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Abstract Background Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). Methods TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2 G2019S) and LRRK2 knockout (Lrrk2 −/−) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. Results The Lrrk2 −/−-HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p

We investigated fourteen antibiotics, three illegal drugs, and two toxic elements in commercially available gastropods from southeast China. The data revealed high detection frequencies (DFs) for florfenicol (61.32%), florfenicol amine (47.33%), and thiamphenicol (39.88%), with maximum concentrations of 1110, 2222, and 136 μg/kg wet weight (ww), respectively. The DFs of illegal drugs were 3.54% for leucomalachite green and 0.3% for chloramphenicol. The average levels of Cd and As were 1.17 and 6.12 mg/kg ww, respectively. All chemicals presented diverse DFs in different sampling months. The highest DFs of florfenicol, florfenicol amine, and thiamphenicol were in July. The health risk assessment showed that targeted hazard quotients (THQs) of antibiotics, Cd, and As for children, teens, and adults were all less than one. Notably, the toxic elements (Cd and As) were identified as the primary health risk in gastropods, contributing to over 90% of the total THQs.

This study described the distribution of As, Cd, Cr, Hg, and Pb in 692 bean samples from Zhejiang province, southeast China, and estimated the health risk using Monte Carlo simulation. The average levels of As, Cd, Cr, Hg, and Pb were 0.0349, 0.0379, 0.246, 0.0019, and 0.0246 mg kg−1. Correlation analyses showed very strong positive correlations for Cd-Pb in kidney beans and mung beans, Cd-As in black beans, and Pb-As in red beans. The target hazard quotients (THQs) were adopted for non-carcinogenic risk assessment, and THQs at the 50th percentile were all less than 1, indicating that there are no deleterious effects from rice exposure to these elements. When evaluating THQ for multiple elements, the certainty with a hazard index (HI) greater than 1 for children was 12.64%, for teens 11.54%, and for adults 1.01%. The sensitivity analysis reveals that the concentration of Cd in beans and ED (exposure duration) are the main principal factors that contributed to the total risk. The mean carcinogenic risks for children, teens, and adults were all less than 1 × 10−4, indicating no potential carcinogenic risk. Despite that, the routine monitoring of these elements, especially for Cd should be continued.

Tetrodotoxin (TTX) is an extremely potent marine biotoxin. An analytical method was developed for both trace contamination and extremely high levels of TTX in gastropods by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with clean-up of cation exchange solid phase extraction (SPE) in this study. The limit of detection (LOD) in the sample matrix was 0.5 μg/kg. With the calibration of a screened internal standard (validamycin, IS), the linear range was 0.1–100 ng/mL (1.5–1500 μg/kg in sample matrix) with a correlation coefficient of r2 > 0.999. The average recoveries at three spiking levels (1.5 μg/kg, 44 μg/kg, and 1500 μg/kg) were 82.6–94.4% with relative standard deviations (RSDs) less than 8.4%. TTX levels in seven gastropods (741 samples) were studied. The contamination and analogues in Neverita didyma (N. didyma, 565 samples collected in Zhejiang province, China, from 2016 to 2022) were first reported. The detection rate of TTX in N. didyma was 34.2%. The average concentration was 23.1 μg/kg, and the maximum value was 2327 μg/kg. The time distribution study indicated that high contaminations of TTX occurred from May to August for N. didyma.

In the test of the electromagnetic radiation blocking effect of the navigation receiver, it is found that the sensitivity of the navigation receiver to single frequency continuous waves and sinusoidal amplitude modulation waves will change with the change in the satellite useful signal strength. This phenomenon reflects that the sensitivity of frequency equipment to multi-frequency electromagnetic radiation is not fixed to a certain extent. In order to make up for the deficiency that the existing multi-frequency electromagnetic radiation evaluation methods can only deal with a single situation, this paper uses the time delay characteristics of the circuit response, introduces the concepts of normalized interference levels and signal duty cycles, establishes the evaluation model of the multi-frequency non-intermodulation electromagnetic radiation blocking effect of frequency equipment, and puts forward the prediction method of the multi-frequency electromagnetic radiation blocking effect of frequency equipment. Taking a certain type of BeiDou navigation receiver as the test object, the single-frequency continuous wave and double-frequency continuous wave electromagnetic radiation blocking effect tests are carried out by using the full-level irradiation method. The test data are substituted into the model established in this paper for verification. The results show that the maximum evaluation error of the model is 2.23 dB. The model and the effect prediction method established in this paper are of great significance for the survival ability evaluation of frequency equipment in complex electromagnetic environments.

Abstract Environmental pollution with toxic metals can lead to the possible contamination of the marine fish. We investigated the levels of As, Cd, Cr, Hg and Pb in 652 marine fish samples (15 species) collected from coastal areas of Zhejiang, China and estimated their health risk. Mean concentrations of As, Cd, Cr, Hg and Pb were 0.783, 0.009, 0.114, 0.031, 0.043 mg/kg wet weight. The average estimated daily intakes (EDIs) for As, Cd, Cr, Hg and Pb were 1.214, 0.014, 0.177, 0.048 and 0.067 μg/kg bw/day. The risk assessment at mean exposure level showed that there was no health risk associated with these elements through consumption of marine fish. However, potential health risk may exist for high exposure consumers considering the possible contamination of As and Hg. Given that the different levels of certain elements in marine fish in China, this study provides a scientific basis for food safety assessment and suggestions for risk management.

This study investigated concentrations of cadmium (Cd) in 2465 vegetable samples (52 species) from 2018 to 2022 and estimated the associated health risk for local consumers. The average concentration of Cd was 0.035 mg kg−1, and the percentage of samples exceeding the Chinese maximum allowed concentration was 3.89% (96/2465). The top five species with highest Cd levels were Lilium brownii F (0.182 mg kg−1), Allium chinense G (0.117 mg kg−1), Allium macrostemon Bunge (0.105 mg kg−1), Colocasia esculenta (0.064 mg kg−1), and Amaranthus tricolor L (0.054 mg kg−1). Bulb vegetables had a higher relative accumulation of Cd compared to other vegetables. The levels of Cd in vegetables varied significantly across sampling areas and years. The mean estimated daily intake (EDI) of cadmium through consumption of vegetables was 0.519 μg kg−1 bw per day for adults and 0.217 μg kg−1 bw per day for children. The target hazard quotients (THQs) were all less than the threshold of 1 for both adults and children. This indicates that there is low health risk for Cd through vegetable consumption. However, routine monitoring of Cd levels in food is still crucial to ensure food safety and protect public health.

In order to master the law of the pseudo-signal interference effect of dual-frequency electromagnetic radiation in typical radar equipment, a certain type of Ku-band swept-frequency ranging radar was used as the test object to carry out single-frequency continuous wave and dual-frequency continuous wave pseudo-signal interference effect experiments. Through experiments, it is found that dual-frequency electromagnetic radiation will cause “hill” and “spike” type pseudo-signal interference to the swept-frequency radar. Based on the frequency analysis of the radar receiving circuit, the interference mechanism of the dual-frequency pseudo-signal is revealed, and the morphological characteristics and distance law of the pseudo-signal are explained. The variation law of the pseudo-signal level with interference field strength is obtained. The results show that the in-band dual-frequency nonintermodulation interference is similar to the single-frequency interference, and the only difference is that the number of pseudo-signals increases; when the interference frequency difference is about 400∼600 MHz, the out-of-band dual-frequency second-order intermodulation signal will cause “hill” type pseudo-signal interference, and the pseudo-signal distance is random; when the interference frequency difference is less than 5 MHz, both the dual-frequency second-order intermodulation signal and the third-order intermodulation signal will cause “spike” pseudo-signal interference inside and outside the radar operating frequency band; the pseudo-signal distance is fixed.

Changbai Mountains intraplate volcanism (NE China) developed above the 500 km deep stagnant portion of the Pacific slab in the last 20 Ma. The more recent activity includes a shield-forming stage (2.8–0.3 Ma), the Tianchi cone construction stage (1.5–0.01 Ma), and a caldera-forming stage (0.2 Ma-present). Detailed studies on the petrogenesis of the volcanic products between the first two stages and the possible role of geodynamics and local tectonics in controlling the volcanism, however, are lacking. Here, we present structural and whole-rock geochemical and zircon Hf isotopic data on Pleistocene dikes of the Changbai Mountains at the transition from the shield-forming to the Tianchi stage with the aim to constrain their age and the source(s) of their parental magma. The dikes represent the shallower feeding system of monogenetic cones and have a NW-SE strike, which is also the preferred strike of the major fault affecting the area and along which the Changbai Mountains monogenetic scoria cones align. The dikes have a potassic affinity and a trachybasaltic composition. Their zircon U–Pb age is 1.19–1.20 Ma (Calabrian). The trachybasalts are enriched in Rb, Ba, Th, U, Nb, Ta, K, Pb, and LREE and slightly depleted in Sr, Zr, Hf, Ti, and HREE with a weak negative Eu/Eu* (δEu = 0.96–0.97). Trace elements and isotopic compositions are compatible with an OIB-type source with an EMI signature. The calculated (87Sr/86Sr)i (=0.705165–0.705324), (143Nd/144Nd)i (= 0.512552–0.512607, εNd(t) = −0.58 to −1.65), and Hf model ages (TDM2) of 1768–1562 Ma suggest that the trachybasaltic dikes were contaminated by a Mesoproterozoic, relatively basic lower crust. The source of the Calabrian trachybasalts consists of asthenospheric melts modified by a subcontinental lithospheric mantle. These melts upwell from depth and stop at the crust-mantle interface where underplating processes favor the assimilation of ancient lower crust material. During the ascent to the surface along deep-seated crustal discontinuities, these magmas weakly differentiate.

Vitamin D is the name given to a series of compounds with antirachitic activity. In this study, we developed a method for quantification of the common Vitamin D, ergocalciferol (vitamin D2), and cholecalciferol (vitamin D3), in edible fungus by reversed-phase two-dimensional liquid chromatography. The sample was saponified by KOH ethanol solution and extracted with ethyl acetate and n-hexane. After reconcentration, the sample was directly injected for instrumental analysis. The results showed that the spiking recoveries of vitamin D2 and vitamin D3 were 80.4–93.8% and 82.3–92.0%, respectively. The relative standard deviations (RSDs) were all less than 5%. Comparing to the results of isotope dilution liquid chromatography tandem mass spectrometry, there were no significant differences (P>0.05). The method was applied for testing vitamin D2 and D3 in 9 kinds of edible mushrooms. It showed that vitamin D3 was not detected. The content of vitamin D2 ranged from 0.11 μg/100 g to 123 μg/100 g. The content of vitamin D2 in dried mushroom was the highest, while that in fresh mushroom was the lowest. The limit of quantification was 0.025 μg/100 g.

Abstract Concern about metals and metalloids, especially heavy metals in seaweeds has risen due to potential health risk. This study investigated the distribution of 10 metals and metalloids in 295 dried seaweeds (brown and red) and estimated the possible health risk via hazard index (HI). Elements in seaweeds can be sequenced in descending order by mean values: Al > Mn > As > Cu > Cr > Ni > Cd > Se > Pb > Hg. The levels of Cd, Cu, Mn and Ni in red seaweeds were significantly higher than those in brown seaweeds (P

Background: Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. Methods: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1–42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. Results: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1–42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation. Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

Background: Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods: The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway. Results: Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions: These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.

Tear is an accessible fluid for exploring biomarkers of dry eye disease. This study describes a fast proteomic method by LC-Q-orbitrap-MS analysis with in-strip digestion and investigates the tear proteome of dry eye patients. Schirmer's strips were used for collection of tear fluid from patients. These strips were cut into pieces and directly digested with trypsin before mass spectrometry analysis. The data showed that more than 50 proteins were found in tear fluid from dry eye patients. Gene Ontology (GO) annotation showed that most of proteins were transfer/carrier proteins, hydrolyses, enzyme modulators and signaling molecules. Targeted proteomics strategy revealed that 18 proteins were differentially expressed in dry eye patients. Furthermore, it was showed that the common post-translational modification in tear proteins is deamidation of Asn.

Mammalian target of rapamycin (mTOR)in renal cell carcinoma (RCC) represents a valuable oncotarget for treatment. We here tested the potential anti-RCC activity by a novel mTOR kinase inhibitor WYE-687in vitro and in vivo.WYE-687 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. Yet, it was non-cytotoxic toHK-2 tubular epithelial cells.WYE-687 provoked caspase-dependent apoptosis in the RCC cells. At the molecular level, WYE-687 almost completely blocked mTORC1 (p-S6K1 and p-S6) and mTORC2 (p-Akt Ser 473) activation in both 786-Ocells and primary human RCC cells, where it downregulated both hypoxia-inducible factor (HIF)-1α and HIF-2α expression. Significantly, oral administration of WYE-687 potently suppressed786-O tumor xenograft growth in nude mice. mTORC1/2 activation and HIF-1α/2α expression were also remarkably downregulated in WYE-687-treated tumor tissues. Thus, our preclinical results imply that WYE-687 may have important translational value for the treatment of RCC.

DOI：10.3969/j.issn.1672-6731.2010.02.005

Familial hypercholesterolemia is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is mainly caused by mutations of the low-density lipoprotein receptor (LDLR) gene. Currently, the methods of whole genome sequencing or whole exome sequencing for screening mutations in familial hypercholesterolemia are not applicable in China due to high cost. We performed targeted exome sequencing of 167 genes implicated in the homozygous phenotype of a proband pedigree to identify candidate mutations, validated them in the family of the proband, studied the functions of the mutant protein, and followed up serum lipid levels after treatment. We discovered that exon 9 c.1268 T>C and exon 8 c.1129 T>G compound heterozygous mutations in the LDLR gene in the proband derived from the mother and father, respectively, in which the mutation of c.1129 T>G has not been reported previously. The mutant LDL-R protein had 57% and 52% binding and internalization functions, respectively, compared with that of the wild type. After 6 months of therapy, the LDL-C level of the proband decreased by more than 50% and the LDL-C of the other family members with heterozygous mutation also reduced to normal. Targeted exome sequencing is an effective method for screening mutation genes in familial hypercholesterolemia. The exon 8 and 9 mutations of the LDLR gene were pedigree mutations. The functions of the mutant LDL-R protein were decreased significantly compared with that of the wild type. Simvastatin plus ezetimibe was proven safe and effective in this preschool-age child.

Environmental pollution with toxic heavy metals can lead to the possible contamination of the rice. Selected metals (As, Cd, Hg and Pb) and their accumulation in rice collected from Zhejiang, China were analyzed to evaluate the potential health risk to the local adults and children. The mean levels found in rice were as follows: As, 0.080 mg/kg; Cd, 0.037 mg/kg; Hg, 0.005 mg/kg; Pb, 0.060 mg/kg. The estimated daily intakes (EDIs) were calculated in combination of the rice consumption data. The mean intakes of As, Cd, Hg and Pb through rice were estimated to be 0.49, 0.23, 0.03 and 0.37 µg/kg bw/day for adults, and 0.34, 0.29, 0.04 and 0.47 µg/kg bw/day for children. The 97.5th percentile (P97.5) daily intakes of As, Cd, Hg and Pb were 1.02, 0.64, 0.37 and 1.26 µg/kg bw/day for adults, and 0.63, 0.83, 0.47 and 1.63 µg/kg bw/day for children. The risk assessment in mean levels showed that health risk associated with these elements through consumption of rice was absent. However, estimates in P97.5 level of Cd and Pb for children, and Hg for adults have exceeded the respective safe limits.

Hyperpolarization-activated currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate excitability of myelinated A- and Ah-type visceral ganglion neurons (VGN). Whether alterations in Ih underlie the previously reported reduction of excitability of myelinated Ah-type VGNs following ovariectomy (OVX) has remained unclear. Here we used the intact nodose ganglion preparation in conjunction with electrophysiological approaches to examine the role of Ih remodeling in altering Ah-type neuron excitability following ovariectomy in adult rats. Ah-type neurons were identified based on their afferent conduction velocity. Ah-type neurons in nodose ganglia from non-OVX rats exhibited a voltage 'sag' as well as 'rebound' action potentials immediately following hyperpolarizing current injections, which both were suppressed by the Ih blocker ZD7288. Repetitive spike activity induced afterhyperpolarizations lasting several hundreds of milliseconds (termed post-excitatory membrane hyperpolarizations, PEMHs), which were significantly reduced by ZD7288, suggesting that they resulted from transient deactivation of Ih during the preceding spike trains. Ovariectomy reduced whole-cell Ih density, caused a hyperpolarizing shift of the voltage-dependence of Ih activation, and slowed Ih activation. OVX-induced Ih remodeling was accompanied by a flattening of the stimulus frequency/response curve and loss of PEMHs. Also, HCN1 mRNA levels were reduced by ∼30% in nodose ganglia from OVX rats compared with their non-OVX counterparts. Acute exposure of nodose ganglia to 17beta-estradiol partly restored Ih density and accelerated Ih activation in Ah-type cells. In conclusion, Ih plays a significant role in modulating the excitability of myelinated Ah-type VGNs in adult female rats.