The point of maximum curvature as a marker for physiological time series

We present a geometric analysis of the model of Stirling. In particular we analyze the curvature of a heart rate time series in response to a step like increment in the exercise intensity. We present solutions for the point of maximum curvature which can be used as a marker of physiological interest. This marker defines the point after which the heart rate no longer continues to rapidly rise and instead follows either a steady state or slow rise. These methods are then applied to find analytic solutions for a mono exponential model which is commonly used in the literature to model the response to a moderate exercise intensity. Numerical solutions are then found for the full model and parameter values presented in Stirling

Solubility limit and precipitate formation in Al-doped 4H-SiC epitaxial material

Heavily Al-doped 4H–SiC structures have been prepared by vapor phase epitaxy. Subsequent anneals have been carried out in an Ar atmosphere in a rf-heated furnace between 1500 °C and 2000 °C for 0.5 to 3 h. Secondary ion mass spectrometry has been utilized to obtain Al concentration versus depth as well as lateral distributions (ion images). Transmission electron microscopy(TEM) has been employed to study the crystallinity and determine phase composition after heat treatment. A solubility limit of ∼2×10²⁰ Al/cm³ (1900 °C) is extracted. Three-dimensional ion images show that the Al distribution does not remain homogeneous in layers heat treated at 1700 °C or above when the Al concentration exceeds 2×10²⁰ cm⁻³. Al-containing precipitates are identified by energy-filtered TEM.Financial support was partly received from the Swedish Foundation for Strategic Research (SSF) SiCEP program

First principles study of the origin and nature of ferromagnetism in (Ga,Mn)As

The properties of diluted Ga$_{1-x}$Mn$_x$As are calculated for a wide range of Mn concentrations within the local spin density approximation of density functional theory. M\"ulliken population analyses and orbital-resolved densities of states show that the configuration of Mn in GaAs is compatible with either 3d$^5$ or 3d$^6$, however the occupation is not integer due to the large $p$-$d$ hybridization between the Mn $d$ states and the valence band of GaAs. The spin splitting of the conduction band of GaAs has a mean field-like linear variation with the Mn concentration and indicates ferromagnetic coupling with the Mn ions. In contrast the valence band is antiferromagnetically coupled with the Mn impurities and the spin splitting is not linearly dependent on the Mn concentration. This suggests that the mean field approximation breaks down in the case of Mn-doped GaAs and corrections due to multiple scattering must be considered. We calculate these corrections within a simple free electron model and find good agreement with our {\it ab initio} results if a large exchange constant ($N\beta=-4.5$eV) is assumed.Comment: 15 pages, 14 figure

A roadmap for the Human Developmental Cell Atlas

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression

Impact of Treadmill Running and Sex on Hippocampal Neurogenesis in the Mouse Model of Amyotrophic Lateral Sclerosis

Hippocampal neurogenesis in the subgranular zone (SGZ) of dentate gyrus (DG) occurs throughout life and is regulated by pathological and physiological processes. The role of oxidative stress in hippocampal neurogenesis and its response to exercise or neurodegenerative diseases remains controversial. The present study was designed to investigate the impact of oxidative stress, treadmill exercise and sex on hippocampal neurogenesis in a murine model of heightened oxidative stress (G93A mice). G93A and wild type (WT) mice were randomized to a treadmill running (EX) or a sedentary (SED) group for 1 or 4 wk. Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) labeled proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress (3-NT; 8-OHdG). BDNF and IGF1 mRNA expression was assessed by in situ hybridization. Results showed that: (1) G93A-SED mice had greater hippocampal neurogenesis, BDNF mRNA, and 3-NT, as compared to WT-SED mice. (2) Treadmill running promoted hippocampal neurogenesis and BDNF mRNA content and lowered DNA oxidative damage (8-OHdG) in WT mice. (3) Male G93A mice showed significantly higher cell proliferation but a lower level of survival vs. female G93A mice. We conclude that G93A mice show higher hippocampal neurogenesis, in association with higher BDNF expression, yet running did not further enhance these phenomena in G93A mice, probably due to a ‘ceiling effect’ of an already heightened basal levels of hippocampal neurogenesis and BDNF expression

Genetic identification of brain cell types underlying schizophrenia

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to sets of genes specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (synaptic genes, FMRP interactors, antipsychotic targets, etc.) generally implicate the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with medium spiny neurons did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Short-arm centrifugation as a partially effective musculoskeletal countermeasure during 5-day head-down tilt bed rest - results from the BRAG1 study

PURPOSE: Human centrifugation, also called artificial gravity (AG), is proposed as a combined strategy against detrimental effects of microgravity in long-term space missions. This study scrutinized human short-arm centrifugation as countermeasure against musculoskeletal de-conditioning. METHOD: Eleven healthy male subjects [mean age of 34 (SD 7) years] completed the cross-over trial, including three campaigns of -6° head-down tilt bed rest (HDT) for 5 days, with preceding baseline data collection and recovery phases. Bed rest without AG was used as control condition (Ctrl), and AG with 1 g at the center of mass applied once per day for 30 min in one bout (AG1×30) and in 6 bouts of 5 min (AG6×5, 3-min rest between bouts) as experimental conditions. End-points were muscle strength, vertical jump performance, and biomarkers of bone and protein metabolism. RESULT: AG6×5 was better tolerated than AG1×30. Bone resorption markers CTX, NTX, and DPD all increased by approximately 25 % toward the end of bed rest (P 0.4). Decreases in vertical jump height by 2.1 (SE 0.6) cm after Ctrl bed rest was prevented by either of the AG protocols (P = 0.039). CONCLUSION: The present study yielded succinct catabolic effects upon muscle and bone metabolism that were un-prevented by AG. The preservation of vertical jump performance by AG in this study is likely caused by central nervous rather than by peripheral musculoskeletal effects