distribution width. In group 2, patients' serum sTfR levels did not correlate with ferritin levels and TIBC, but had a significant relationship with other iron indices. Hb and serum sTfR levels had a significant inverse relationship in both groups; however, in group 1, there was no correlation between Hb and serum ferritin levels. In 30 patients of group 1, serum sTfR levels were significantly decreased with an increase in Hb levels after iron supplementation for 1 month.ConclusionSerum sTfR levels significantly correlated with other diagnostic iron parameters of IDA and inversely correlated with an increase in Hb levels following iron supplementation. Therefore, serum sTfR levels can be a useful marker for the diagnosis and treatment of IDA in children

DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy

Prediction for serious bacterial infection in febrile children aged 3 years or younger: comparison of inflammatory markers, the Laboratory-score, and a new laboratory combined model

Purpose To compare the efficacy of inflammatory markers, the Laboratory-score, and a new laboratory combined model for predicting serious bacterial infection (SBI) in young febrile children. Methods The presence of SBI was reviewed in previously healthy children aged 3 years or younger with fever (> 38℃) who visited the emergency department from 2017 through 2018. Areas under the curves (AUCs) of the receiver operating characteristic curve for SBI were compared with individual inflammatory markers (white blood cells [WBC] count, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], procalcitonin [PCT], and urine WBC count), the Laboratory-score, and a laboratory combined model. The latter model was developed using logistic regression analysis including ESR, CRP, and PCT. Results Of the 203 enrolled children, SBI was diagnosed in 58 (28.6%). For SBI prediction, the Laboratory-score showed 51.7% sensitivity (95% confidence interval [CI], 38.2%-65.0%) and 83.5% specificity (95% CI, 76.4%-89.1%). The AUC of the Laboratory-score (0.76) was significantly superior to the values of all individual inflammatory markers (WBC, 0.59 [P = 0.032]; ESR, 0.69; and CRP, 0.74 [P < 0.001]) except that of PCT (0.77, [P < 0.001]). The AUC of the laboratory combined model (0.80) was superior to that of the Laboratory-score (0.76) (P < 0.001). Conclusion In this study, the new laboratory combined model showed good predictability for SBI. This finding suggests the usefulness of combining ESR, CRP, and PCT in predicting SBI