[Temporal variability of the isotope compositions of plum rain in Nanjing from event to interannual time scales]. / å—äº¬æ¢ é›¨é™æ°´åŒä½ç´ ç»„æˆä»Žäº‹ä»¶åˆ°å¹´é™ å°ºåº¦çš„å˜åŒ–ç‰¹å¾.

Precipitation in the plum rain period accounts for 40%-50% of annual precipitation in the monsoon region. To clarify the temporal variability of the isotopic composition of precipitation during the plum rain period from event to interannual time scale and identify the influencing factors, we analyzed the isotopic composition of precipitation and its influencing factors in Nanjing from 2015 to 2022. By using the Hybrid Single-particle Lagran-gian Integrated Trajectory (HYSPLIT) model with specific humidity analysis, we investigated the water vapor source and influencing factors. The results showed that 1) the isotopic abundance of atmospheric precipitation was depleted in the summer and enriched in winter. dx was lower in summer and higher in winter. The isotopic abundance of precipitation from the plum rain was depleted compared to mean value of the whole-year. 2) There was no significant correlation between δ2H and δ18O of the plum rain (precipitation) with local meteorological factors. However, dx was lower in light rain, reflecting the effect of sub-cloud evaporation. The average dx was higher during plum rain period in years with more total plum rain precipitation. 3) The low-latitude South China Sea and the western Pacific Ocean source area provided water vapor for the plum rain. The shift of moisture source region led to abrupt changes in precipitation isotopes. Our results could provide data support for studies on precipitation isotopes in the monsoon region, as well as a reference point for further understanding the precipitation mechanism of the plum rain and stu-dying the seasonal variability of atmospheric circulation in the East Asian monsoon region.

Adult-Onset Neuronal Ceroid Lipofuscinosis With a Novel DNAJC5 Mutation Exhibits Aberrant Protein Palmitoylation.

Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits.

microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron-specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD-associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA-425 (miR-425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque-associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR-425, a neuronal-specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR-425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR-425-deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR-425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal-specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s).

Characteristics of the 24-h ambulatory blood pressure monitoring in patients with Parkinson's disease - the SFC BP multicentre study in China.

OBJECTIVES: Cardiovascular dysautonomia can be present at early, late and even prodromal stages of Parkinson's disease. This study aimed to describe the characteristics of 24-h ambulatory blood pressure (BP) monitoring and investigate the frequency of cardiovascular dysautonomia in Parkinson's disease without an abnormal BP history. METHODS: Parkinson's disease patients without history of abnormal BP were consecutively enrolled from three Chinese centres, on whom office BP measurement, neurological evaluations and 24-h ambulatory BP monitoring were performed. RESULTS: Totally, 101 Parkinson's disease patients (42.6% women) with an average age of 66.6 ±â€Š8.2 years were included in our cohort, and data analysis revealed that 26 (25.74%) patients suffered from orthostatic hypotension, among whom 18 (69.23%) were symptomatic. Patients with orthostatic hypotension compared with those without had significantly higher nocturnal SBP level, and more severe nonmotor symptoms, autonomic dysfunction and cognitive impairment. Further, 54 out of 101 (53.47%) individuals had a reverse dipping pattern in SBP and/or DBP. Reverse dippers had more cases of orthostatic hypotension (P < 0.001), and more severe nonmotor symptoms. SBP dipping ratio of less than -2.98% generated 76.9% of sensitivity, 69.3% of specificity, 46.5% of positive predictive value (PPV), 89.7% of negative predictive value (NPV) and 77.4% of accuracy, while diastolic dipping ratio of less than -1.80% generated 76.9% of sensitivity, 70.7% specificity, 47.6% of PPV, 89.8% of NPV and 77.8% of accuracy for suspecting orthostatic hypotension. CONCLUSION: Orthostatic hypotension can occur in one-fourth Parkinson's disease patients without abnormal BP history, and reverse dipping was present in more than half of patients with Parkinson's disease. Reverse dipping pattern was helpful to suspect orthostatic hypotension.

miR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson's disease.

A major hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra, and the causative mechanism is thought to be the activation of programmed neuronal death. Necroptosis is a regulated process of cell death triggered by RIPK1. Although the pathophysiology of PD has been studied extensively, the cellular mechanism underlying dopaminergic neuron death remains unclear. In this study, we detected a specific miRNA, miR-425, in response to MPTP toxicity and dopaminergic degeneration. In MPTP-treated mice, we observed necroptosis activation and miR-425 deficiency in the substantia nigra, which is correlated with dopaminergic neuron loss. This miRNA targeted RIPK1 transcripts and promoted the phosphorylation of MLKL and necroptosis. Similarly, in the brains of PD patients, miR-425 deficiency and necroptosis activation were also confirmed in dopaminergic neuron. Furthermore, we found that genetic knockdown of miR-425 aggravated MPTP-induced motor deficits and dopaminergic neurodegeneration via early upregulation of necroptotic genes. Intracerebral miR-425 mimics (AgomiR-425) treatment attenuated necroptosis activation and dopaminergic neuron loss, and improved locomotor behaviors. In conclusion, our study suggests that miR-425 deficiency triggers necroptosis of dopaminergic neurons, and targeting miR-425 in MPTP-treated mice restored dysfunctional dopaminergic neurodegeneration and ameliorated behavioral deficits. These findings identify brain delivery of miR-425 as a potential therapeutic approach for the treatment of PD.

Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology.

Rho-associated coiled-coil kinase 1 (ROCK1) is proposed to be implicated in Aß suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce Aß was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased ß-secretase cleavage of APP. Furthermore, we firstly confirmed that APP served as a substrate for ROCK1 and its major phosphorylation site was located at Ser655. The increased level of APP Ser655 phosphorylation was observed in the brain of APP/PS1 mice and AD patients compared to controls. Moreover, blockade of APP Ser655 phosphorylation, or inhibition of ROCK1 activity with either shRNA knockdown or Y-27632, ameliorated amyloid pathology and improved learning and memory in APP/PS1 mice. These findings suggest that activated ROCK1 targets APP Ser655 phosphorylation, which promotes amyloid processing and pathology. Inhibition of ROCK1 could be a potential therapeutic approach for AD.

Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease.

Causative mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) account for a majority of cases of familial Alzheimer disease (FAD) inherited in an autosomal-dominant pattern. For the sake of characterizing mutations, index patients from 148 families with FAD were enrolled from mainland China. Sanger sequencing of the genes APP, PSEN1, and PSEN2 was performed to characterize the mutation spectrum of the Chinese population. Thirteen of 148 (8.8%) individuals had possible pathogenic APP, PSEN1, or PSEN2 variants, including 2 (15.4%) APP variants, 8 (61.5%) PSEN1 variants, and 3 (23.1%) PSEN2 variants. PSEN1 variants represented the largest proportion in Chinese FAD, and PSEN2 variants are responsible for late-onset FAD in China. Analysis of genetic-clinical correlations permitted the conclusion that FAD phenotypes were mainly influenced by specific genetic defects.

[Effects of Water Vapor Source and Local Evaporation on the Stable Hydrogen and Oxygen Isotopic Compositions of Precipitation].

Stable hydrogen and oxygen isotopic compositions in precipitation are good tracers and can provide unique information about the water cycle. Precipitation samples were collected at the Nanjing, Liyang, Yixing, and Dongshan sites in 2016, and the HDO and H218O compositions of precipitation were measured. The temporal variability of HDO and H218O compositions and deuterium-excess of precipitation were analyzed, and the influence of the water vapor source and local evaporation on stable isotopic composition of precipitation were discussed. The results indicated that:① Seasonal variations in the HDO composition, H218O composition, and deuterium-excess of precipitation occurred due to different water vapor sources during the summer and winter monsoon seasons. The HDO and H218O compositions were depleted during the summer monsoon season and enriched during the winter monsoon season. The deuterium-excess during the summer monsoon season was lower compared to the winter monsoon season. ② During the summer monsoon, the evaporation of Lake Taihu made the deuterium-excess of downwind precipitation and the downwind intercept of the local meteoric water line higher. During the winter monsoon season, local evaporation had little influence on HDO and H218O components in precipitation. ③ Both of the intercepts and slopes of the local meteoric water line were higher than those of the global meteoric water line, due to moisture recycling during the winter monsoon season and different water vapor sources between the summer and winter monsoon seasons.

[Quantification of Methane Ebullition Flux from Small Ponds Using the Inverted-Funnel Method].

To quantify the ratio of CH4 ebullition to total flux in subtropical shallow ponds, the CH4 flux at the water-air interface was measured using the inverted-funnel and water equilibrium methods in two small ponds in Quanjiao, Anhui Province from July 28 to August 13, 2016. The average CH4 ebullition fluxes were 121.78 and 161.08 mg·(m2·d)-1 and the average diffusion fluxes were 3.38 and 3.79 mg·(m2·d)-1 over pond A and pond B, respectively. The ebullition flux accounted for 97.5% and 96.4% of the total flux over pond A and pond B, respectively. Methane ebullition ranged from 0.11 to 446.90 mg·(m2·d)-1 over pond A and from 0.05 to 607.51 mg·(m2·d)-1 over pond B. Gas ebullition rate during the day was higher than that at night and was controlled by wind speed. Methane ebullition flux was influenced by wind speed over the shallow pond at hourly scale and by water depth and wind speed at daily scale, with positive correlation with wind speed and negative correlation with water depth. Varying with latitude, methane ebullition flux was higher for the water bodies in the mid-latitude region compared to those in the high-latitude region. Direct observations of the methane ebullition flux over small ponds provide data support and theoretical reference to precisely estimate the contribution of inland water bodies to regional and global carbon cycle.

Caregivers' attitude toward disclosure of Alzheimer's disease diagnosis in Urban China.

BACKGROUND: Disclosing the diagnosis of Alzheimer's disease (AD) to a patient is controversial. There is significant stigma associated with a diagnosis of AD or dementia in China, but the attitude of the society toward disclosure of such a diagnosis had not been formally evaluated prior to our study. Therefore, we aimed to evaluate the attitude toward disclosing an AD diagnosis to patients in China with cognitive impairment from their caregivers, and the factors that may affect their attitude. METHODS: We designed a 17-item questionnaire and administered this questionnaire to caregivers, who accompanied patients with cognitive impairment or dementia in three major hospitals in Shanghai, China. The caregiver's attitude toward disclosing the diagnosis of AD as evaluated by the questionnaire was compared to that of disclosing the diagnosis of terminal cancer. RESULTS: A majority (95.7%) of the 175 interviewed participants (mean 14.2 years of education received) wished to know their own diagnosis if they were diagnosed with AD, and 97.6% preferred the doctor to tell their family members if they were diagnosed with AD. If a family member of the participants suffered from AD, 82.9% preferred to have the diagnosis disclosed to the patient. "Cognitive impairment" was the most accepted term by caregivers to disclose AD diagnosis in Chinese. CONCLUSION: This study suggests most of the well-educated individuals in a Chinese urban area favored disclosing the diagnosis when they or their family members were diagnosed with AD.

Corrigendum: Diagnostic Value of microRNA for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

[This corrects the article on p. 13 in vol. 8, PMID: 26903857.].

[Characteristics of Methane Emission from Urban Traffic in Nanjing].

Urban traffic is an important source of greenhouse gases such as CH4. The observations on CH4 are the basis for quantitative analysis of urban carbon emissions. Taken into consideration the weekly and daily changing characteristics of urban traffic, we conducted experiments to analyze the features of traffic CH4emission and its influential factors. The experiments were conducted on 3 main roads in Nanjing on Oct. 17, 18, 20, 23, 2014 with 5 periods of observation per day, and in Nanjing Yangtze River tunnel in the morning and at night of Sep.11 2014. The results showed that:① The average concentration of CH4 on the urban main road of Nanjing city was greater than that of the background atmosphere. Affected by traffic conditions, the spatial difference of ΔCH4 concentration was significant on three typical main roads. ΔCH4 concentration's diurnal variation showed inverted "W" type, and its peak appeared in the morning and evening rush hours. ② Due to the "piston wind" in the tunnel, the CH4 concentration in Nanjing Yangtze River tunnel gradually increased from the inlet to the outlet and the difference of concentration between the inlet and the outlet was 0.21×10-6-0.38×10-6. ③ There was a good linear correlation between CH4 concentration and CO2 concentration. The atmospheric ΔCH4:ΔCO2 value of urban main road in Nanjing was 0.0091 and the atmospheric ΔCH4:ΔCO2 value of Nanjing Yangtze River Tunnel was 0.00047-0.0014. ④ Traffic volume and the proportion of natural gas vehicles were the main factors influencing atmospheric ΔCH4 concentration and ΔCH4:ΔCO2.

ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aß Clearance.

Alzheimer's disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-ß (Aß) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aß in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model). In vitro over-expression of ROCK1 leads to a decrease in Aß secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aß. Reciprocally, overexpression of APP/Aß promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aß secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.

Diagnostic Value of microRNA for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Sound evidence indicates that microRNAs (miRNAs) are aberrantly expressed in Alzheimer's disease (AD) patients. We performed a systematic review and meta-analysis to investigate the role of miRNA in AD pathogenesis and their clinical diagnostic value; a systematic review of literature and meta-analysis of clinical trials were performed. In the systematic review, 236 papers were included, and we reviewed the dysregulated miRNA expression in different parts of AD patients in order to identify the relationship between aberrantly expressed miRNAs and AD pathology. In the subsequent meta-analysis, seven studies were statistically analyzed with the following results: pooled sensitivity 0.86 (95%CI 0.79-0.90), pooled specificity 0.87 (95%CI 0.72-0.95), diagnostic odds ratio (28.29), and the area under the curve (0.87). In conclusion, our review indicated that aberrant expression of various miRNAs plays an important role in the pathological process of AD, and statistical analysis of quantitative studies reveal the potential value of specific miRNAs in the diagnosis of AD.

The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration.

The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer's disease (AD).

[Epidemiological investigation on natural infection of different canine breeds with Borna disease virus in Ili, China].

OBJECTIVE: To investigate the epidemiological pattern of Borna disease virus (BDV) among different canine breeds in Ili, China, and to analyze its potential phylogeny. METHODS: BDV p24 RNA fragments were detected from peripheral blood mononuclear cells (PBMCs) of canine by modified nested RT-PCR (nRT-PCR). Possible false positives were excluded by determination of both BDV p40 RNA fragments and PMD19 plasmid standards. Analysis were performed on genetic sequence, homologous comparison, amino acid sequence and phylogeny after p24 positive products were validated. RESULTS: BDV p24 RNA fragments were found only in Kazakh Tobet (a shepherd dog) in 8 breeds of 150 cases and their overall positive rate was 11.0% (10/91). Compared with the strain of He/80 from horse and that of S6 from sheep in Germany, the homologous similarities of Kazakh Tobet was 99.2% and 95.7%, and that of amino acid as 100% and 89.3%, respectively. The kinship of Kazakh Tobet was close to He/80 and next to S6. CONCLUSION: There was potential natural BDV infection in Kazakh Tobet in Ili, and its endemic strain was concerned with He/80 infecting Ili horse and S6 of German Merino sheep introduced into the region from Germany.

Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines.

The serine/threonine kinase AKT/PKB plays a critical role in cancer and represents a rational target for therapy. Although efforts in targeting AKT pathway have accelerated in recent years, relatively few small molecule inhibitors of AKT have been reported. The development of selective AKT inhibitors is further challenged by the extensive conservation of the ATP-binding sites of the AGC kinase family. In this report, we have conducted a high-throughput screen for inhibitors of activated AKT1. We have identified lactoquinomycin as a potent inhibitor of AKT kinases (AKT1 IC(50), 0.149 +/- 0.045 micromol/L). Biochemical studies implicated a novel irreversible interaction of the inhibitor and AKT involving a critical cysteine residue(s). To examine the role of conserved cysteines in the activation loop (T-loop), we studied mutant AKT1 harboring C296A, C310A, and C296A/C310A. Whereas the ATP-pocket inhibitor, staurosporine, indiscriminately targeted the wild-type and all three mutant-enzymes, the inhibition by lactoquinomycin was drastically diminished in the single mutants C296A and C310A, and completely abolished in the double mutant C296A/C310A. These data strongly implicate the binding of lactoquinomycin to the T-loop cysteines as critical for abrogation of catalysis, and define an unprecedented mechanism of AKT inhibition by a small molecule. Lactoquinomycin inhibited cellular AKT substrate phosphorylation induced by growth factor, loss of PTEN, and myristoylated AKT. The inhibition was substantially attenuated by coexpression of C296A/C310A. Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors.