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Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson’s disease (PD), a recent meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores at baseline and 6–12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation.

Hepatitis C: model answer The development of an effective vaccine and specific antiviral therapies against hepatitis C virus (HCV), a leading cause of liver disease, has been hampered by the lack of a convenient small animal model. With the identification of the gap junction protein occludin as the fourth and final key component of the hepatitis C virus cell-entry receptor, that elusive lab model may have come a step nearer. In addition to human occludin, viral infection of murine cells requires expression of the previously identified HCV entry factors CD81, scavenger receptor class B type I, and claudin-1. This report identifies the gap junction protein occludin as the fourth and final key component of the hepatitis C virus cell-entry receptor, paving the way towards the development of a small animal model for hepatitis C virus. Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of much needed specific antiviral therapies and an effective vaccine has been hampered by the lack of a convenient small animal model. The determinants restricting HCV tropism to human and chimpanzee hosts are unknown. Replication of the viral RNA has been demonstrated in mouse cells 1 , 2 , but these cells are not infectable with either lentiviral particles bearing HCV glycoproteins (HCVpp) 3 or HCV produced in cell culture (HCVcc) (A.P., M.E. and C.M.R., unpublished observations), suggesting that there is a block at the level of entry. Here we show, using an iterative complementary DNA library screening approach, that human occludin (OCLN) is an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for the HCV-susceptibility of human cells, because its overexpression in uninfectable cells specifically enhanced HCVpp uptake, whereas its silencing in permissive cells impaired both HCVpp and HCVcc infection. In addition to OCLN, HCVpp infection of murine cells required expression of the previously identified HCV entry factors CD81 (ref. 4 ), scavenger receptor class B type I (SR-BI, also known as SCARB1) 5 and claudin-1 (CLDN1) 6 . Although the mouse versions of SR-BI and CLDN1 function at least as well as the human proteins in promoting HCV entry, both OCLN and CD81 must be of human origin to allow efficient infection. The species-specific determinants of OCLN were mapped to its second extracellular loop. The identification of OCLN as a new HCV entry factor further highlights the importance of the tight junction complex in the viral entry process, and provides an important advance towards efforts to develop small animal models for HCV.

There is currently no cure for Parkinson’s disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson’s disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.

Organic amendment application is one of the sustainable options to provide nutrients and carbon resources for plant and soil microbes. However, it is complicated to predict how the organic amendment will affect nutrient availability in the soil and plant growth due to the complex interaction between soil, plants, and microbes. In chapter 2 we explored the influence of liquid organic amendments and rhizodeposition on litter decomposition under different background media. Liquid organic fertilizer derived from food waste not only contains plant available nutrients, but also contains labile C which is a great resource for soil microbes. Plant roots can manipulate the rhizosphere using similar processes, by adding labile carbon compounds to the immediate root environment, either through active exudation or sloughing off mucilage or dead root material. Using a container study, we found that when ample organic matter was available in the growing media, the presence of plant roots had a strong positive impact on litter decomposition. In both low and high organic matter growing media a one-time addition of fertilizer had minimal or negative effects on litter decomposition. Boosting root length growth via the one-time addition of inorganic fertilizer when organic matter was negligible, likely let the plant outcompete decomposer microbes for N, while selecting for microbes that primarily feed on root exudates. A shift that would retard litter decomposition rates once the easily decomposed portion of the litter was broken down.Recycling old orchards by chipping the trees and incorporating the wood chips into the soil can be one option for the disposal of discarded trees. In chapter 3, we examined how wood chip incorporation into an orchard soil prior to planting affects root architecture and soil biological activity. We found significant increases in standing root length density in planting berms with wood chip incorporation two and three years after trees were planted. This was due to an increase in root mass per soil volume rather than an increase in specific root length or a change in proportion of fine roots produced. Thus, although root foraging was increased, this was not due to a change in root architectural traits. In the fourth chapter we assessed how wood chip incorporation in the soil affected microbial composition in bulk soil and rhizosphere. Wood chip incorporation increased bacterial diversity in the soil and rhizosphere but did not affect fungal diversity in the soil. We did find an increase in fungal diversity in the rhizosphere when wood chips were incorporated in the soil. When we studied diversity along the root axis, we found that young root tips (more active) had greater bacterial diversity in the rhizosphere than the diversity in the bulk soil, but this was not the case for fungal community. Overall, we found that differences in diversity and community composition between blocks were greater than the impact of incorporating wood chips or the differences between rhizosphere and bulk soil.

BackgroundNMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson’s disease (PD).MethodsPatients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations.Results310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa.ConclusionsThis is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.

Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, and analysed their associations with enzyme activity, Saposin C (SapC) interaction and PD progression in 639 patients with heterozygous GBA1 variants from five cohorts. Principal component analysis (PCA) identified two components: PC1, associated with reduced β-glucocerebosidase activity, the GD clinical severity classification, younger age at PD diagnosis, and faster cognitive and motor decline; and PC2, associated with surface-exposed, flexible regions involved in SapC interactions, younger age at PD diagnosis, and slightly with motor decline. These findings highlight that impaired SapC interactions, in addition to reduced activity, may contribute to PD severity in GBA1 variant carriers. This is relevant for therapeutic approaches aimed at stabilizing β-glucocerebosidase or enhancing its enzymatic activity in PD.

Natural regeneration is an essential component of forest dynamics and the recovery of ecosystem functions. Therefore, understanding regeneration status, and how abiotic and biotic factors affect it, is important for ecological studies. This study discovered different regeneration statuses of tropical forests in response to differences in rainfall in Myanmar, and the environmental and overstory factors that had the most influence on understory regeneration. Study sites were set up in regions with 625 to 2035 mm of annual rainfall, and ecological characteristics were measured. According to the results, natural regeneration increased with rainfall, showing a good regeneration status at all sites. Forests within a range of 1411–2035 mm of annual rainfall had a significantly higher density and species diversity at specific natural regeneration stages than those with 625–1029 mm. Not only abiotic but also overstory structure affected the natural regeneration of forests. However, not all factors influenced natural regeneration status. Overstory size distribution parameters did not show a significant influence on natural regeneration. Average annual rainfall (abiotic), as well as ecosystem complexity, density, species richness, and diversity (overstory), were found to be the most influential factors for the density and diversity of natural regeneration. The results of this study will support silviculture and the management of tropical forests.

An understanding of how species diversity, structural pattern, and species distribution vary across different environmental regions is crucially important for tropical ecology. In this study, we explored how these ecological parameters vary across various rainfall regions in the tropics with annual rainfall levels ranging from 843 to 2035 mm. Diversity, similarity, structure, and forest classification, and their correspondence with rainfall regions were tested. We found that species diversity, site class, and structural complexity increased with rainfall, with differences of 1000 mm having significant effects on diversity. The structure and heterogeneity of forests were higher in the high rainfall regions than the low rainfall regions. The forest structure was significantly correlated with rainfall, and the structure differed substantially where annual rainfall differed among sites by approximately 200 or 400 mm. Forests could be classified into two types according to whether they had high annual rainfall (1411–2035 mm) or low annual rainfall (843–1029 mm). In addition, the dominance of species changed noticeably from high- to low-rainfall regions, with Tectona hamiltoniana and Terminalia oliveri only being abundant in the low rainfall region. Species diversity and richness were significantly correlated with rainfall and average temperature. These findings will provide invaluable information for forest management and ecological phytogeography.

Hepatitis C: model answer