Neurochemical Characterization of the Tree Shrew Dorsal Striatum

The striatum is a major component of the basal ganglia and is associated with motor and cognitive functions. Striatal pathologies have been linked to several disorders, including Huntington’s, Tourette’s syndrome, obsessive–compulsive disorders, and schizophrenia. For the study of these striatal pathologies different animal models have been used, including rodents and non-human primates. Rodents lack on morphological complexity (for example, the lack of well defined caudate and putamen nuclei), which makes it difficult to translate data to the human paradigm. Primates, and especially higher primates, are the closest model to humans, but there are ever-increasing restrictions to the use of these animals for research. In our search for a non-primate animal model with a striatum that anatomically (and perhaps functionally) can resemble that of humans, we turned our attention to the tree shrew. Evolutionary genetic studies have provided strong data supporting that the tree shrews (Scadentia) are one of the closest groups to primates, although their brain anatomy has only been studied in detail for specific brain areas. Morphologically, the tree shrew striatum resembles the primate striatum with the presence of an internal capsule separating the caudate and putamen, but little is known about its neurochemical composition. Here we analyzed the expression of calcium-binding proteins, the presence and distribution of the striosome and matrix compartments (by the use of calbindin, tyrosine hydroxylase, and acetylcholinesterase immunohistochemistry), and the GABAergic system by immunohistochemistry against glutamic acid decarboxylase and Golgi impregnation. In summary, our results show that when compared to primates, the tree shrew dorsal striatum presents striking similarities in the distribution of most of the markers studied, while presenting some marked divergences when compared to the rodent striatum

Dopamine Pathology in Schizophrenia: Analysis of Total and Phosphorylated Tyrosine Hydroxylase in the Substantia Nigra

Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect

Light and Electron Microscopy Study of Glycogen Synthase Kinase-3β in the Mouse Brain

Glycogen synthase kinase-3β (GSK3β) is highly abundant in the brain. Various biochemical analyses have indicated that GSK3β is localized to different intracellular compartments within brain cells. However, ultrastructural visualization of this kinase in various brain regions and in different brain cell types has not been reported. The goal of the present study was to examine GSK3β distribution and subcellular localization in the brain using immunohistochemistry combined with light and electron microscopy. Initial examination by light microscopy revealed that GSK3β is expressed in brain neurons and their dendrites throughout all the rostrocaudal extent of the adult mouse brain, and abundant GSK3β staining was found in the cortex, hippocampus, basal ganglia, the cerebellum, and some brainstem nuclei. Examination by transmission electron microscopy revealed highly specific subcellular localization of GSK3β in neurons and astrocytes. At the subcellular level, GSK3β was present in the rough endoplasmic reticulum, free ribosomes, and mitochondria of neurons and astrocytes. In addition GSK3β was also present in dendrites and dendritic spines, with some postsynaptic densities clearly labeled for GSK3β. Phosphorylation at serine-9 of GSK3β (pSer9GSK3β) reduces kinase activity. pSer9GSK3β labeling was present in all brain regions, but the pattern of staining was clearly different, with an abundance of labeling in microglia cells in all regions analyzed and much less neuronal staining in the subcortical regions. At the subcellular level pSer9GSK3β labeling was located in the endoplasmic reticulum, free ribosomes and in some of the nuclei. Overall, in normal brains constitutively active GSK3β is predominantly present in neurons while pSer9GSK3β is more evident in resting microglia cells. This visual assessment of GSK3β localization within the subcellular structures of various brain cells may help in understanding the diverse role of GSK3β signaling in the brain

A review of community-based solar home system projects in the Philippines

Solar Home Systems (SHS) are easy to deploy in island and in remote communities where grid connection is costly. However, issues related to maintenance of these systems emerge after they are deployed because of the remoteness and inaccessibility of the communities. This study looked into community-based programs in the Philippines and investigated the following: (1) social preparation, (2) role of the community in the project, and (3) sustainability of the program. In this paper, three communities under two government programs offering SHS are presented. These programs are the Solar Power Technology Support (SPOTS) program of the Department of Agrarian Reform (DAR) and the Household Electrification Program (HEP) of the Department of Energy (DOE). A focused group discussion and key informant interviews were conducted in two communities in Bukidnon province and in a community in Kalinga to obtain information from the project beneficiaries and SHS users on the preparation, implementation and maintenance of the projects. The results revealed that emphasis on the economic value of the technology, proper training of the locals on the technical and management aspects of the project, as well as the establishment of a supply chain for replacement parts are crucial factors for the sustainability of the programs

Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

Although an effective treatment for pediatric brain tumors, cranial radiation therapy (CRT) damages surrounding healthy tissue, thereby disrupting brain development. Animal models of pediatric CRT have primarily relied on visual tasks to assess cognitive impairment. Moreover, there has been a lack of sex comparisons as most research on the cognitive effects of pediatric CRT does not include females. Therefore, we utilized olfaction, an ethologically relevant sensory modality, to assess cognitive impairment in an animal model of CRT that included both male and female mice. Specifically, we used the novel odor recognition (NOdorR) task with social odors to test recognition memory, a cognitive parameter that has been associated with olfactory neurogenesis, a form of cellular plasticity damaged by CRT. In addition to odor recognition memory, olfactory ability or discrimination of non-social and social odors were assessed both acutely and 3 months after CRT. Magnetic resonance imaging (MRI) and histology were performed after behavioral testing to assess long-term damage by CRT. Long-term but not acute radiation-induced impairment in odor recognition memory was observed, consistent with delayed onset of cognitive impairment in human patients. Males showed greater exploration of social odors than females, but general exploration was not affected by irradiation. However, irradiated males had impaired odor recognition memory in adulthood, compared to non-irradiated males (or simply male controls). Female olfactory recognition memory, in contrast, was dependent on estrus stage. CRT damage was demonstrated by (1) histological evaluation of olfactory neurogenesis, which suggested a reduction in CRT versus control, and (2) imaging analyses which showed that the majority of brain regions were reduced in volume by CRT. Specifically, two regions involved in social odor processing (amygdala and piriform cortex) were damaged by cranial irradiation in males but not females, paralleling olfactory recognition findings

Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk:A Mendelian randomization analysis

BACKGROUND The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. METHODS We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). RESULTS In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. CONCLUSIONS We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies

Persistence of anticancer activity in berry extracts after simulated gastrointestinal digestion and colonic fermentation

Fruit and vegetable consumption is associated at the population level with a protective effect against colorectal cancer. Phenolic compounds, especially abundant in berries, are of interest due to their putative anticancer activity. After consumption, however, phenolic compounds are subject to digestive conditions within the gastrointestinal tract that alter their structures and potentially their function. However, the majority of phenolic compounds are not efficiently absorbed in the small intestine and a substantial portion pass into the colon. We characterized berry extracts (raspberries, strawberries, blackcurrants) produced by in vitro-simulated upper intestinal tract digestion and subsequent fecal fermentation. These extracts and selected individual colonic metabolites were then evaluated for their putative anticancer activities using in vitro models of colorectal cancer, representing the key stages of initiation, promotion and invasion. Over a physiologically-relevant dose range (0–50 µg/ml gallic acid equivalents), the digested and fermented extracts demonstrated significant anti-genotoxic, anti-mutagenic and anti-invasive activity on colonocytes. This work indicates that phenolic compounds from berries undergo considerable structural modifications during their passage through the gastrointestinal tract but their breakdown products and metabolites retain biological activity and can modulate cellular processes associated with colon cancer

Dialogue across Indigenous, local and scientific knowledge systems reflecting on the IPBES Assessment on Pollinators, Pollination and Food Production

The Dialogue across Indigenous, local and scientific knowledge systems reflecting on the IPBES Assessment on Pollinators, Pollination and Food Production report presents the main outcomes of a Dialogue across Indigenous, local and scientific knowledge systems that revisited and reflected on the key messages derived from the Assessment Report on Pollinators, Pollination and Food Production of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES). The Dialogue was hosted from the 21st to the 25th of January 2019 by the Karen community of Hin Lad Nai, Chiang Rai, Thailand, and it was co-convened and jointly designed by the Inter Mountain Peoples Education and Culture in Thailand Association (IMPECT) and Pgakenyaw Association for Sustainable Development (PASD) together with SwedBio at the Stockholm Resilience Centre and UNESCO Natural Science Sector

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.This work was supported by NIH grants R01 CA220234, R01 HL144072, P01 HL131478, and NWO/ZonMW Vici 91818622 (to W.J.M.M.); R01 HL143814 and P01HL131478 (to Z.A.F.); R01 AI139623 (to J.O.); and P30 CA008748 (to T.R.). M.M.T.v.L. was supported by the American Heart Association (grant 19PRE34380423). M.G.N. was supported by a Spinoza grant from the Netherlands Organization for Scientific Research and an ERC Advanced Grant (no. 833247); L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587).S

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis