INTRODUCTION: Though there has been an increasing number of clinical trials focused on modulating stem/progenitor cell proliferation in the spinal cord after spinal cord injury (SCI), little is known ...about the acute response of stem/progenitor cells in supraspinal structures. We hypothesized that the signals stimulating stem/progenitor cell proliferation in the spinal cord after SCI activate similar responses in supraspinal regions because pathways injured in the spinal cord have their targets or sources in the brain. METHODS: We employed a mouse model of SCI, bromodeoxyuridine (BrdU) labeling of cells in S-phase, and co-labeling of markers of astrocytes, microglia, glial/oligodendrocyte precursor cells, and neuronal lineages to characterize the proliferative response within the brainstem of C57BL/6J mice 96 hours after a thoracic SCI. The extent of SCI and white matter (WM) spared was quantified by labeling of beta amyloid precursor protein and eriochrome cyanine R staining, respectively. RESULTS: Compared to sham-operated mice, there was a significant increase (3-fold; p < 0.01) in BrdU-labeled cells in the ventral-caudal medulla of injured mice. This response was consistent with the extent of SCI and primarily in WM tracts (57%) and the inferior olive (41%; IO). Co-labeling with cell-specific markers indicated that this response is glial (i.e., NG-2+ glial/oligodendrocyte precursor cells and GFAP+ astrocytes) with the largest increase in the number of BrdU-labeled cells occurring in the IO (6-fold increase; p < 0.01). Notably, there were no BrdU-labeled cells that co-labeled with markers of microglia or neuronal lineages. CONCLUSIONS: Our results demonstrate a stem/progenitor cell response within days of SCI that occurs distant from the injury site, notably in brainstem structures involved in motor learning and coordination. These findings highlight an acute response of glial/oligodendrocyte precursor cells in the brainstem as a potential target for future studies and therapeutic intervention after SCI.
Background: Widespread radiation is a threat unique to the modern world. A recent report reveals that sub‐clinical damage to human foetuses between 8 and 25 weeks of gestation can result in cognitive ...deficits still manifest 16–18 years after birth. These previously unrecognised, long‐term effects are apparently produced by a relatively short pulse of exposure to radioactive fallout at levels that were previously thought not to be deleterious. This idea is plausible given the nature of the developmental events occurring in the brain during this period of gestation.
Conclusion: This exposed population should be examined for other neurological and psychiatric syndromes. If these findings are corroborated, in the event of future radiation exposures, steps should be taken to shield pregnant women who are within this window of vulnerability.
Diseases caused by invasive pathogens are an increasing threat to forest health, and early and accurate disease detection is essential for timely and precision forest management. The recent ...technological advancements in spectral imaging and artificial intelligence have opened up new possibilities for plant disease detection in both crops and trees. In this study, Dutch elm disease (DED; caused by Ophiostoma novo-ulmi,) and American elm (Ulmus americana) was used as example pathosystem to evaluate the accuracy of two in-house developed high-precision portable hyper- and multi-spectral leaf imagers combined with machine learning as new tools for forest disease detection. Hyper- and multi-spectral images were collected from leaves of American elm genotypes with varied disease susceptibilities after mock-inoculation and inoculation with O. novo-ulmi under greenhouse conditions. Both traditional machine learning and state-of-art deep learning models were built upon derived spectra and directly upon spectral image cubes. Deep learning models that incorporate both spectral and spatial features of high-resolution spectral leaf images have better performance than traditional machine learning models built upon spectral features alone in detecting DED. Edges and symptomatic spots on the leaves were highlighted in the deep learning model as important spatial features to distinguish leaves from inoculated and mock-inoculated trees. In addition, spectral and spatial feature patterns identified in the machine learning-based models were found relative to the DED susceptibility of elm genotypes. Though further studies are needed to assess applications in other pathosystems, hyper- and multi-spectral leaf imagers combined with machine learning show potential as new tools for disease phenotyping in trees.
•Two in-house developed leaf imagers were evaluated for tree disease phenotyping.•Models based on both spectral and spatial features outperformed spectral-only ones.•Elm genotypes varied in spectral and spatial feature patterns to disease infection.•This study may aid in-field elm disease detection and resistant genotype screening.
In albino mammals, lack of pigment in the retinal pigment epithelium is associated with retinal defects, including poor visual acuity from a photoreceptor deficit in the central retina and poor depth ...perception from a decrease in ipsilaterally projecting retinal fibers. Possible contributors to these abnormalities are reported delays in neuronogenesis (Ilia and Jeffery, 1996) and retinal maturation (Webster and Rowe, 1991). To further determine possible perturbations in neuronogenesis and/or differentiation, we used cell-specific markers and refined birth dating methods to examine these events during retinal ganglion cell (RGC) genesis in albino and pigmented mice from embryonic day 11 (E11) to E18. Our data indicate that relative to pigmented mice, more ganglion cells are born in the early stages of neuronogenesis in the albino retina, although the initiation of RGC genesis in the albino is unchanged. The cellular organization of the albino retina is perturbed as early as E12. In addition, cell cycle kinetics and output along the nasotemporal axis differ in retinas of albino and pigmented mice, both absolutely, with the temporal aspect of the retina expanded in albino, and relative to the position of the optic nerve head. Finally, blocking melanin synthesis in pigmented eyecups in culture leads to an increase in RGC differentiation, consistent with a role for melanin formation in regulating RGC neuronogenesis. These results point to spatiotemporal defects in neuronal production in the albino retina, which could perturb expression of genes that specify cell fate, number, and/or projection phenotype.
We describe the molecular cloning and expression of cDNAs encoding human PPARγ1 and PPARγ2. Our sequences are distinct from the published sequence at 3 positions, resulting in nonconservative amino ...acid substitutions. In humans, PPARγ mRNA is expressed in spleen, bone marrow, liver, testis, skeletal muscle and brain, in addition to fat. Three thiazolidinediones were found to 1) displace a radiolabeled thiazolidinedione from both receptors with essentially the same IC50s and 2) to transactivate both PPARγ isoforms with similar EC50s in transient cotransfection assays utilizing the adipocyte-specific aP2 promoter. Saturating concentrations of these 3 thiazolidinediones altered the conformation ofin vitrosynthesized PPARγ protein producing a 27 kDa protease-resistant fragment. These results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPARγ1 and γ2.
The investigation of endo and exo-aryl substitutions and the discovery of the tert-butyl group as a central scaffold on the novel class of FLAP inhibitors are reported.
A search for a suitable ...replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Neuron production takes place continuously in the rostral migratory stream (RMS) of the adult mammalian brain. The molecular mechanisms that regulate progenitor cell division and differentiation in ...the RMS remain largely unknown. Here, we surveyed the mouse genome in an unbiased manner to identify candidate gene loci that regulate proliferation in the adult RMS. We quantified neurogenesis in adult C57BL/6J and A/J mice, and 27 recombinant inbred lines derived from those parental strains. We showed that the A/J RMS had greater numbers of bromodeoxyuridine‐labeled cells than that of C57BL/6J mice with similar cell cycle parameters, indicating that the differences in the number of bromodeoxyuridine‐positive cells reflected the number of proliferating cells between the strains. AXB and BXA recombinant inbred strains demonstrated even greater variation in the numbers of proliferating cells. Genome‐wide mapping of this trait revealed that chromosome 11 harbors a significant quantitative trait locus at 116.75 ± 0.75 Mb that affects cell proliferation in the adult RMS. The genomic regions that influence RMS proliferation did not overlap with genomic regions regulating proliferation in the adult subgranular zone of the hippocampal dentate gyrus. On the contrary, a different, suggestive locus that modulates cell proliferation in the subgranular zone was mapped to chromosome 3 at 102 ± 7 Mb. A subset of genes in the chromosome 11 quantitative trait locus region is associated with neurogenesis and cell proliferation. Our findings provide new insights into the genetic control of neural proliferation and an excellent starting point to identify genes critical to this process.
The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 ...(formerly known asABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRα (NR1H3) and LXRβ (NR1H2). In transient transactivation assays, APD was ∼1000-fold more potent, and yielded ∼6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.
The reduction of a variety of highly functionalized N-acylated dihydropyrazoles (1) with BH3·pyridine is described. The process through which this unexpectedly difficult reduction was discovered and ...developed is reported. A facile atom-efficient route to the N-acylated dihydropyrazole reduction precursors (1) is also illustrated. The resulting acylpyrazolidine products (2) that arise upon reduction were isolated in good to high yields following exposure to reaction conditions which have been shown to tolerate a variety of different functional groups. Finally, this route has been demonstrated on a kilogram scale and provides direct access to potential proline surrogates for peptidomimetic applications.
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