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Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson’s Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 ( GBA1 ), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn). As autophagy is one of the main systems involved in the proteolytic degradation of α-syn, pharmacological enhancement of autophagy may be an attractive strategy to combat α-syn aggregation in PD. Here, we review the potential of autophagy enhancement as disease-modifying therapy in PD based on preclinical evidence. In particular, we provide an overview of the molecular regulation of autophagy and targets for pharmacological modulation within the ALP. In experimental models, beneficial effects on multiple pathological processes involved in PD, including α-syn aggregation, cell death, oxidative stress and mitochondrial dysfunction, have been demonstrated using the autophagy enhancers rapamycin and lithium. However, selectivity of these agents is limited, while upstream ALP signaling proteins are involved in many other pathways than autophagy. Broad stimulation of autophagy may therefore cause a wide spectrum of dose-dependent side-effects, suggesting that its clinical applicability is limited. However, recently developed agents selectively targeting core ALP components, including Transcription Factor EB (TFEB), lysosomes, GCase as well as chaperone-mediated autophagy regulators, exert more specific effects on molecular pathogenetic processes causing PD. To conclude, the targeted manipulation of downstream ALP components, rather than broad autophagy stimulation, may be an attractive strategy for the development of novel pharmacological therapies in PD. Further characterization of dysfunctional autophagy in different stages and molecular subtypes of PD in combination with the clinical translation of downstream autophagy regulation offers exciting new avenues for future drug development.

Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)—including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn—accumulate in Lewy bodies (LBs) in different regions of the Parkinson’s disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.

We use eddy covariance measurements of net ecosystem productivity (NEP) from 21 FLUXNET sites (153 site-years of data) to investigate relationships between phenology and productivity (in terms of both NEP and gross ecosystem photosynthesis, GEP) in temperate and boreal forests. Results are used to evaluate the plausibility of four different conceptual models. Phenological indicators were derived from the eddy covariance time series, and from remote sensing and models. We examine spatial patterns (across sites) and temporal patterns (across years); an important conclusion is that it is likely that neither of these accurately represents how productivity will respond to future phenological shifts resulting from ongoing climate change. In spring and autumn, increased GEP resulting from an ‘extra’ day tends to be offset by concurrent, but smaller, increases in ecosystem respiration, and thus the effect on NEP is still positive. Spring productivity anomalies appear to have carry-over effects that translate to productivity anomalies in the following autumn, but it is not clear that these result directly from phenological anomalies. Finally, the productivity of evergreen needleleaf forests is less sensitive to phenology than is productivity of deciduous broadleaf forests. This has implications for how climate change may drive shifts in competition within mixed-species stands.

The response of crops to changing climate and atmospheric CO2 concentration ([CO2]) could have large effects on food production, and impact carbon, water, and energy fluxes, causing feedbacks to the climate. To simulate the response of temperate crops to changing climate and [CO2], which accounts for the specific phenology of crops mediated by management practice, we describe here the development of a process-oriented terrestrial biogeochemical model named ORCHIDEE-CROP (v0), which integrates a generic crop phenology and harvest module, and a very simple parameterization of nitrogen fertilization, into the land surface model (LSM) ORCHIDEEv196, in order to simulate biophysical and biochemical interactions in croplands, as well as plant productivity and harvested yield. The model is applicable for a range of temperate crops, but is tested here using maize and winter wheat, with the phenological parameterizations of two European varieties originating from the STICS agronomical model. We evaluate the ORCHIDEE-CROP (v0) model against eddy covariance and biometric measurements at seven winter wheat and maize sites in Europe. The specific ecosystem variables used in the evaluation are CO2 fluxes (net ecosystem exchange, NEE), latent heat, and sensible heat fluxes. Additional measurements of leaf area index (LAI) and aboveground biomass and yield are used as well. Evaluation results revealed that ORCHIDEE-CROP (v0) reproduced the observed timing of crop development stages and the amplitude of the LAI changes. This is in contrast to ORCHIDEEv196 where, by default, crops have the same phenology as grass. A halving of the root mean square error for LAI from 2.38 ± 0.77 to 1.08 ± 0.34 m2 m−2 was obtained when ORCHIDEEv196 and ORCHIDEE-CROP (v0) were compared across the seven study sites. Improved crop phenology and carbon allocation led to a good match between modeled and observed aboveground biomass (with a normalized root mean squared error (NRMSE) of 11.0–54.2 %), crop yield, daily carbon and energy fluxes (with a NRMSE of  ∼  9.0–20.1 and  ∼  9.4–22.3 % for NEE), and sensible and latent heat fluxes. The simulated yields for winter wheat and maize from ORCHIDEE-CROP (v0) showed a good match with the simulated results from STICS for three sites with available crop yield observations, where the average NRMSE was  ∼  8.8 %. The model data misfit for energy fluxes were within the uncertainties of the measurements, which themselves showed an incomplete energy balance closure within the range 80.6–86.3 %. The remaining discrepancies between the modeled and observed LAI and other variables at specific sites were partly attributable to unrealistic representations of management events by the model. ORCHIDEE-CROP (v0) has the ability to capture the spatial gradients of carbon and energy-related variables, such as gross primary productivity, NEE, and sensible and latent heat fluxes across the sites in Europe, which is an important requirement for future spatially explicit simulations. Further improvement of the model, with an explicit parameterization of nutritional dynamics and management, is expected to improve its predictive ability to simulate croplands in an Earth system model.

Gross primary productivity (GPP) is the largest and most variable component of the global terrestrial carbon cycle. Repeatable and accurate monitoring of terrestrial GPP is therefore critical for quantifying dynamics in regional-to-global carbon budgets. Remote sensing provides high frequency observations of terrestrial ecosystems and is widely used to monitor and model spatiotemporal variability in ecosystem properties and processes that affect terrestrial GPP. We used data from the Moderate Resolution Imaging Spectroradiometer (MODIS) and FLUXNET to assess how well four metrics derived from remotely sensed vegetation indices (hereafter referred to as proxies) and six remote sensing-based models capture spatial and temporal variations in annual GPP. Specifically, we used the FLUXNET La Thuile data set, which includes several times more sites (144) and site years (422) than previous studies have used. Our results show that remotely sensed proxies and modeled GPP are able to capture significant spatial variation in mean annual GPP in every biome except croplands, but that the percentage of explained variance differed substantially across biomes (10–80%). The ability of remotely sensed proxies and models to explain interannual variability in GPP was even more limited. Remotely sensed proxies explained 40–60% of interannual variance in annual GPP in moisture-limited biomes, including grasslands and shrublands. However, none of the models or remotely sensed proxies explained statistically significant amounts of interannual variation in GPP in croplands, evergreen needleleaf forests, or deciduous broadleaf forests. Robust and repeatable characterization of spatiotemporal variability in carbon budgets is critically important and the carbon cycle science community is increasingly relying on remotely sensing data. Our analyses highlight the power of remote sensing-based models, but also provide bounds on the uncertainties associated with these models. Uncertainty in flux tower GPP, and difference between the footprints of MODIS pixels and flux tower measurements are acknowledged as unresolved challenges.

Background The radial forearm free flap (RFFF) is widely used in microvascular reconstructions. However, donor site morbidity remains a concern, with complications such as wound healing issues, functional impairments, and aesthetic concerns. While both full-thickness skin grafts (FTSG) and split-thickness skin grafts (STSG) are commonly used for donor site closure, there is insufficient evidence to determine which technique leads to fewer complications. This study aims to systematically compare FTSG and STSG in RFFF donor site closure. Methods We searched six databases and four clinical trial registries up to 1 March 2025. We focused on studies comparing FTSG and STSG. Primary outcome was the incidence of wound complications. Secondary outcomes included functional and aesthetic impairment. Risk of bias was assessed using the Risk Of Bias In Non-Randomized Studies—of Interventions (ROBINS-I) and quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Fifteen studies were analyzed, involving 933 donor site closures. No RCTs met our inclusion criteria. Meta-analysis comparing FTSG versus STSG revealed no significant differences in major wound complications ( RR 0.43; 95% CI 0.11 to 1.70; p  = 0.23) and minor wound healing complications ( RR 0.83; 95% CI 0.60 to 1.13; p  = 0.23), with the evidence graded as low to very low certainty. Conclusion Current evidence does not conclusively favor either FTSG or STSG for radial forearm free flap donor site closure regarding wound, functional, or aesthetic outcomes. Future well-designed RCTs are needed to provide higher-quality evidence to guide clinical decision-making. Until more robust evidence becomes available, the optimal skin graft choice should be guided by patient-specific factors, surgical considerations, and donor site characteristics. Systematic review registration PROSPERO CRD42023351903.

In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA −/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129A KI ) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker.

Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson’s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein–lipid compartmentalization not previously described in the Parkinsons’ disease brain.

Croplands cover about 12% of the ice-free terrestrial land surface. Compared with natural ecosystems, croplands have distinct characteristics due to anthropogenic influences. Their global gross primary production (GPP) is not well constrained and estimates vary between 8.2 and 14.2 Pg C yr−1. We quantified global cropland GPP using a light use efficiency (LUE) model, employing satellite observations and survey data of crop types and distribution. A novel step in our analysis was to assign a maximum light use efficiency estimate (ϵ*GPP) to each of the 26 different crop types, instead of taking a uniform value as done in the past. These ϵ*GPP values were calculated based on flux tower CO2 exchange measurements and a literature survey of field studies, and ranged from 1.20 g CMJ−1 to 2.96 g CMJ−1. Global cropland GPP was estimated to be 11.05 Pg C yr−1 in the year 2000. Maize contributed most to this (1.55 Pg C yr−1), and the continent of Asia contributed most with 38.9% of global cropland GPP. In the continental United States, annual cropland GPP (1.28 Pg C yr−1) was close to values reported previously (1.24 Pg C yr−1) constrained by harvest records, but our estimates of ϵ*GPP values were much higher. Our results are sensitive to satellite information and survey data on crop type and extent, but provide a consistent and data-driven approach to generate a look-up table of ϵ*GPP for the 26 crop types for potential use in other vegetation models.