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

From Single-Visit to Multi-Visit Image-Based Models: Single-Visit Models are Enough to Predict Obstructive Hydronephrosis

Previous work has shown the potential of deep learning to predict renal obstruction using kidney ultrasound images. However, these image-based classifiers have been trained with the goal of single-visit inference in mind. We compare methods from video action recognition (i.e. convolutional pooling, LSTM, TSM) to adapt single-visit convolutional models to handle multiple visit inference. We demonstrate that incorporating images from a patient's past hospital visits provides only a small benefit for the prediction of obstructive hydronephrosis. Therefore, inclusion of prior ultrasounds is beneficial, but prediction based on the latest ultrasound is sufficient for patient risk stratification.Comment: Paper accepted to SIPAIM 2022 (in Valparaiso, Chile

Effectiveness and cost-effectiveness of psychiatric mother and baby units: quasi-experimental study

BACKGROUND: Psychiatric mother and baby units (MBUs) are recommended for severe perinatal mental illness, but effectiveness compared with other forms of acute care remains unknown. AIMS: We hypothesised that women admitted to MBUs would be less likely to be readmitted to acute care in the 12 months following discharge, compared with women admitted to non-MBU acute care (generic psychiatric wards or crisis resolution teams (CRTs)). METHOD: Quasi-experimental cohort study of women accessing acute psychiatric care up to 1 year postpartum in 42 healthcare organisations across England and Wales. Primary outcome was readmission within 12 months post-discharge. Propensity scores were used to account for systematic differences between MBU and non-MBU participants. Secondary outcomes included assessment of cost-effectiveness, experience of services, unmet needs, perceived bonding, observed mother-infant interaction quality and safeguarding outcome. RESULTS: Of 279 women, 108 (39%) received MBU care, 62 (22%) generic ward care and 109 (39%) CRT care only. The MBU group (n = 105) had similar readmission rates to the non-MBU group (n = 158) (aOR = 0.95, 95% CI 0.86-1.04, P = 0.29; an absolute difference of -5%, 95% CI -14 to 4%). Service satisfaction was significantly higher among women accessing MBUs compared with non-MBUs; no significant differences were observed for any other secondary outcomes. CONCLUSIONS: We found no significant differences in rates of readmission, but MBU advantage might have been masked by residual confounders; readmission will also depend on quality of care after discharge and type of illness. Future studies should attempt to identify the effective ingredients of specialist perinatal in-patient and community care to improve outcomes

Continuing evolution of Burkholderia mallei through genome reduction and large-scale rearrangements

Burkholderia mallei (Bm), the causative agent of the predominately equine disease glanders, is a genetically uniform species that is very closely related to the much more diverse species Burkholderia pseudomallei (Bp), an opportunistic human pathogen and the primary cause of melioidosis. To gain insight into the relative lack of genetic diversity within Bm, we performed whole-genome comparative analysis of seven Bm strains and contrasted these with eight Bp strains. The Bm core genome (shared by all seven strains) is smaller in size than that of Bp, but the inverse is true for the variable gene sets that are distributed across strains. Interestingly, the biological roles of the Bm variable gene sets are much more homogeneous than those of Bp. The Bm variable genes are found mostly in contiguous regions flanked by insertion sequence (IS) elements, which appear to mediate excision and subsequent elimination of groups of genes that are under reduced selection in the mammalian host. The analysis suggests that the Bm genome continues to evolve through random IS-mediated recombination events, and differences in gene content may contribute to differences in virulence observed among Bm strains. The results are consistent with the view that Bm recently evolved from a single strain of Bp upon introduction into an animal host followed by expansion of IS elements, prophage elimination, and genome rearrangements and reduction mediated by homologous recombination across IS elements

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures

Light and flow regimes regulate the metabolism of rivers

Mean annual temperature and mean annual precipitation drive much of the variation in productivity across Earth's terrestrial ecosystems but do not explain variation in gross primary productivity (GPP) or ecosystem respiration (ER) in flowing waters. We document substantial variation in the magnitude and seasonality of GPP and ER across 222 US rivers. In contrast to their terrestrial counterparts, most river ecosystems respire far more carbon than they fix and have less pronounced and consistent seasonality in their metabolic rates. We find that variation in annual solar energy inputs and stability of flows are the primary drivers of GPP and ER across rivers. A classification schema based on these drivers advances river science and informs management.We thank Ted Stets, Jordan Read, Tom Battin, Sophia Bonjour, Marina Palta, and members of the Duke River Center for their help in developing these ideas. This work was supported by grants from the NSF 1442439 (to E.S.B. and J.W.H.), 1834679 (to R.O.H.), 1442451 (to R.O.H.), 2019528 (to R.O.H. and J.R.B.), 1442140 (to M.C.), 1442451 (to A.M.H.), 1442467 (to E.H.S.), 1442522 (to N.B.G.), 1624807 (to N.B.G.), and US Geological Survey funding for the working group was supported by the John Wesley Power Center for Analysis and Synthesis. Phil Savoy contributed as a postdoc- toral associate at Duke University and as a postdoctoral associate (contractor) at the US Geological Survey

Herbivory and nutrients shape grassland soil seed banks

Anthropogenic nutrient enrichment and shifts in herbivory can lead to dramatic changes in the composition and diversity of aboveground plant communities. In turn, this can alter seed banks in the soil, which are cryptic reservoirs of plant diversity. Here, we use data from seven Nutrient Network grassland sites on four continents, encompassing a range of climatic and environmental conditions, to test the joint effects of fertilization and aboveground mammalian herbivory on seed banks and on the similarity between aboveground plant communities and seed banks. We find that fertilization decreases plant species richness and diversity in seed banks, and homogenizes composition between aboveground and seed bank communities. Fertilization increases seed bank abundance especially in the presence of herbivores, while this effect is smaller in the absence of herbivores. Our findings highlight that nutrient enrichment can weaken a diversity maintaining mechanism in grasslands, and that herbivory needs to be considered when assessing nutrient enrichment effects on seed bank abundance.EEA Santa CruzFil: Eskelinen, Anu. German Centre for Integrative Biodiversity Research; AlemaniaFil: Eskelinen, Anu. Helmholtz Centre for Environmental Research. Department of Physiological Diversity; AlemaniaFil: Eskelinen, Anu. University of Oulu. Ecology & Genetics; FinlandiaFil: Jessen, Maria Theresa. Helmholtz Centre for Environmental Research. Department of Physiological Diversity; AlemaniaFil: Jessen, Maria Theresa. German Centre for Integrative Biodiversity Research; AlemaniaFil: Jessen, Maria Theresa. Helmholtz Centre for Environmental Research – UFZ. Department of Community Ecology; AlemaniaFil: Bahamonde, Hector Alejandro. Universidad Nacional de La Plata. Ciencias Agrarias y Forestales; Argentina.Fil: Bakker, Jonathan D. University of Washington. School of Environmental and Forest Sciences; Estados UnidosFil: Borer, Elizabeth T. University of Minnesota. Department of Ecology, Evolution & Behavior; Estados UnidosFil: Caldeira, Maria C. University of Lisbon. Forest Research Centre. Associate Laboratory TERRA. School of Agriculture; Portugal.Fil: Harpole, William Stanley. German Centre for Integrative Biodiversity Research (iDiv); AlemaniaFil: Harpole, William Stanley. Helmholtz Centre for Environmental Research – UFZ. Department of Community Ecology; AlemaniaFil: Harpole, William Stanley. Martin Luther University. Institute of Biology; AlemaniaFil: Jia, Meiyu. University of Washington. School of Environmental and Forest Sciences; Estados UnidosFil: Jia, Meiyu. East China University of Technology. School of Water Resources & Environmental Engineering; China.Fil: Jia, Meiyu. Beijing Normal University. College of Life Sciences; China.Fil: Lannes, Luciola S. São Paulo State University-UNESP. Department of Biology and Animal Sciences; Brasil.Fil: Nogueira, Carla. University of Lisbon. Forest Research Centre. Associate Laboratory TERRA. School of Agriculture; Portugal.Fil: Venterink, Harry Olde. Vrije Universiteit Brussel (VUB). Department of Biology; BélgicaFil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santa Cruz; Argentina.Fil: Peri, Pablo Luis. Universidad Nacional de la Patagonia Austral; Argentina.Fil: Peri, Pablo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Porath-Krause, Anita J. University of Minnesota. Department of Ecology, Evolution & Behavior; Estados UnidosFil: Seabloom, Eric William. University of Minnesota. Department of Ecology, Evolution & Behavior; Estados UnidosFil: Schroeder, Katie. University of Minnesota. Department of Ecology, Evolution & Behavior; Estados UnidosFil: Schroeder, Katie. University of Georgia. Odum School of Ecology; Estados UnidosFil: Tognetti, Pedro M. Universidad de Buenos Aires. Facultad de Agronomía; Argentina.Fil: Tognetti, Pedro M. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA); Argentina.Fil: Tognetti, Pedro M. Swiss Federal Institute for Forest, Snow and Landscape Research WSL; SuizaFil: Yasui, Simone-Louise E. Queensland University of Technology. School of Biological and Environmental Sciences; Australia.Fil: Virtanen, Risto. University of Oulu. Ecology & Genetics; FinlandiaFil: Sullivan, Lauren L. University of Missouri. Division of Biological Sciences; Estados UnidosFil: Sullivan, Lauren L. Michigan State University. Department of Plant Biology; Estados UnidosFil: Sullivan, Lauren L. Michigan State University. W. K. Kellogg Biological Station; Estados UnidosFil: Sullivan, Lauren L. Michigan State University. Ecology, Evolution and Behavior Program; Estados Unido

Enabling structural resilience of street-involved children and youth in Kenya: reintegration outcomes and the Flourishing Community model

IntroductionMillions of children and youth live on city streets across the globe, vulnerable to substance use, abuse, material and structural neglect. Structural resilience, the re-establishment of access to structural goods within a society such as housing, education, and healthcare following some interruption, provides an orientation for research and interventional efforts with street-involved children and youth (SICY). Further, a structural resilience framework supports organizing interactions between levels and sectors of a socio-ecology.MethodsFollowing the expressed interests of Kenyan SICY, and consistent with emerging policy interests at national and global levels, we assess reintegration trajectories of Kenyan SICY (n = 227) participating in a new program intervention and model. The intervention combines two coordinated, parallel programs – one focused on the rescue, rehabilitation, reintegration and resocialization of SICY, and the other focused on empowering families and communities to provide better care for children and youth who are reintegrating from life on the streets to the broader community. Data were collected and analyzed from multiple stages across SICY involvement with the intervention.ResultsWe found 79% of SICY participants reintegrated with the broader community, and 50% reintegrated with families of origin and returned to school. Twenty-five percent of participants reintegrated to a boarding school, polytechnical school, or began a business. Probability of reintegrating successfully was significantly improved among participants whose families participated in the family- and community-oriented program, who were younger, with less street-exposure, expressed more personal interests, and desired to reintegrate with family.DiscussionTo our knowledge, these are the first quantitative data published of successful reintegration of SICY to the broader, non-institutionalized community in any low- or middle-income country. Future research should (1) identify factors across socio-ecological levels and sectors contributing to health and developmental outcomes of reintegrated children and youth, (2) mechanisms to support SICY for whom the interventional strategy did not work, (3) methods to prevent street-migration by children and youth, and (4) system development to coordinate follow-up and relevant investment by institutions, organizations and community leaders to continue reintegration work

Consequences Matter : Compassion in Conservation Means Caring for Individuals, Populations and Species

Funding This research received no external funding. Acknowledgments The manuscript benefitted from significant input from Dan Brockington, J.B. Callicott, Peter Coals, Tim Hodgetts, David Macdonald and Jeremy Wilson. Conflicts of Interest The authors declare no conflict of interest.Peer reviewedPublisher PD