Perivascular mesenchymal stem cells in the adult human brain: a future target for neuroregeneration?

Perivascular adult stem cells have been isolated from several tissues, including the adult human brain. They have unique signatures resembling both pericytes and mesenchymal stem cells. Understanding the nature of these cells in their specific vascular niches is important to determine their clinical potential as a new adult stem cell source. Indeed, they have promising features in vitro in terms of multipotency, immunomodulation and secretion of growth factors and cytokines. However, their in vivo function is less known as yet. Recent emerging data show a crucial role of perivascular mesenchymal stem cells in tissue homeostasis and repair. Furthermore, these cells may play an important role in adult stem cell niche regulation and in neurodegeneration. Here we review the recent literature on perivascular mesenchymal stem cells, discuss their different in vitro functions and highlight especially the specific properties of brain-derived perivascular mesenchymal stem cells. We summarize current evidence that suggests an important in vivo function of these cells in terms of their regenerative potential that may indicate a new target cell for endogenous tissue regeneration and repair

Endogenous brain pericytes are widely activated and contribute to mouse glioma microvasculature.

Glioblastoma multiforme (GBM) is the most common brain tumor in adults. It presents an extremely challenging clinical problem, and treatment very frequently fails due to the infiltrative growth, facilitated by extensive angiogenesis and neovascularization. Pericytes constitute an important part of the GBM microvasculature. The contribution of endogenous brain pericytes to the tumor vasculature in GBM is, however, unclear. In this study, we determine the site of activation and the extent of contribution of endogenous brain pericytes to the GBM vasculature. GL261 mouse glioma was orthotopically implanted in mice expressing green fluorescent protein (GFP) under the pericyte marker regulator of G protein signaling 5 (RGS5). Host pericytes were not only activated within the glioma, but also in cortical areas overlying the tumor, the ipsilateral subventricular zone and within the hemisphere contralateral to the tumor. The host-derived activated pericytes that infiltrated the glioma were mainly localized to the tumor vessel wall. Infiltrating GFP positive pericytes co-expressed the pericyte markers platelet-derived growth factor receptor-β (PDGFR-β) and neuron-glial antigen 2. Interestingly, more than half of all PDGFR-β positive pericytes within the tumor were contributed by the host brain. We did not find any evidence that RGS5 positive pericytes adopt another phenotype within glioma in this paradigm. We conclude that endogenous pericytes become activated in widespread areas of the brain in response to an orthotopic mouse glioma. Host pericytes are recruited into the tumor and constitute a major part of the tumor pericyte population

Anomaly Detection in Networks with Application to Financial Transaction Networks

This paper is motivated by the task of detecting anomalies in networks of financial transactions, with accounts as nodes and a directed weighted edge between two nodes denoting a money transfer. The weight of the edge is the transaction amount. Examples of anomalies in networks include long paths of large transaction amounts, rings of large payments, and cliques of accounts. There are many methods available which detect such specific structures in networks. Here we introduce a method which is able to detect previously unspecified anomalies in networks. The method is based on a combination of features from network comparison and spectral analysis as well as local statistics, yielding 140 main features. We then use a simple feature sum method, as well as a random forest method, in order to classify nodes as normal or anomalous. We test the method first on synthetic networks which we generated, and second on a set of synthetic networks which were generated without the methods team having access to the ground truth. The first set of synthetic networks was split in a training set of 70 percent of the networks, and a test set of 30 percent of the networks. The resulting classifier was then applied to the second set of synthetic networks. We compare our method with Oddball, a widely used method for anomaly detection in networks, as well as to random classification. While Oddball outperforms random classification, both our feature sum method and our random forest method outperform Oddball. On the test set, the random forest outperforms feature sum, whereas on the second synthetic data set, initially feature sum tends to pick up more anomalies than random forest, with this behaviour reversing for lower-scoring anomalies. In all cases, the top 2 percent of flagged anomalies contained on average over 90 percent of the planted anomalies

Trophic factors for Parkinson's disease: Where are we and where do we go from here?

Perhaps the most important unmet clinical need in Parkinson's disease (PD) is the development of a therapy that can slow or halt disease progression. Extensive preclinical research has provided evidence for the neurorestorative properties of several growth factors, yet only a few have been evaluated in clinical studies. Attempts to achieve neuroprotection by addressing cell-autonomous mechanisms and targeting dopaminergic neurons have been disappointing. Four different trophic factors have so far entered clinical trials in PD: glial cell line-derived growth factor, its close structural and functional analog neurturin, platelet-derived growth factor and cerebral dopaminergic neurotrophic factor. This article reviews the pre-clinical evidence for the neuroprotective and neurorestorative actions of these growth factors and discusses limitations of preclinical models, which may hamper successful translation to the clinic. We summarize the previous and ongoing clinical trials using growth factors in PD and emphasize the caveats in clinical trial design that may prevent the further development and registration of potentially neuroprotective and neurorestorative treatments for individuals suffering from PD

Canine Brucellosis: Insights Into the Epidemiologic Situation in Europe

Brucella canis is one of many responsible pathogens of discospondylitis in dogs and infections require specific management. Little is known about the epidemiologic situation in Europe. The purpose of the study was to get insights into the occurrence of brucellosis in dogs in Europe. The database of a European veterinary laboratory was screened for Brucella positive samples. Additionally, medical records of a veterinary hospital in Germany were screened for diagnosis of discospondylitis and brucellosis. The laboratory received samples from 20 European countries for Brucella testing in dogs: 3.7% of submitted samples were Brucella spp. PCR-positive (61/1,657), and Brucella canis antibodies were identified in 5.4% of submitted samples (150/2,764). Brucella spp. PCR-positive samples originated from Spain (11.1% of submitted samples), Poland (6.7% of submitted samples) and rarely from Italy and France. Samples with Brucella canis antibodies originated from 13 European countries (Sweden, Belgium, Austria, Switzerland, Italy, Finland, Germany, Denmark, Hungary, Norway, Poland, France, Netherlands). Young dogs (0-24 months) had a 5.4-fold increased risk of PCR positive samples. The supplementary medical records search identified four young female dogs (7-30 months) with Brucella canis discospondylitis in Germany. The four dogs had been imported to Germany from Eastern European countries (Moldavia, Romania, Macedonia). In conclusion, infection with Brucella canis needs to be considered in dogs in Europe and diagnostics for Brucella canis infection appear indicated in young dogs with discospondylitis

Particulate and dissolved organic carbon in the Lena Delta – the Arctic Ocean interface

Rapid Arctic warming accelerates permafrost thaw releasing aged organic matter (OM) to inland aquatic ecosystems and ultimately, after transport via estuaries or deltas, to the Arctic Ocean nearshore. Despite the importance of Arctic deltas, their functioning is still poorly studied. Here, we examined seasonal fluctuations and spatial differences in the quantity and composition of OM in the Lena Delta, measuring dissolved and particulate organic carbon (DOC and POC) concentrations, carbon isotopes (δ13C and Δ14C), and total suspended matter (TSM). We compared deltaic POC to the POC in the Lena River main stem over a ~1600 km transect, from Yakutsk to the Lena Delta. We further examined and compared dynamics of DOC and POC in summer and winter across a ~140 km transect in the Lena Delta. TSM and POC concentrations decreased by 75 % during transit from Yakutsk to the Lena Delta. 18 % of deltaic and 5 % of river main stem POC originated from Yedoma deposits. Thus, despite lower concentrations of POC in the delta, amount of POC from Yedoma deposits in deltaic waters were almost twice as large as in the main stem (0.07 ±0.02 and 0.04 ±0.02 mg L-1, respectively). Deltaic POC was strongly depleted in 13C due to significant phytoplankton contributions (~-68 ±6 %). Strong differences between winter and summer samples in DOC and POC concentrations and their properties in the Lena Delta were also found. Combined analyses of DOC and POC revealed that Pleistocene-aged Yedoma deposits were still actively degrading in winter influencing the quantity and composition of OM of the Lena Delta and exported OC loads. Deltaic processes control the type and amount of OM exported to the Arctic Ocean and require deeper investigations as crucial processes for the riverine and oceans pathways in a warming Arctic

Particulate organic matter in the Lena River and its Delta: From the permafrost catchment to the Arctic Ocean

Rapid Arctic warming accelerates permafrost thaw, causing an additional release of terrestrial organic matter (OM) into rivers, and ultimately, after transport via deltas and estuaries, to the Arctic Ocean nearshore. The majority of our understanding of nearshore OM dynamics and fate has been developed from freshwater rivers, despite the likely impact of highly dynamic estuarine and deltaic environments on transformation, storage, and age of OM delivered to coastal waters. Here, we studied OM dynamics within the Lena River main stem and Lena Delta along an approximately ∼1600 km long transect from Yakutsk, downstream to the delta disembogue into the Laptev Sea. We measured particulate organic carbon (POC), total suspended matter (TSM), and carbon isotopes (δ13C and ∆14C) in POC to compare riverine and deltaic OM composition and changes in OM source and fate during transport offshore. We found that TSM and POC concentrations decreased by 55 and 70 %, respectively, during transit from the main stem to the delta and Arctic Ocean. We found deltaic POC to be strongly depleted in 13C relative to fluvial POC, indicating a significant phytoplankton contribution to deltaic POC (∼68 ±6 %). Dual-carbon (∆14C and δ13C) isotope mixing model analyses suggested an additional input of permafrost-derived OM into deltaic waters (∼18 ±4 % of deltaic POC originates from Pleistocene deposits vs ∼ 5 ±4 % in the river main stem). Despite the lower concentration of POC in the delta than in the main stem (0.41 ±0.10 vs. 0.79 ±0.30 mg L-1, respectively ), the amount of POC derived from Pleistocene deposits in deltaic waters was almost twice as large as POC of Yedoma origin in the main stem (0.07 ±0.02 and 0.04 ±0.02 mg L-1, respectively). We assert that estuarine and deltaic processes require consideration in order to correctly understand OM dynamics throughout Arctic nearshore coastal zones and how these processes may evolve under future climate-driven change

Enhanced river runoff and permafrost thaw affect Arctic shelf processes

Enhanced river runoff and coastal erosion are causing greater amounts of terrestrial material supply to Arctic shelf waters. Increasing freshwater export of carbon and nutrient loads from land (terr-OM) together with compositional shifts - due to changing hydrologic flow paths and permafrost thaw, can modify shelf water chemistry and biogeochemical processes. Here, we examine how shifts in land-ocean terr-OM supply may alter shelf primary productivity, respiration and ultimately net regional CO2 air–sea fluxes. Unique insights into terr-OM dynamics and composition during transit through riverine, deltaic and shelf waters were collected through multiple field campaigns on the Lena River and Laptev Sea shelf region. Harnessing these field data, we examine the effects of contemporary and future terr-OM supply to shelf waters using newly developed 1-D and 3-D regional biogeochemical models specifically capable of parameterising terr-OM, composition and degradation. In agreement with prior studies, we find that land-derived nutrients could strengthen coastal production sustaining up to ~50% of primary productivity under current terr-OM conditions. However, we also found that additional terr-OM supply caused increased light limitation in coastal waters, offsetting nutrient fertilization effects and stimulating zooplankton grazing. Model experiments indicate that future increases in terr-OM of between 25-50% and/ or shifts to more biologically reactive coastal OM -such as to be expected with permafrost thaw, will reduce net CO2 uptake and lead to positive CO2 feedback from Arctic shelf waters. Our results question the capacity of the coastal Arctic Ocean to serve as a net sink for atmospheric CO2 with future increasing land-ocean connectivity and terr-OM supply

Organic matter characteristics of a rapidly eroding permafrost cliff in NE Siberia (Lena Delta, Laptev Sea region)

Organic carbon (OC) stored in Arctic permafrost represents one of Earth’s largest and most vulnerable terrestrial carbon pools. Amplified climate warming across the Arctic results in widespread permafrost thaw. Permafrost deposits exposed at river cliffs and coasts are particularly susceptible to thawing processes. Accelerating erosion of terrestrial permafrost along shorelines leads to increased transfer of organic matter (OM) to nearshore waters. However, the amount of terrestrial permafrost carbon and nitrogen as well as the OM quality in these deposits is still poorly quantified. We define the OM quality as the intrinsic potential for further transformation, decomposition and mineralisation. Here, we characterise the sources and the quality of OM supplied to the Lena River at a rapidly eroding permafrost river shoreline cliff in the eastern part of the delta (Sobo-Sise Island). Our multi-proxy approach captures bulk elemental, molecular geochemical and carbon isotopic analyses of Late Pleistocene Yedoma permafrost and Holocene cover deposits, discontinuously spanning the last ~52 kyr. We showed that the ancient permafrost exposed in the Sobo-Sise cliff has a high organic carbon content (mean of about 5 wt %). The oldest sediments stem from Marine Isotope Stage (MIS) 3 interstadial deposits (dated to 52 to 28 cal ka BP) and are overlaid by last glacial MIS 2 (dated to 28 to 15 cal ka BP) and Holocene MIS 1 (dated to 7–0 cal ka BP) deposits. The relatively high average chain length (ACL) index of n-alkanes along the cliff profile indicates a predominant contribution of vascular plants to the OM composition. The elevated ratio of iso and anteiso-branched fatty acids (FAs) relative to mid- and long-chain (C�20) n-FAs in the interstadial MIS 3 and the interglacial MIS 1 deposits suggests stronger microbial activity and consequently higher input of bacterial biomass during these climatically warmer periods. The overall high carbon preference index (CPI) and higher plant fatty acid (HPFA) values as well as high C=N ratios point to a good quality of the preserved OM and thus to a high potential of the OM for decomposition upon thaw. A decrease in HPFA values downwards along the profile probably indicates stronger OM decomposition in the oldest (MIS 3) deposits of the cliff. The characterisation of OM from eroding permafrost leads to a better assessment of the greenhouse gas potential of the OC released into river and nearshore waters in the future

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease.

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. OBJECTIVES: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. METHODS: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. RESULTS: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. CONCLUSIONS: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression