The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Effects of climate change and land use intensification on regional biological soil crust cover and composition in southern Africa

Biological soil crusts (biocrusts) form a regular and relevant feature in drylands, as they stabilize the soil, fix nutrients, and influence water cycling. However, biocrust forming organisms have been shown to be dramatically vulnerable to climate and land use change occurring in these regions. In this study, we used Normalized Difference Vegetation Index (NDVI) data of biocrust-dominated pixels (NDVIbiocrust) obtained from hyperspectral and LANDSAT-7 data to analyse biocrust development over time and to forecast future NDVIbiocrust development under different climate change and livestock density scenarios in southern Africa. We validated these results by analysing the occurrence and composition of biocrusts along a mesoclimatic gradient within the study region. Our results show that NDVIbiocrust, which reached maximum values of 0.2 and 0.4 in drier and wetter years, respectively, mainly depended on water availability. A predicted decrease in rainfall events according to all future climate scenarios combined with increased temperatures suggested a pronounced decrease in NDVIbiocrust by the end of the 21st century caused by reduced biocrust coverage. Livestock trampling had similar effects and exacerbated the negative impacts of climate change on biocrust coverage and composition. Data assessed in the field concurred with these results, as reduced biocrust cover and a shift from well-developed to early stages of biocrust development were observed along a gradient of decreasing precipitation and increasing temperatures and livestock density. Our study demonstrates the suitability of multi-temporal series of historical satellite images combined with high-resolution mapping data and Earth system models to identify climate change patterns and their effects on biocrust and vegetation patterns at regional scales.ERC was supported by a Nobel Laureate Paul Crutzen fellowship; the REBIOARID (2018-101921-B-I00) project, funded by the FEDER/Science and Innovation Ministry-National Research Agency through the Spanish National Plan for Research and the European Union Funds for Regional Development; Consejería de Economía, Conocimiento, Empresas y Universidad from the Junta de Andalucía (GlobCRUST project EMERGIA20_0033), the Biodiversity Foundation of the Ministry for the Ecological Transition (BIOCOST project) and the RH2OARID (P18-RT-5130) funded by Consejería de Economía, Conocimiento, Empresas y Universidad from the Junta de Andalucía and the European Union Funds for Regional Development. BW was supported by the Max Planck Society (Nobel Laureate Fellowship) and the German Research Foundation (projects WE2393/2-1 and WE2393/2-2). EG is supported by the European Research Council grant agreement n° 647038 (BIODESERT). The research of US was supported by the German Federal Ministry of Education and Research (BMBF, promotion number 01LG1201N)

Ecophysiological properties of three biological soil crust types and their photoautotrophs from the Succulent Karoo, South Africa

Background and Aims Biological soil crusts cover about one third of the terrestrial soil surfaces in drylands, fulfilling highly important ecosystem services. Their relevance to global carbon cycling, however, is still under debate. Methods We utilized CO2 gas exchange measurements to investigate the net photosynthetic response of combined cyanobacteria/cyanolichen-, chlorolichen- and moss-dominated biocrusts and their isolated photoautotrophic components to light, temperature, and water. The results were compared with field studies to evaluate their compatibility. Results Different biocrust types responded similarly, being inhibited by limited and excess water, saturated by increasing light intensities, and having optimum temperatures. Cyanobacteria/cyanolichen-dominated biocrusts reached their water optimum at lowest contents (0.52–0.78 mm H2O), were saturated at highest light intensities, and had a comparably high temperature optimum at 37 °C. Chlorolichen-dominated crusts had a medium water optimum (0.75–1.15 mm H2O), medium saturating light intensities and a moderate temperature optimum of 22 °C. Moss-dominated biocrusts had the highest water optimum (1.76–2.38 mm H2O), lowest saturating light intensities, and a similar temperature optimum at 22 °C. Isolated photoautotrophs responded similar to complete crusts, only isolated moss stems revealed much lower respiration rates compared to complete crusts. Conclusions In addition to their overall functional similarities, cyanobacteria/cyanolichen-dominated biocrusts appeared to be best adapted to predicted climate change of increasing temperatures and smaller precipitation events, followed by chlorolichen-dominated biocrusts. Moss-dominated biocrusts needed by far the largest amounts of water, thus likely being prone to anticipated climate change

Knowledge, attitude, and perception of Nigerian-based physiotherapists on the utilization of musculoskeletal ultrasound imaging in the clinical management of musculoskeletal conditions

Background: Musculoskeletal ultrasound imaging (MSUI) is an efficient monitoring and re-evaluation tool used for the management of musculoskeletal conditions in several clinical domains. Its utilization among physiotherapists, particularly in African countries, is yet to be explored. Objective: This study investigated the knowledge, attitude, and perception of physiotherapists on the utilization of MSUI in the clinical management of musculoskeletal conditions. Methods: One hundred and ninety-two consenting Nigerian-based physiotherapists practicing in public and private health institutions participated in this cross-sectional survey. They responded to a three-sectioned structured questionnaire, investigating socio-demographic and occupational characteristics, knowledge, attitude, and utilization of MSUI for the management of musculoskeletal conditions. Data were analyzed with descriptive statistics and Pearson’s chi-square test at a significant level of 0.05. Results: The majority (79.2%) of the respondents had positive knowledge of MSUI and its benefits as a clinical modality for managing MSCs. However, only 4.2% had utilized MSUI in clinical practice. Non-utilization of MSUI was commonly attributed to a lack of access to MSUI (60.3%) and its unavailability in most diagnostic centers (42.9%). Almost all (99.0%) of them agreed to the necessity for increased availability of MSUI to physiotherapists for enhancement of physiotherapy interventions in the management of MSCs. Conclusion: Knowledge of MSUI among Nigerian-based physiotherapists is adequate, but its utilization as a clinical tool is poor. Improved availability of MSUI to physiotherapists is necessary as well as specialty training on the utilization and interpretation of MSUI

A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

Age-related cognitive decline has been linked to a diverse set of neurobiological mechanisms, including bidirectional changes in proteins critical for neuron function. Importantly, these alterations are not uniform across the brain. For example, the hippocampus (HPC) and prefrontal cortex (PFC) show distinct patterns of dysfunction in advanced age. Because higher cognitive functions require large–scale interactions across prefrontal cortical and hippocampal networks, selectively targeting an alteration within one region may not broadly restore function to improve cognition. One mechanism for decline that the PFC and HPC share, however, is a reduced ability to utilize glucose for energy metabolism. Although this suggests that therapeutic strategies bypassing the need for neuronal glycolysis may be beneficial for treating cognitive aging, this approach has not been empirically tested. Thus, the current study used a ketogenic diet (KD) as a global metabolic strategy for improving brain function in young and aged rats. After 12 weeks, rats were trained to perform a spatial alternation task through an asymmetrical maze, in which one arm was closed and the other was open. Both young and aged KD-fed rats showed resilience against the anxiogenic open arm, training to alternation criterion performance faster than control animals. Following alternation testing, rats were trained to perform a cognitive dual task that required working memory while simultaneously performing a bi-conditional association task (WM/BAT), which requires PFC–HPC interactions. All KD-fed rats also demonstrated improved performance on WM/BAT. At the completion of behavioral testing, tissue punches were collected from the PFC for biochemical analysis. KD-fed rats had biochemical alterations within PFC that were dissociable from previous results in the HPC. Specifically, MCT1 and MCT4, which transport ketone bodies, were significantly increased in KD-fed rats compared to controls. GLUT1, which transports glucose across the blood brain barrier, was decreased in KD-fed rats. Contrary to previous observations within the HPC, the vesicular glutamate transporter (VGLUT1) did not change with age or diet within the PFC. The vesicular GABA transporter (VGAT), however, was increased within PFC similar to HPC. These data suggest that KDs could be optimal for enhancing large-scale network function that is critical for higher cognition

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment