Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing ...analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.
Increasing use of automated soil respiration chambers in recent years has demonstrated complex diel relationships between soil respiration and temperature that are not apparent from less frequent ...measurements. Soil surface flux is often lagged from soil temperature by several hours, which results in semielliptical hysteresis loops when surface flux is plotted as a function of soil temperature. Both biological and physical explanations have been suggested for hysteresis patterns, and there is currently no consensus on their causes or how such data should be analyzed to interpret the sensitivity of respiration to temperature. We used a one-dimensional soil CO₂ and heat transport model based on physical first principles to demonstrate a theoretical basis for lags between surface flux and soil temperatures. Using numerical simulations, we demonstrated that diel phase lags between surface flux and soil temperature can result from heat and CO₂ transport processes alone. While factors other than temperature that vary on a diel basis, such as carbon substrate supply and atmospheric CO₂ concentration, can additionally alter lag times and hysteresis patterns to varying degrees, physical transport processes alone are sufficient to create hysteresis. Therefore, the existence of hysteresis does not necessarily indicate soil respiration is influenced by photosynthetic carbon supply. We also demonstrated how lags can cause errors in Q₁₀ values calculated from regressions of surface flux and soil temperature measured at a single depth. Furthermore, synchronizing surface flux and soil temperature to account for transport-related lags generally does not improve Q₁₀ estimation. In order to calculate the sensitivity of soil respiration to temperature, we suggest using approaches that account for the gradients in temperature and production existing within the soil. We conclude that consideration of heat and CO₂ transport processes is a requirement to correctly interpret diel soil respiration patterns.
Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence ...indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH.
Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student's t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher's exact test, depending on the analytical question.
Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period.
These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.
Abstract
In salmon aquaculture, the sustainable management of salmon lice (Lepeophtheirus salmonis) is limited by the adaptive capacity of the parasite. This is evident in the repeated evolution of ...pesticide resistance in the salmon louse population. To better prepare for resistance, we constructed a numerical metapopulation model that predicts the evolutionary dynamics of lice across an interconnected farm network. This model integrates within-farm population dynamics and between-farm louse dispersal, the latter using outputs from a state-of-the-art particle-tracking model. Distinct from previous metapopulation models, it also simulates spatial and temporal genetic variation arising from selection. The model was parameterized to simulate the evolution of resistance to the pesticide azamethiphos on farms in southern Norway. It successfully reproduced the rapid (within 10 years) evolution of azamethiphos resistance following extensive delousing treatments. It also identified strong spatial patterns in resistance, with regions of high farm connectivity being potential hotspots of louse adaptation. Rates of infestation and evolution were significantly reduced when highly connected farms were excluded from the simulation, compared to when low-connectivity or random sites were excluded. This model can be a valuable tool for coordinating pest management at a regional scale, in a way that slows or prevents the spread of resistance.
Multiple and complex aetiological processes underlie diabetes mellitus, which invariably result in the development of hyperglycaemia. Although there are two prevalent distinct forms of the disease, ...that is, type 1 and type 2 diabetes, accumulating evidence indicates that these syndromes share more aetiopathological mechanisms than originally thought. This compels a rethinking of the approaches to prevent and treat the different manifestations of what eventually becomes a hyperglycaemic state. This review aims to address the involvement of neutrophils, the most abundant type of granulocytes involved in the initiation of the acute phase of inflammation, in the aetiopathogenesis of diabetes mellitus, with a focus on type 1 and type 2 diabetes. We review the evidence that neutrophils are the first leucocytes to react to and accumulate inside target tissues of diabetes, such as the pancreas and insulin‐sensitive tissues. We then review available data on the role of neutrophils and their functional alteration, with a focus on NETosis, in the progression towards clinical disease. Finally, we review potential approaches as secondary and adjunctive treatments to limit neutrophil‐mediated damage in the prevention of the progression of subclinical disease to clinical hyperglycaemia.
Tolerogenic dendritic cells and T-regulatory cells are two immune cell populations with the potential to prevent the onset of clinical stage type 1 diabetes, and manage the beginning of underlying ...autoimmunity, at the time-at-onset and onwards. Initial phase I trials demonstrated that the administration of a number of these cell populations, generated
from peripheral blood leukocytes, was safe. Outcomes of some of these trials also suggested some level of autoimmunity regulation, by the increase in the numbers of regulatory cells at different points in a network of immune regulation
. As these cell populations come to the cusp of pivotal phase II efficacy trials, a number of questions still need to be addressed. At least one mechanism of action needs to be verified as operational, and through this mechanism biomarkers predictive of the underlying autoimmunity need to be identified. Efficacy in the regulation of the underlying autoimmunity also need to be monitored. At the same time, the absence of a common phenotype core among the different dendritic cell and T-regulatory cell populations, that have completed phase I and early phase II trials, necessitates a better understanding of what makes these cells tolerogenic, especially if a uniform phenotypic core cannot be identified. Finally, the inter-relationship of tolerogenic dendritic cells and T-regulatory cells for survival, induction, and maintenance of a tolerogenic state that manages the underlying diabetes autoimmunity, raises the possibility to co-administer, or even to serially-administer tolerogenic dendritic cells together with T-regulatory cells as a cellular co-therapy, enabling the best possible outcome. This is currently a knowledge gap that this review aims to address.
Uncontrolled hemorrhage from vessel injuries within the torso remains a significant source of prehospital trauma mortality. Resuscitative endovascular balloon occlusion of the aorta can effectively ...control noncompressible hemorrhage, but this minimally invasive technique relies heavily on imaging not available in the field. Our goal was to develop morphometric roadmaps to enhance the safety and accuracy of fluoroscopy-free endovascular navigation of hemorrhage control devices.
Three-dimensional reconstructions of computed tomographic angiography scans from 122 trauma patients (mean SD age, 47 24 years; range 5-93 years; 64 males; 58 females) were used to measure centerline distances from femoral artery access sites to the major aortic branch artery origins. Morphometric roadmap equations were created using multiple linear regression analysis to predict distances to the origins of the major arteries in the chest, abdomen, and pelvis using torso length, demographics, and risk factors as independent variables. A 40-mm-long occlusion balloon was then virtually deployed targeting Zones 1 and 3 of the aorta using these equations. Balloon placement accuracy was determined by comparing predicted versus actual measured distances to the target zone locations within the aortas from the database.
Torso length and age were the strongest predictors of centerline distances from femoral artery access sites to the major artery origins. Male sex contributed to longer distances, while diabetes and smoking were associated with shorter distances. Hypertension, dyslipidemia, and coronary artery disease had no effect. With the use of morphometric roadmaps, virtual occlusion balloon placement accuracy was 100% for Zone 3 of the aorta, compared with 87% accuracy when using torso length alone.
Morphometric roadmaps demonstrate a potential for improving the safety and accuracy of fluoroscopy-free aortic occlusion balloon delivery. Continued development of minimally invasive hemorrhage control techniques holds promise to improve prehospital mortality for patients with noncompressible exsanguinating torso injuries.
Therapeutic study, level IV; diagnostic study, level III.
Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile ...morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.
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