Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the ...most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation
impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of
(
), a gene that is associated with recessive Parkinsonism. Combining
and
does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1
, resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of
and
pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis.
Understanding midbrain dopaminergic (DAergic) neuron-selective vulnerability in PD is essential for the development of targeted therapeutics. We report, for the first time, a nerve terminal impairment in SV trafficking selectively in MB neurons but not cortical neurons caused by two PARK genes:
(PARK8) and
(PARK20). We demonstrate that the enhanced kinase activity resulting from the most frequent
mutation in
is the key to this impairment. We provide evidence suggesting that
and
loss of function share a similar pathogenic pathway in deregulating DAergic neuron SV endocytosis and that they play additive roles in facilitating each other's pathogenic functions in PD.
Fungi are key components of microbial communities in mangrove wetlands, with important roles in the transformation of nutrients and energy. However, existing studies typically focus on cultivable ...fungi and seldom on the structure and driving factors of entire fungal communities. The compositions, community assembly, and interaction patterns of mangrove fungal communities on a large scale remain elusive. Here, biogeography, assembly, and co-occurrence patterns of fungal communities in mangroves across eastern to southern China were systematically analyzed by targeting the entire internal transcribed spacer (ITS) region with high-throughput Pacific Biosciences single-molecule real-time sequencing. The analysis revealed a high level of fungal diversity, including a number of basal fungal lineages not previously reported in mangroves, such as
and
. Beta nearest-taxon index analyses suggested a determinant role of dispersal limitation on fungal community in overall and most individual mangroves, with support from the strong distance-decay patterns of community similarity. Further, nonmetric multidimensional scaling analyses revealed similar biogeographies of dominant and rare fungal communities. A minor role of environmental selection on the fungal community was noted, with geographical location and sediment depth as crucial factors driving the distribution of both, the dominant and rare taxa. Finally, network analysis revealed high modularized co-occurrence patterns of fungal community in mangrove sediments, and the keystone taxa might play important roles in microbial interactions and ecological functions. The investigation expands our understanding of biogeography, assembly patterns, driving factors, and co-occurrence relationships of mangrove fungi and will spur the further functional exploration and protection of fungal resources in mangroves.
As key components of microbial community in mangroves, fungi have important ecological functions. However, the fungal community in mangroves on a large scale is generally elusive, and mangroves are declining rapidly due to climate change and anthropogenic activities. This work provides an overview of fungal community structure and biogeography in mangrove wetlands along a >9,000-km coastline across eastern to southern China. Our study observed a high number of basal fungal lineages, such as
and
, in mangrove sediments. In addition, our results highlight a crucial role of dispersal limitation and a minor role of environmental selections on fungal communities in mangrove sediments. These novel findings add important knowledge about the structure, assembly processes, and driving factors of fungal communities in mangrove sediments.
Baseflow plays a vital role in protecting the environment and ensuring a stable water supply for farming. There are still gaps in the current understanding of baseflow convergence rates in the humid ...region due to the abundance of rainfall and the high‐water table. Therefore, this study focused on the evolution and hysteresis characteristics of baseflow in humid basins of southeastern China. The baseflow ensemble simulation (BES) method was established to improve the reliability and applicability of baseflow simulation. We suggest a way of differentiating the wet and dry seasons based on the multi‐year average monthly baseflow index (BFI) to determine the intra‐annual distribution of water effectively and simply. The hydrological hysteresis effect of baseflow on precipitation is revealed by characterizing baseflow response to precipitation under precipitation events during wet and dry seasons. A methodology for assessing the performance of baseflow simulation was proposed from observations of streamflow and precipitation. We found that the BES method performed better in baseflow simulation than other single separation methods. Using the BES method, the lag time of baseflow to precipitation during the wet and dry seasons was found to be 3.09 and 4.04 days after utilizing the BFI to divide the hydrological situation into wet and dry seasons. Additionally, precipitation had nearly twice as much intensity influence on baseflow during the dry season compared to the wet season. These findings have significant ramifications for the use, management, and planning of water resources in humid areas of China.
Plain Language Summary
The importance of researching baseflow in humid places is expanding as drought conditions occur more frequently. The lag time effect of baseflow on precipitation varies spatially and temporally, while the applicability of each baseflow simulation method varies in different regions. In this study, we validated the performance of a baseflow ensemble simulation method in the humid region of southeastern China. Humid regions had a shorter lag between baseflow and precipitation than desert, semiarid, and semi‐humid zones. The lag time of baseflow for rainfall simulated by the BES method was in the middle of the four methods. Additionally, compared to the dry season, the baseflow lag time was noticeably shorter during the wet season. This is because the humid region basin receives most of its yearly precipitation during the rainy season, primarily in the form of intense rainfall that lasts just a brief time. In addition, baseflow variations coincided with variations in precipitation during the rainy season, while there was a delay between variations in baseflow and changes in precipitation during the dry season. Understanding the effects of climate change and water use on groundwater‐surface water interactions in humid regions of China is significantly impacted by these findings.
Key Points
An ensemble‐based baseflow simulation method is proposed to characterize the uncertainty of each baseflow separation method
The hydrologic hysteresis between baseflow and rainfall was found to be within 1 week in the humid basins of Southeastern China
The influence of precipitation on baseflow in the humid basins is significantly stronger in the dry season than in the wet season
Background Double-balloon endoscopy (DBE) has been used in clinical practice for nearly 10 years. Objective To systematically collect and produce pooled data on indications, detection rate, total ...enteroscopy, complications, and the composition of positive findings in diagnostic DBE. Design A systematic review. Main Outcome Measurements We searched PubMed between January 1, 2001 and March 31, 2010 for original articles about DBE evaluation of small-bowel diseases. Data on total number of procedures, distribution of indications, pooled detection rate, pooled total enteroscopy rate, and composition of positive findings were extracted and/or calculated. In addition, the data involving DBE-associated complications were analyzed. Results A total of 66 English-language original articles involving 12,823 procedures were included. Suspected mid-GI bleeding (MGIB) was the most common indication (62.5%), followed by symptoms/signs only (7.9%), small-bowel obstruction (5.8%), and Crohn's disease (5.8%). The pooled detection rates were 68.1%, 68.0%, 53.6%, 63.4%, and 85.8% for overall, suspected MGIB, symptoms/signs only, Crohn's disease, and small-bowel obstruction, respectively. Inflammatory lesions (37.6%) and vascular lesions (65.9%) were the most common findings, respectively, in suspected MGIB patients of Eastern and Western countries. The pooled total enteroscopy rate was 44.0% by combined or antegrade-only approach. The pooled minor and major complication rates were 9.1% and 0.72%, respectively. Limitations Inclusion and exclusion criteria were loosely defined. Conclusion The detectability and complication risk of diagnostic DBE are acceptable. Suspected MGIB is the most common indication, with a relatively high detection rate, but there was a difference in its causes between Western and Eastern countries.
Long intergenic noncoding RNAs (lincRNAs) play a vital role in the occurrence and progression of cancer. The mechanism of lincRNAs in colorectal cancer (CRC) has not been fully elucidated. In this ...context, an integrated comparative long noncoding RNA (lncRNA) microarray technology was used to determine the expression profile of lncRNAs in CRC. The roles of LINC00908 are unclear. We found that LINC00908 was significantly upregulated in CRC. Inhibition of LINC00908 resulted in reduced cell proliferation and G1 cell cycle arrest, which was mediated by cyclin D1, cyclin‐dependent kinase 4, and phosphorylated retinoblastoma. Moreover, inhibition of LINC00908‐induced apoptosis through the intrinsic apoptosis signaling pathway, as shown by the activation of caspase‐9 and caspase‐3. Mechanistically, miR‐143‐3p directly bound to LINC00908. miR‐143‐3p expression was negatively correlated with LINC00908 expression in CRC tissue. Functional experiments revealed opposing roles for miR‐143‐3p and LINC00908, suggesting that LINC00908 negatively regulates miR‐143‐3p. Mechanistically, miR‐143‐3p directly targets LINC00908. The KLF5 inhibitor ML264 affected proliferation and apoptosis, indicating that LINC00908 may act as a competing endogenous RNA to facilitate the expression of the miR‐143‐3p target gene KLF5. Thus, LINC00908 has an important proliferative and antiapoptotic role in CRC by regulating the cell cycle and intrinsic apoptosis. LINC00908 could be a potential biomarker and a new therapeutic target for CRC.
The KLF5 inhibitor ML264 affected proliferation and apoptosis, indicating that LINC00908 may act as a competing endogenous RNA to facilitate the expression of the miR‐143‐3p target gene KLF5. Thus, LINC00908 has an important proliferative and antiapoptotic role in colorectal cancer (CRC) by regulating the cell cycle and intrinsic apoptosis. LINC00908 could be a potential biomarker and a new therapeutic target for CRC.
Introduction
The therapeutic efficacy of systemic Janus kinase (JAK) inhibitors in moderate-to-severe atopic dermatitis (AD) is well established. However, the associated risk of incident acne, which ...is a prevalent adverse event in AD patients treated with systemic JAK inhibitors, has yet to be systematically analyzed.
Methodology
To evaluate the risk of incident acne in AD patients treated with systemic JAK inhibitors, an extensive database search (clinicaltrials.gov, PubMed) was performed to identify publications eligible for inclusion from January 2020 to October 2022. Five randomized clinical trials (RCTs) of abrocitinib, four RCTs of upadacitinib, and one RCT of baricitinib, encompassing a total of 7901 participants, were included in the analysis. The risk difference for incident acne between systemic JAK inhibitors and controls was assessed using Review Manager, version 5.3, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Results
Meta-analysis elucidated a significant difference in the risk of incident acne between AD participants receiving 200 mg abrocitinib (Mantel–Haenszel risk difference, 3.69; 95% CI 1.60–8.48;
P
< 0.01), 15 mg upadacitinib (Mantel–Haenszel risk difference, 4.61; 95% CI 2.79–7.62;
P
< 0.00001), and 30 mg upadacitinib (Mantel–Haenszel risk difference, 6.82; 95% CI 4.59–10.13;
P
< 0.00001) compared with controls receiving placebo or dupilumab. In contrast, no significant difference was found in the risk of incident acne between participants receiving 100 mg abrocitinib, 2 mg baricitinib, and 4 mg baricitinib, as compared with controls.
Conclusions
Based on the current evidence, there is an increased risk of acne related to systemic JAK inhibitors, particularly with abrocitinib and upadacitinib. For patients predisposed to acne, the balance between the benefits of symptomatic relief from AD and the potential risk of acne may need to be carefully considered. This study contributes to a nuanced understanding of the risk profile of systemic JAK inhibitors and has the potential to guide personalized treatment decisions for AD patients.
Global surface evapotranspiration is one of the most significant components of the response of the water cycle to a warming climate. However, trends in surface evapotranspiration differ considerably ...from the trend in climate warming according to recent studies, with some studies even showing an opposing trend. The reason for this difference in the response of surface evapotranspiration to climate warming is still not completely understood. We validated the gridded FLUXNET evapotranspiration dataset and the Global Land Surface Assimilation Dataset (GLDAS) against evapotranspiration data observed in northern China using the eddy covariance system. The response of surface evapotranspiration to an increase in temperature varied with the type of climate (classified by the amount of precipitation) and the trend of surface evapotranspiration with warming showed similar features to the transitions between these climate types. The climate type with precipitation in the range of 250–350 mm was the most sensitive to the effects of warming on evapotranspiration. In more humid climates, surface evapotranspiration increased with increasing temperature, whereas in drier climates surface evapotranspiration decreased with increasing temperature. A similar response of evapotranspiration to increasing temperatures was also observed elsewhere in regions of climate transition. There are two main mechanisms of evapotranspiration: (1) an increase in temperature resulting in a direct increase in potential evapotranspiration; and (2) an increase in temperature resulting in a loss of soil moisture due to the increase in evapotranspiration, which in turn will indirectly suppress surface evapotranspiration due to the loss of vegetation.
Potential evapotranspiration is an important component of hydrological modeling. In this study, the objective is to project potential evapotranspiration in the future period 2011–2040 and understand ...their changes in Zhejiang Province, East China. The sensitivity of potential evapotranspiration to five climatic variables (solar radiation, daily minimum and maximum air temperature, relative humidity, and wind speed) is analyzed based on observation data from 1955–2008 using a global sensitivity analysis method, Sobol's method. The changes in potential evapotranspiration during the future period are generated using one regional climate model, Providing Regional Climates for Impacts Studies, with two global climate models, ECHAM5 and Hadley Centre Coupled Model version 3, and their causes are analyzed based on sensitivity analysis results. Global sensitivity analysis results reveal substantial spatial‐temporal variations in the sensitivity of potential evapotranspiration to climatic variables and unignorable interactions among climatic variables. Rather similar spatial change patterns of annual mean potential evapotranspiration (PET) are generated for both general circulation models; however, seasonal or monthly changes are very different due to different spatial‐temporal changes in climatic variables. Different contributory sources to potential evapotranspiration changes are identified at different months and stations; the PET changes in 2011–2040 are mainly due to three climatic variables including solar radiation, relative humidity, and daily minimum temperature.
Key Points
Changes in future monthly PET are substantial for HadCM3
Future PET changes are mainly due to changes in three climatic variables
Causes of future PET changes are varied at different stations and months
•We propose a many-objective optimization methodology to water resources allocation for inter-basin water transfers.•An improved shuffled frog leaping algorithm is developed to solve the optimization ...problem.•The proposed methodology performs well in the Eastern Route of South-to-North Water Transfer Project in Jiangsu, China.
Inter-basin water transfers (IBWT) are implemented to re-allocate unevenly distributed water resources. However, many conflicting objectives associated with society, economy, and environment have made the water resources allocation problem in IBWT more complicated than ever before. Thus, there is a continuous need for in-depth research with the latest optimization techniques to secure many-objective allocation of water resources for IBWT. In addition, being troubled of easily falling into local minima and premature convergence in some multi-objective optimization algorithms, it is necessary to explore new alternatives to improve their search quality. Here we propose a many-objective optimization methodology for IBWT, which includes three modules: (1) formulating a many-objective optimization problem based on realistic controls; (2) developing a new multi-objective real-coded quantum inspired shuffled frog leaping algorithm (r-MQSFLA) to solve the optimization problem; (3) utilizing the Analytic Hierarchy Process (AHP)-Entropy method to filter the Pareto solutions. In r-MQSFLA, the real-coded quantum computer and the external archive with dynamic updating mechanism are applied to SFLA. The performance of r-MQSFLA is first compared to that of other multi-objective evolutionary algorithms (MOEAs) in solving mathematical benchmark problems. A case study of the Eastern Route of South-to-North Water Transfer Project in Jiangsu Province, China varying from a normal to an extremely dry year, demonstrates that r-MQSFLA displays approximate performance on some compared algorithms and is improved significantly than MOSFLA in terms of convergence, diversity and reasonable solutions. This study can update the understanding of quantum theory to MOEAs and will provide a reference for better water resources allocation in IBWT under uncertainty.
Satellite and reanalysis precipitation products are widely utilized for streamflow simulation, which is one critical hydrological application, especially for ungauged regions. Possible ways to ...improve streamflow simulation are investigated in this study by merging multi-source precipitation products, or directly merging streamflow simulated with different precipitation products. Two satellite-based precipitation products, Tropical Rainfall Measuring Mission (3B42 Version 7) and Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks-Climate Data Record (PERSIANN-CDR), and one reanalysis precipitation product, National Centers for Environment Prediction-Climate Forecast System Reanalysis (NCEP-CFSR) are selected. Bayesian model averaging (BMA) is used to merge multi-source precipitation estimates and streamflow simulations. The results show that merging multi-source precipitation products made little difference to improve streamflow simulation. Merging multi-source streamflow simulations using the BMA generally achieved better performance on streamflow simulation, indicating that this approach is more efficient than merging multi-source precipitation products.
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