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Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting 1% of people aged over 60. Currently, there is only symptomatic relief for PD patients, with levodopa being the gold standard of PD treatment. Deep brain stimulation (DBS) is a surgical option to treat PD patients. DBS improves motor functions and may also allow a significant reduction in dopaminergic medication. Important parameters for DBS outcomes are the disease duration, the age of disease onset, responsiveness to levodopa and cognitive or psychiatric comorbidities. Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline. [ABSTRACT FROM AUTHOR]

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids' serum levels in a cohort of Parkinson's Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher's exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn's test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention. [ABSTRACT FROM AUTHOR]

Parknson's disease (PD) is the second most common neurodegenerative disease, affecting 1% of people aged over 60. PD is characterized by a wide range of motor symptoms, however the clinical spectrum of PD covers a wide range of non-motor symptoms, as well. Sleep disorders are among the most common non-motor symptoms of PD, can occur at any stage of the disease and significantly affect quality of life. These include rapid eye movement sleep behavior disorder (RBD), restless legs syndrome (RLS), excessive daytime sleepiness (EDS), insomnia, obstructive sleep apnea (OSA) and circadian rhythm disturbances. One of the main challenges in PD research is identifying individuals during the prodromal phase of the disease. Combining genetic and prodromal data may aid the early identification of individuals susceptible to PD. This review highlights current data regarding the genetic component of sleep disorders in PD patients, focusing on genes that have currently been associated with this PD co-morbidity. [ABSTRACT FROM AUTHOR]

Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information. [ABSTRACT FROM AUTHOR]

Background: ship emissions have an adverse effect on air quality in coastal regions, and this effect can be exacerbated by onshore winds. Objectives and methods: to investigate the impact of ship emissions on air pollutant concentrations during the onshore wind period in a low-latitude region in China, this study applied the WRF/Chem model to simulate the contribution of ship emissions to PM2.5 and O3 by "zero-out" in 2018, in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA). Results/findings: results show that the onshore winds facilitated the transport of ship-emitted pollutants to inland areas, causing the contribution of ship emissions to PM2.5 exceeding 4 μg/m3 to areas north of Guangzhou in April and west of the GBA in October. The impact of onshore winds on the ship contribution to the O3 concentration shows a bidirectional trend both spatially and monthly. The onshore winds raised the ship contribution to O3 concentrations in April by 1.54 μg/m3, while exacerbated the decreasing contribution in other months. In VOC-sensitive cities such as Foshan, onshore winds exacerbated the negative contribution of ship emissions to O3 concentrations; while in NOx-sensitive cities such as Huizhou, they enhanced the contribution of ship-induced O3. Novelty/Improvement: this paper fills a gap in the study of pollutants transportation characteristics from ship emissions under the influence of onshore winds in the GBA. Our results demonstrate the importance of considering meteorological conditions and atmospheric chemical mechanisms regarding the coastal air pollution prevention caused by ship emissions. [ABSTRACT FROM AUTHOR]

An emergy analysis is used to assess the sustainability of urban agglomerations' eco-economic systems, which are generally measured by emergy–value sustainability indicators using a combination of several system indicators. However, this assessment approach is not applicable to economically developed high-density urban agglomerations. The application of the traditional entropy value evaluation method needs to be expanded to further strengthen the sustainability of the complex eco-economic–social relationships in megacity cluster regions. In this study, taking the Guangdong–Hong Kong–Macau Greater Bay Area (GBA) as a case study, we study a new evaluation method for evaluating the sustainable development capacity of cities. This method is based on the entropy power method and is used to construct the evaluation system of all indicators of the social–economic–natural subsystems of the eco-economic system, and it couples the development degree with the coordination degree. (1) This study shows that the new method is applicable for the sustainability assessment of high-density megacity clusters and is more accurate and comprehensive. The sustainability rankings are provided for Zhaoqing, Jiangmen, Huizhou, Guangzhou, Macau, Foshan, Zhongshan, Dongguan, Zhuhai, and Shenzhen. Hong Kong is the most representative, with a high sustainability index, but has the lowest level of coordination and a clear incoherence within the system. (2) The current emergy structure of the GBA city cluster is extremely unreasonable. The GBA city cluster is a resource-consuming city with a common characteristic of a low level of coordinated development. Although urban clusters have some potential in terms of renewable emergy and resources, the recycling rate of waste is low, and the consumption rate of nonrenewable resources is high. The effective use of land resources has become an important factor in the bottlenecking of sustainable development, and all other cities face such problems, except Zhaoqing, Jiangmen, and Huizhou. (3) The GBA city cluster can be divided into three categories according to the new method. Category 1 mainly includes Hong Kong, Shenzhen, Dongguan, and Zhuhai, which have coordinated development degrees ranging between 0.0 and 0.135 and the highest emergy density (ED) values but are extremely dependent on external emergy. They have high levels of emergy use per capita (EUC), high living standards, and high quality of life. The effective use of land resources severely restricts sustainable economic development, resulting in extreme ecological and environmental carrying pressure. Category 2 includes Guangzhou, Macau, Foshan, and Zhongshan, whose coordinated development degrees range from 0.143 to 0.179. The sustainable development capacity of these cities is at the middle level amongst the whole GBA. Their main emergy characteristics are emergy flow and subsystem evaluation indices that are between category 1 and category 3, but each has its own characteristics. The category 3 cities include Zhaoqing, Jiangmen, and Huizhou, whose coordinated development degrees are between 0.192 and 0.369. These cities are characterized by relatively low ED and EUC values, living standards, and quality, but their land resources have certain potential. These cities have a high emergy self-sufficiency rate (ESR) and natural environmental support capacity, but their environmental loading ratio (ELR) is still much higher than the national average. In terms of the economic development and innovation development levels, these cities are ranked as category 1 > category 2 > category 3. In terms of the ecological and environmental conditions and blue–green space protection, these cities are ranked as category 1 < category 2 < category 3. The results of this study can provide cities in the GBA with more scientific and consistent directions for the coordinated development of their ecological–economic–social systems to provide sustainable development decision-making services for megacity cluster systems. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated α-synuclein. Although the α-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

GBA gene variants were the first genetic risk factor for Parkinson's disease. GBA encodes the lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. GBA exhibits a complex physiological function that includes not only the degradation of its substrate glucosylceramide but also the metabolism of other sphingolipids and additional lipids such as cholesterol, particularly when glucocerebrosidase activity is deficient. In the context of Parkinson's disease associated with GBA, the loss of GBA activity has been associated with the accumulation of α-synuclein species. In recent years, several hypotheses have proposed alternative and complementary pathological mechanisms to explain why lysosomal enzyme mutations lead to α-synuclein accumulation and become important risk factors in Parkinson's disease etiology. Classically, loss of GBA activity has been linked to a dysfunctional autophagy–lysosome system and to a subsequent decrease in autophagy-dependent α-synuclein turnover; however, several other pathological mechanisms underlying GBA-associated parkinsonism have been proposed. This review summarizes and discusses the different hypotheses with a special focus on autophagy-dependent mechanisms, as well as autophagy-independent mechanisms, where the role of other players such as sphingolipids, cholesterol and other GBA-related proteins make important contributions to Parkinson's disease pathogenesis. [ABSTRACT FROM AUTHOR]

The protection of mangroves through nature reserves has been demonstrated to be effective. There were many studies evaluating the mangrove protection effect. However, the evaluation of mangrove growth quality with positive or negative growth trends, as well as restoration potential against disturbance in nature reserves, is still lacking. Thus, this study proposed a hierarchical evaluation framework for mangrove protection in nature reserves, which takes long-term metrics at three levels of loss and gain areas, patch pattern dynamics, and pixel growth trends into account. The continuous change detection and classification (CCDC) was utilized to identify the change condition of mangroves in six nature reserves of the Guangdong–Hong Kong–Macao Greater Bay Area. The Entropy Weight Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) was utilized for scores evaluation of protection effort comparison from 2000 to 2020. The study results had the following three main findings. Firstly, the mangrove forest area increased by about 294.66 ha in four reserves and slightly decreased by about 58.86 ha in two. Most reserves showed an improved patches intact pattern and more positive growth trends. Secondly, the establishment of nature reserves and afforestation were the main causes of mangrove area gain. Until 2010, aquaculture, agriculture, and urban development were the biggest threats to mangroves. Finally, the protection of the reserves was successful in the early decades, but the general evaluation scores showed a decline in recent years once we considered the growth trends for quality. The proposed hierarchical evaluation methods provide a new sight to research the impacts of abrupt change and protection resilience status of the gradual restoration of nature reserves. [ABSTRACT FROM AUTHOR]

Understanding the pathophysiology and genetic background of Parkinson's disease (PD) increases the likelihood of developing effective disease-modifying therapeutic strategies. In particular, the discovery of genetic variants causing or increasing the risk for PD has contributed to refining the clinical, biological, and molecular classification of the disease and has offered new insights into sporadic forms. It is even more evident that specific genetic mutations can show different responses to pharmacological and device-aided therapies. To date, several agents acting on multiple PD-causing pathogenic pathways have been tested as disease-modifying strategies, with disappointing results. This may be caused by the recruitment of PD populations whose underlying molecular pathophysiology is heterogeneous. We believe that an effective model of personalized medicine must be prioritized in the near future. Here, we review the current therapeutic options under clinical and preclinical development for PD and discuss the key pending questions and challenges to face for successful clinical trials. Furthermore, we provide some insights into the role of genetics in guiding the decision-making process on symptomatic and device-aided therapies for PD in daily clinical practice. [ABSTRACT FROM AUTHOR]

Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson's disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies. [ABSTRACT FROM AUTHOR]

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson's disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis. [ABSTRACT FROM AUTHOR]

The imbalance of intestinal microbiota can cause the accumulation of endotoxin in the main circulation system of the human body, which has a great impact on human health. Increased work and life pressure have led to a rise in the number of people falling into depression, which has also reduced their quality of life. The gut–brain axis (GBA) is closely related to the pathological basis of depression, and intestinal microbiota can improve depressive symptoms through GBA. Previous studies have proven that prebiotics can modulate intestinal microbiota and thus participate in human health regulation. We reviewed the regulatory mechanism of intestinal microbiota on depression through GBA, and discussed the effects of prebiotics, including plant polysaccharides and polyphenols on the regulation of intestinal microbiota, providing new clues for the prevention and treatment of depression. [ABSTRACT FROM AUTHOR]

United Nations Sustainable Development Goal SDG11.3.1—the ratio of land consumption rate (LCR) to population growth rate (PGR) (LCRPGR)—aims to measure the efficiency and sustainability of urban land use. In recent years, SDG11.3.1 has been widely used in sustainable urban development research. However, previous studies have focused on the urban core area, while the sustainable development status of the urban peripheral areas (suburban and rural areas) that contribute significantly to the ecological environment has been neglected. To this end, relying on land use/cover change (LUCC) data obtained from high-resolution remote sensing satellite images rather than the single impervious surface data used in traditional research, according to the multiple functions of the land use type, the city is divided into three types of space: production, living, and ecological spaces. Research from the perspective of multi-scale coordination is of great significance for gaining a comprehensive understanding of the sustainable development status of urban space. Taking the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) in China as an example, in this paper, LUCC remote sensing data and comprehensive population and gross domestic product (GDP) data are used. From the multi-functional production-living-ecological space perspective, based on the original land use efficiency indicator, the ratio of land consumption rate (LCR) to economic growth rate (EGR) (LCREGR) is introduced and the analytic hierarchy process (AHP) is used to comprehensively evaluate the sustainable development level (SDL) of the space between 2000–2010 and 2010–2020 on the urban agglomeration and prefecture-level city scales. The results show that (1) the level of and changes in the spatial sustainable development are significantly different at different scales; (2) the division of the production-living-ecological spaces can guide cities to optimize different types of spaces in the future. This paper proposes a new evaluation method for spatial sustainable development, which provides a useful reference for any country or region in the world. [ABSTRACT FROM AUTHOR]

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration. [ABSTRACT FROM AUTHOR]

Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson's disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one's lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) is an autosomal recessive lysosomal disorder due to beta-glucosidase gene (GBA) mutations. The molecular diagnosis of GD is complicated by the presence of recombinant alleles originating from a highly homologous pseudogene. Clinical exome sequencing (CES) is a rapid genetic approach for identifying disease-causing mutations. However, copy number variation and recombination events are poorly detected, and further investigations are required to avoid mis-genotyping. The aim of this work was to set-up an integrated strategy for GD patients genotyping using CES as a first-line test. Eight patients diagnosed with GD were analyzed by CES. Five patients were fully genotyped, while three were revealed to be homozygous for mutations that were not confirmed in the parents. Therefore, MLPA (multiplex ligation-dependent probe amplification) and specific long-range PCR were performed, and two recombinant alleles, one of them novel, and one large deletion were identified. Furthermore, an MLPA assay performed in one family resulted in the identification of an additional novel mutation (p.M124V) in a relative, in trans with the known p.N409S mutation. In conclusion, even though CES has become extensively used in clinical practice, our study emphasizes the importance of a comprehensive molecular strategy to provide proper GBA genotyping and genetic counseling. [ABSTRACT FROM AUTHOR]

The intensity of human activity, habitat loss and habitat degradation have significant impacts on biodiversity. Habitat quality plays an important role in spatial dynamics when evaluating fragmented landscapes and the effectiveness of biodiversity conservation. This study aimed to evaluate the status and characteristic variation in habitat quality to analyze the underlying factors affecting habitat quality in the Guangdong–Hong Kong–Macao Greater Bay Area (GBA). Here, we applied Kendall's rank correlation method to calculate the sensitivity of habitat types to threat factors for the Integrated Valuation of Ecosystem Services and Tradeoffs habitat quality (InVEST-HQ) model. The spatiotemporal variation in habitat quality of the GBA in the period 1995–2015 was estimated based on the InVEST-HQ model. We analyzed the characteristic habitat quality using different ecosystem classifications and at different elevation gradients. Fractional vegetation cover, the proportion of impervious surface, population distribution and gross domestic product were included as the effect factors for habitat quality. The correlation between the effect factors and habitat quality was analyzed using Pearson's correlation tests. The results showed that the spatial pattern of habitat quality decreased from fringe areas to central areas in the GBA, that the forest ecosystem had the highest value of habitat quality, and that habitat quality increased with elevation. In the period from 1995 to 2015, habitat quality declined markedly and this could be related to vegetation loss, land use change and intensity of human activity. Built-up land expansion and forest land fragmentation were clear markers of land use change. This study has great significance as an operational approach to mitigating the tradeoff between natural environment conservation and rapid economic development. [ABSTRACT FROM AUTHOR]

Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements. [ABSTRACT FROM AUTHOR]

Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson's disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson's disease. [ABSTRACT FROM AUTHOR]